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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 153





    Carbaryl



    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    First draft prepared by Professor F. Kaloyanova
    (National Center of Hygiene and Medical Ecology
    Sofia, Bulgaria) and Dr. P.P. Simeonova
    (University of Sofia, Bulgaria)

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1994

          The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
    Labour Organisation, and the World Health Organization.  The main
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    the effects of chemicals on human health and the quality of the
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    carried out by the IPCS include the development of know-how for coping
    with chemical accidents, coordination of laboratory testing and
    epidemiological studies, and promotion of research on the mechanisms
    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Hexachlorobutadiene.

          (Environmental health criteria: 153)

          1. Carbaryl - adverse effects    2. Carbaryl - toxicity
          3. Environmental exposure        I.Series

          ISBN 92 4 157153 5         (NLM Classification QU 98)
          ISSN 0250-863X

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    CONTENTS

    1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

         1.1. Summary and evaluation
               1.1.1. Identity, properties, and analytical methods
               1.1.2. Production and uses
               1.1.3. Environmental transport, distribution, and
                       transformation
               1.1.4. Environmental levels and human exposure
               1.1.5. Kinetics and metabolism
               1.1.6. Effects on organisms in the environment.
               1.1.7. Effects on experimental animals and  in vitro
                       test systems
                       1.1.7.1   Reproduction
                       1.1.7.2   Mutagenicity
                       1.1.7.3   Carcinogenicity
                       1.1.7.4   Effects on different organs and systems
                       1.1.7.5   Primary mechanism of toxicity
               1.1.8. Effects on humans
         1.2. Conclusions
               1.2.1. General population exposure
               1.2.2. Subpopulations at high risk
               1.2.3. Occupational exposure
               1.2.4. Environmental effects
         1.3. Recommendations

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Volatilization and air transportation
         4.2. Water
               4.2.1. Hydrolysis
               4.2.2. Photolysis

               4.2.3. Degradation by microorganisms
               4.2.4. Persistence in surface water
               4.2.5. Removal from water
               4.2.6. Persistence in sea water
               4.2.7. Bioaccumulation/biomagnification
         4.3. Soil
               4.3.1. Adsorption, desorption
               4.3.2. Transformation
                       4.3.2.1   Photolysis in soil
               4.3.3. Biotransformation in soil
               4.3.4. Degradation by microorganisms
               4.3.5. Persistence in soil
               4.3.6. Interaction with other physical, chemical, or
                       biological factors
               4.3.7. Vegetation
                       4.3.7.1   Uptake and transformation in plants

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
               5.1.1. Air
               5.1.2. Water
               5.1.3. Soil
               5.1.4. Food and animal feed
                       5.1.4.1   Fruit, vegetables, and grain
                       5.1.4.2   Animal products
                       5.1.4.3   Animal feed crops
               5.1.5. Other products
               5.1.6. Terrestrial organisms
         5.2. General population exposure
               5.2.1. Exposure through the food
               5.2.2. Exposure during insect control
         5.3. Occupational exposure during manufacture, formulation,
               or use

    6. KINETICS AND METABOLISM

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolism
               6.3.1.  In vitro studies on animal tissues
               6.3.2.  In vivo studies on animals
               6.3.3. Metabolic transformation in plants
               6.3.4.  In vitro studies with human tissues
               6.3.5.  In vivo studies on humans
         6.4. Elimination and excretion in expired air, faeces, urine,
               milk, and eggs

    7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1. Microorganisms
               7.1.1. Soil microorganisms
               7.1.2. Aquatic microorganisms
               7.2.1. Aquatic invertebrates
               7.2.2. Fish
                       7.2.2.1   Acute toxicity
                       7.2.2.2   Short-term
                                 and long-term toxicity
               7.2.3. Amphibians
         7.3. Terrestrial organisms
               7.3.1. Worms
               7.3.2. Insects
               7.3.3. Birds
               7.3.4. Mammals
         7.4. Effects on the population and ecosystem

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         8.1. Single exposures
               8.1.1. Oral toxicity
               8.1.2. Acute inhalation toxicity
               8.1.3. Dermal toxicity
               8.1.4. Other routes of exposure
         8.2. Skin and eye irritation, sensitization
               8.2.1. Skin and eye irritation
               8.2.2. Sensitization
         8.3. Short- and long-term oral exposure
         8.4. Short- and long-term inhalation toxicity
         8.5. Reproduction and developmental toxicity
               8.5.1. Mammalian reproductive
                       toxicity studies
                       8.5.1.1   Mouse
                       8.5.1.2   Rat
                       8.5.1.3   Gerbil
               8.5.2. Mammalian developmental
                       toxicity studies
                       8.5.2.1   Mouse
                       8.5.2.2   Rat
                       8.5.2.3   Guinea-pig
                       8.5.2.4   Rabbit
                       8.5.2.5   Dog
                       8.5.2.6   Pig
                       8.5.2.7   Monkey
               8.5.3. Reproductive and developmental toxicity studies
                       in non-mammalian species
                       8.5.3.1   Fish
                       8.5.3.2   Amphibian
                       8.5.3.3   Birds
               8.5.4. Appraisal

         8.6. Mutagenicity of carbary
               and  N-nitrosocarbaryl
               8.6.1. Genotoxicity assays  in vitro
                       8.6.1.1   Primary DNA damage
                       8.6.1.2   Gene mutation assay
                       8.6.1.3   Chromosomal aberration
                                 assays and sister
                                 chromatid exchange
               8.6.2. Genotoxicity  in vivo
                       8.6.2.1   Host-mediated assay
                       8.6.2.2   Drosophila melanogaster and
                                 other insects
                       8.6.2.3   Chromosomal aberrations
                                 and sister chromatid
                                 exchange
                       8.6.2.4   Dominant lethal assays
                                 in rodents
               8.6.3. Other end-points
                       8.6.3.1   Cell transformation
                       8.6.3.2   Aneuploidy induction
               8.6.4. Appraisal
         8.7. Carcinogenicity
               8.7.1. Carcinogenicity studies
                       of carbaryl in rodents
                       8.7.1.1   Mouse
                       8.7.1.2   Rats
                       8.7.1.3   Overall appraisal of carbaryl 
                                 carcinogenicity
               8.7.2. Carcinogenicity studies
                       of  N-nitrosocarbaryl
                       8.7.2.1   Rats
                       8.7.2.2   Mice
                       8.7.2.3   Overall evaluation
                                 of the carcinogenicity of
                                  N-nitrosocarbaryl
               8.7.3. Carcinogenicity of ß-carbaryl
         8.8. Special studies
               8.8.1. Neurotoxicity
               8.8.2. Effects on the immune system
                       8.8.2.1   Appraisal on immunotoxicology
                       8.8.2.2    In vivo studies
                       8.8.2.3    In vitro studies
               8.8.3. Effects in blood
               8.8.4. Effects on the liver and other organs
               8.8.5. Effects on serum glucose
               8.8.6. Interactions with the
                       drug metabolizing enzyme system
               8.8.7. Effects on the endocrine system
               8.8.8. Other studies

         8.9. Factors modifying toxicity, toxicity of metabolites
               8.9.1. Factors modifying toxicity
               8.9.2. Toxicity of metabolites
               8.9.3.  N-nitrosocarbaryl
         8.10. Mechanism of toxicity - mode of action
               8.10.1. Inhibition of cholineresterase activity

    9. EFFECTS ON HUMAN BEINGS

         9.1. General population exposure
               9.1.1. Acute toxicity, poisoning incidents
               9.1.2. Controlled human studies
               9.1.3. Long-term exposure
         9.2. Occupational exposure
               9.2.1. Epidemiological studies

    10. PREVIOUS EVALUATION BY INTERNATIONAL BODIES

    REFERENCES

    APPENDIX

    RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES
    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CARBARYL

     Members

    Dr C.D. Carrington, Food and Drug Administration (FDA) Washington,
    DC, USA  (Chairman).

    Dr N. Chernoff, US Environmental Protection Agency, Research
    Triangle Park, North Carolina, USA

    Dr T.S.S. Dikshith, VIMTA Labs Ltd, Hyderabad, India

    Professor F. Kaloyanova, National Center of Hygiene and Medical
    Ecology, Sofia, Bulgaria  (Rapporteur)

    Professor Yu.I. Kundiev, Institute for Occupational Health, Kiev,
    Ukraine  (Vice-Chairman)

    Dr D. Osborn, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Huntingdon, United Kingdom

    Professor C. Ramel, University of Stockholm, Stockholm, Sweden

    Professor Shou-Zheng Xue, Shanghai Medical University, Shanghai, The
    People's Republic of China

     Observers

    Dr S. Kozlen, Rhône-Poulenc, Lyon, France (Representative from
    Rhône-Poulenc)

    Dr P.G. Pontal, Rhône-Poulenc, Lyon, France (Representative from
    ECETOC)

    Mr D. Demozay, Rhône-Poulenc, Lyon, France (Representative from
    GIFAP)

     Secretariat

    Dr K.W. Jager, International Programme on Chemical Safety, WHO,
    Geneva, Switzerland  (Secretary)

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the
    criteria monographs as accurately as possible without unduly
    delaying their publication.  In the interest of all users of the
    environmental health criteria monographs, readers are kindly
    requested to communicate any errors that may have occurred to the
    Director of the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland, in order that they may be
    included in corrigenda, which will appear in subsequent volumes.

                                    * * *

         A detailed data profile and a legal file can be obtained from
    the international Register of Potentially Toxic Chemicals, Case
    postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No.
    9799111).

                                    * * *

         This publication was made possible by grant number 5 U01
    ES02617-14 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA.

                                    * * *

     NOTE:  The proprietary information contained in this document
    cannot replace documentation for registration purposes, because the
    latter has to be closely linked to the source, the manufacturing
    route, and the purity/impurities of the substance to be registered. 
    The data should be used in accordance with paragraphs 82-84 and
    recommendations paragraph 90 of the Second FAO Government
    Consultation (1982).

    ENVIRONMENTAL HEALTH CRITERIA FOR CARBARYL

         A WHO Task Group on Environmental Health Criteria for Carbaryl
    met at the World Health Organization, Geneva, from 21 to 25
    September 1992.  Dr K.W. Jager, of the IPCS, welcomed the
    participants on behalf of the Director IPCS and the three IPCS
    cooperating organizations (UNEP/ILO/WHO).  The Group reviewed and
    revised the draft criteria monograph and made an evaluation of the
    risks for human health and the environment from exposure to
    carbaryl.

         The first draft was prepared by Professor F. Kaloyanova of the
    National Center of Hygiene and Medical Ecology and Dr P.P.
    Simeonova, Medical Faculty, University of Sofia, Bulgaria, who also
    prepared the second draft, incorporating comments received following
    circulation of the first drafts to the IPCS contact points for
    Environmental Health Criteria monographs.

         Dr K.W. Jager of the IPCS Central Unit was responsible for the
    scientific content of the document, and Mrs M.O. Head of Oxford,
    England, for the editing.

         The fact that Rhône-Poulenc Agro, Lyon, France, made available
    to the IPCS and the Task Group its proprietary toxicological
    information on the product under discussion is gratefully
    acknowledged.  This allowed the Task Group to make its evaluation on
    a more complete data base.

         The efforts of all who helped in the preparation and
    finalization of this publication are gratefully acknowledged.

    1.  SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Identity, properties, and analytical methods

         Carbaryl is the common name for the carbamic acid derivative
    1-naphthyl  N-methylcarbamate. The technical grade product is a white
    crystalline solid, with a low volatility; it is poorly soluble in
    water, which is stable to light and heat, but easily hydrolysed in
    alkaline media. The FAO has established a minimum specification of
    98% purity, with an impurity limit of 0.05% for ß-naphthyl
     N-methylcarbamate.

         Carbaryl and its metabolites are analysed using numerous
    analytical procedures, such as thin-layer chromatography,
    spectro-photometry, gas chromatography, high pressure liquid
    chromatography, and chemical ionization mass spectrometry. Detection
    limits of below one nanogram are achievable and recovery is usually
    more than 80%.

    1.1.2  Production and uses

         Carbaryl has been used for about 30 years as a contact and
    ingestion insecticide with some systemic properties and controls a
    wide range of pests. The principal production plant is in the USA.
    Carbaryl is processed by more than 290 formulators into over 1500
    different products.

    1.1.3  Environmental transport, distribution, and transformation

         Under most conditions, carbaryl is not persistent in the
    environment. In water, the hydrolysis half-life is dependent on the
    temperature, pH, and the initial concentration, and varies from
    several minutes to several weeks. The major degradation product is
    1-naphthol.

         Accumulation of carbaryl, expressed as a bioconcentration
    factor in the aquatic environment, has been studied in freshwater
    fish and found to be in the range of 14-75. Carbaryl is adsorbed
    more readily on soils with a high organic content than on sandy
    soils. At the usual application rates, under "good agricultural
    practice", dissipation is rapid, with a half-life of 8 days to
    1 month under normal conditions. Carbaryl may occasionally be
    carried by rainfall and soil cultivation from the surface into the
    subsoil (one metre from the surface).

         Carbaryl contaminates vegetation, either during spraying, or by
    migrating through contaminated soil into plants.

         The degradation of carbaryl in the environment is determined by
    the extent of the volatilization, photodecomposition, and chemical
    and microbial degradation occurring in soil, water, and plants. The
    rate of decomposition is more rapid under hot climatic conditions.

    1.1.4  Environmental levels and human exposure

         Food represents the major source of carbaryl intake for the
    general population.

         Residues in total dietary samples are relatively low, ranging
    from trace amounts to 0.05 mg/kg. In the USA, the daily intake
    during the first years of carbaryl application was 0.15 mg/day per
    person (in 7.4% of the composites); this decreased to 0.003 mg/day
    per person in 1969 (in only 0.8% of the composites). During the
    period of application, carbaryl may be found, occasionally, in
    surface water and reservoirs.

         The general population can be exposed to carbaryl during pest
    control operations in both the home and recreation areas.

         Workers can be exposed to carbaryl during its manufacture,
    formulation, packing, transportation, storage, and during and after
    application. Concentrations in the working-air environment during
    production varied from <1 mg/m3 to 30 mg/m3. Significant dermal
    exposure may occur in industrial and agricultural workers if
    protective measures are inadequate.

    1.1.5  Kinetics and metabolism

         Carbaryl is rapidly absorbed in the lungs and digestive tract.
    In human volunteers, dermal absorption of 45% of an applied dose in
    acetone occurred in 8 h. However,  in vitro dermal penetration data
    and toxicity data indicate that dermal absorption usually occurs at
    a much lower rate.

         The principal metabolic pathways of carbaryl are ring
    hydroxylation and hydrolysis. As a result, numerous metabolites are
    formed and subjected to conjugation with the formation of
    water-soluble sulfates, glucuronides, and mercapturates, excreted in
    the urine. Hydrolysis results in the formation of 1-naphthol, carbon
    dioxide, and methylamine. Hydroxylation produces 4-hydroxycarbaryl,
    5-hydroxycarbaryl,  N-hydroxymethylcarbaryl, 5-6-dihydro-5-6-
    dihydroxycarbaryl, and 1,4-naphthalendiol. The principal metabolite
    in humans is 1-naphthol.

         Under normal exposure conditions, the accumulation of carbaryl
    in animals is unlikely. Carbaryl is excreted primarily via the
    urine, since the product of its hydrolysis, 1-naphthol, is mainly
    detoxified to water-soluble conjugates. Enterohepatic cycling of

    carbaryl metabolites is also considerable, especially after oral
    administration.

         The hydrolysis product,  N-naphthol carbamic acid, is
    spontaneously decomposed to methylamine and carbon dioxide. The
    methylamine moiety is later demethylated to carbon dioxide and
    formate, the latter being excreted mainly in the urine.

         Carbaryl metabolites are also present in a small percentage of
    the absorbed doses in saliva and milk.

    1.1.6  Effects on organisms in the environment

         LC50 values for crustacea vary from 5 to 9 µg/litre (water
    fleas, mysid shrimps), 8 to 25 µg/litre (scud), and 500 to
    2500 µg/litre (crayfish). Aquatic insects have a similar range of
    sensitivity. Plecoptera and Ephemeroptera (stoneflies and mayflies)
    are the most sensitive groups. Molluscs are less susceptible with
    EC50s in the range of a few mg/litre. For fish, most LC50 values
    are between 1 and 30 mg/litre. Salmonids are the most sensitive
    group.

         The acute toxicity for birds is low. The LD50 for waterfowl
    and game birds is >1000 mg/kg. The most susceptible bird tested is
    the red-winged blackbird (LD50= 56 mg/kg). There was no evidence
    of field effects on birds in forest areas sprayed with 1.1 kg
    carbaryl/ha.

         Carbaryl is very toxic for honey-bees and earthworms. The oral
    LD50 for the former is 0.18 µg/bee (about 1-2 mg/kg).

         There are indications that carbaryl may temporarily influence
    the species composition of both terrestrial and aquatic ecosystems.
    For instance, one study showed that effects on certain terrestrial
    invertebrate communities may persist for at least 10 months
    following a single application.

    1.1.7  Effects on experimental animals and in vitro test systems

         The acute toxicity, expressed as the LD50, varies
    considerably according to species, formulation, and vehicle.
    Estimates of the oral LD50 for the rat range from 200 to
    850 mg/kg. Cats are more sensitive with an LD50 of 150 mg/kg. Pigs
    and monkeys are less sensitive with an LD50 of >1000 mg/kg.

         The maximum achievable aerosol concentration of carbaryl of
    792 mg a.i./m3 during a 4-h exposure resulted in the mortality of
    one out of five female rats. Carbaryl aerosols, at concentrations of
    20 mg/m3, decreased cholinesterase activity (ChEA) in cats during
    single 4-h exposures, but this concentration did not have any
    observable effects in rats.

         Carbaryl is a mild eye irritant and has little or no
    sensitizing potential. During long-term studies, the NOEL was
    10 mg/kg body weight (200 mg/kg diet) for rats, and 1.8 mg/kg body
    weight (100 mg/kg diet) for dogs. The long-term inhalation NOEL for
    cats is 0.16 mg/m3. Carbaryl has a low cumulative potential.

    1.1.7.1  Reproduction

         Carbaryl has been shown to affect mammalian reproduction and
    perinatal development adversely in a number of species. Effects on
    reproduction include impairment of fertility, decreased litter size,
    and reduced postnatal viability. Developmental toxicity is seen as
    increased  in utero death, reduced fetal weight, and the occurrence
    of malformation. With the exception of a small number of studies,
    all adverse reproductive and developmental effects were noted only
    at doses that caused overt maternal toxicity, and, in a number of
    cases, the maternal animal was more sensitive to carbaryl than the
    conceptus. The maternal toxic effects included lethality, decreased
    growth, and dystocia. Data indicate that the reproductive and
    developmental processes of mammals are not especially sensitive to
    carbaryl compared with the susceptibility of the adult organism.

    1.1.7.2  Mutagenicity

         Carbaryl has been evaluated for its potential mutagenicity in a
    number of  in vitro and  in vivo tests, in bacterial, yeast,
    plant, insect, and mammalian systems, testing a variety of
    end-points.

         The available evidence indicates that carbaryl does not have
    any DNA-damaging properties. There have been no reports of confirmed
    induction of mitotic recombination, gene conversion, and UDS in
    prokaryotes ( H. influenzae, B. subtilis) and eukaryotes
    ( S. cerevisiae, A. nidulans, cultured human lymphocytes, and rat
    hepatocytes)  in vitro.

         Negative results were obtained in tests for gene mutations in a
    large number of bacterial assays, with the exception of two cases.
    In several studies of gene mutations in mammalian cells  in vitro,
    carbaryl produced only one equivocal positive result in a cell
    culture study. However, the study had several shortcomings and the
    result has not been confirmed in any other comparable studies.

         Chromosomal damage with high dosages of carbaryl has been
    reported  in vitro in human, rat, and hamster cells, and in plants.
    No such effects have been observed in mammalian tests  in vivo,
    even at doses as high as 1000 mg/kg.

         Carbaryl has been shown to induce disturbances in the spindle
    fibre mechanism in plant and mammalian cells  in vitro. The
    relevance of plant assays for extrapolation to humans is unclear.

         It can be concluded that the available data-base does not
    support the presumption that carbaryl poses a risk of inducing
    genetic changes in either the somatic or the germinal tissue of
    humans.

         The nitrosated product of carbaryl,  N-nitrosocarbaryl, is
    capable of inducing mitotic recombination and gene conversion in
    prokaryotes ( H. influenzae, B. subtilis) and eukaryotes
    ( S. cerevisiae)  in vitro, and gives positive results in
     E. coli spot tests.

         Furthermore, experimental results indicate that
     N-nitrosocarbaryl binds to DNA, causing alkali-sensitive bonds and
    single-strand breakage.

         Nitrosocarbaryl has not been established as a clastogen
     in vivo (bone marrow and germ cells), even at high toxic doses.

    1.1.7.3  Carcinogenicity

         Carbaryl has been studied for its carcinogenic potential in
    numerous studies on rats and mice. The results of most of these
    studies were negative, but the studies were old and did not meet
    contemporary standards. However, new studies on mice and rats, which
    meet modern standards, are in progress.a

         The latest IARC evaluation (IARC, 1987) concluded that there
    were no data on cancer in humans and that the evidence of
    carcinogenicity in experimental animals was inadequate. Carbaryl
    could not be classified as to its carcinogenicity for humans
    (Group 3).

          N-nitrosocarbaryl has been shown to induce tumours locally in
    rats (either sarcoma at the site of injection or forestomach
    squamous cell carcinoma, when given by the oral route). Given the
    human chemistry of carbaryl, the risk of  N-nitrosocarbaryl
    carcinogenicity in humans from carbaryl exposure can be judged as
    negligible.

                 

    aThese studies have not yet been reviewed by the IPCS.  The
    company performing these studies has indicated that there is a
    significant increase in tumors at the highest dose in both species.

    1.1.7.4  Effects on different organs and systems

          (a) Nervous system

         The effects of carbaryl on the nervous system are primarily
    related to cholinesterase inhibition and are usually transitory. The
    effects on the central nervous system were studied in rats and
    monkeys. Oral doses of 10-20 mg carbaryl/kg for 50 days were
    reported to disrupt learning and performance in rats.

         In a small study on pigs, carbaryl (150 mg/kg body weight in
    the diet for 72-82 days) was reported to produce a number of
    neuromuscular effects. Reversible leg weakness was noticed in
    chickens given high doses of carbaryl. No evidence of demyelination
    was observed in the brain, sciatic nerve, or in spinal cord sections
    examined microscopically. Similar effects were not observed in
    long-term rodent studies.

          (b) Immune system

         Carbaryl, when administered  in vivo, at doses causing overt
    clinical signs, has been reported to produce a variety of effects on
    the immune system. Many of the effects described were detected at
    doses close to the LD50. Most studies on rabbits and mice at doses
    permitting survival have not produced significant effects on the
    immune system. Shortcomings of several of these studies were a lack
    of consistency and, sometimes, overt contradiction between results,
    which prevents the description of a defined immunotoxic mechanism.

          (c) Blood

         Carbaryl has been reported to affect coagulation, but there are
    conflicts about the direction of the effect. In glucose-6-phosphate
    dehydrogenase-deficient sheep erythrocytes, carbaryl produced a
    dose-dependent increase in methaemoglobin (Met-Hb) formation. Human
    serum albumin reacted  in vitro with the ester group of carbaryl.
    Carbaryl binds free blood amino acids.

          (d) Liver

         Disturbances have been reported in the carbohydrate metabolism
    and protein synthesis and detoxification function of the liver in
    mammals. Carbaryl is a weak inducer of hepatic microsomal
    drug-metabolizing activity. Phenobarbital sleeping time is
    shortened. The hepatic levels of cytochrome P-450 and b5 are
    increased. Changes in liver metabolism may account in part for the
    three-fold increase of the carbaryl LD50 in carbaryl-pretreated
    rats.

          (e) Gonadotropic function

         Carbaryl has been reported to increase the gonadotropic
    function of the hypophysis of rats.

    1.1.7.5  Primary mechanism of toxicity

         Carbaryl is an inhibitor of cholinesterase activity. This
    effect is dose-related and quickly reversible. There was no aging of
    the carbamylated cholinesterase. All identified metabolites of
    carbaryl are appreciably less active cholinesterase inhibitors than
    carbaryl itself.

    1.1.8  Effects on humans

         Carbaryl is easily absorbed through inhalation and via the oral
    route and less readily by the dermal route. Since the inhibition of
    cholinesterase (ChE) is the principal mechanism of carbaryl action,
    the clinical picture of intoxication is dominated by ChE inhibition
    symptoms, such as: increased bronchial secretion, excessive
    sweating, salivation, and lacrimation; pinpoint pupils,
    bronchoconstriction, abdominal cramps (vomiting and diarrhoea);
    bradycardia; fasciculation of fine muscles (in severe cases,
    diaphragm and respiratory muscles also involved); tachycardia;
    headache, dizziness, anxiety, mental confusion, convulsions, and
    coma; and depression of the respiratory centre. Signs of
    intoxication develop quickly after absorption and disappear rapidly
    after exposure ends.

         In controlled studies on human volunteers, single doses of less
    than 2 mg/kg were well tolerated. A single dose of 250 mg
    (2.8 mg/kg) produced moderate ChE inhibition symptoms (epigastric
    pain and sweating) within 20 min. Complete recovery occurred within
    2 h of treatment with atropine sulfate.

         In cases of occupational overexposure to carbaryl, mild
    symptoms are observed long before a dangerous dose is absorbed,
    which is why severe cases of occupational intoxication with carbaryl
    are rare. During agricultural application, dermal exposure may play
    an important role. No local irritative effect is usually observed,
    however, the appearance of a skin rash after accidental splashing
    with carbaryl formulations has been described.

         There are conflicting data about the effects of carbaryl on
    sperm count and changes in sperm morphology in plant workers. No
    adverse effects on reproduction have been reported.

         The most sensitive biological indicator of carbaryl exposure is
    the appearance of 1-naphthol in the urine and a decrease in ChE
    activity in the blood. Levels of 1- naphthol in the urine can be
    used as a biological indicator, if there is no 1-naphthol in the

    working environment. During occupational exposure, 40% of the urine
    samples contained more than 10 mg total 1-naphthol/litre. In one
    case of acute intoxication, 31 mg/litre was found in the urine. The
    hazard level is >10 mg/litre and the symptomatic level 30 mg
    1-naphthol/litre urine ( Data sheet on carbaryl, WHO, 1973,
    VBC/DS/75.3).

         Measurement of the ChE activity can be a very sensitive test
    for monitoring, provided that measurement is carried out soon after
    exposure.

    1.2  Conclusions

         The hazards of carbaryl for human beings are judged to be low,
    because of its low vapour pressure, rapid degradation, rapid
    spontaneous recovery of inhibited cholinesterase, and the fact that
    symptoms usually appear well before a dangerous dose has accumulated
    in the body. Good carcinogenicity studies, which meet modern
    standards, are not yet available.

    1.2.1  General population exposure

         Residue levels of carbaryl in food and drinking-water, which
    remain after its normal use in agriculture, are far below the
    acceptable daily intake (ADI) (0.01 mg/kg body weight per day) and
    are not likely to produce health hazards in the general population.

    1.2.2  Subpopulations at high risk

         Use of carbaryl for public health purposes in the home or in
    recreation areas may create overexposure, if the rules for its
    application are neglected.

    1.2.3  Occupational exposure

         By enforcing reasonable work practices, including safety
    precautions, personnel protection, and proper supervision,
    occupational exposure during the manufacture, formulation, and
    application of carbaryl will not create hazards. Undiluted
    concentrations must be handled with great care, because improper
    work practices may cause skin contamination. Air concentrations in
    the workplace should not exceed 5 mg/m3.

    1.2.4  Environmental effects

         Carbaryl is toxic for honey-bees and earthworms. It should not
    be applied to crops during flowering.

         With normal use, carbaryl should not cause environmental
    concern. Carbaryl is adsorbed on soil to a great extent and does not
    readily leach into ground water. It is rapidly degraded in the

    environment and therefore is not persistent. Use of carbaryl should
    not result in harmful short-term effects on the ecosystem.

    1.3  Recommendations

         *     The handling and application of carbaryl should be
               accomplished with the care given to all pesticides.
               Instructions for proper usage, provided on the package
               containing the chemical, should be carefully followed.

         *     The manufacture, formulation, use, and disposal of
               carbaryl should be carefully managed to minimize
               contamination of the environment.

         *     Regularly exposed worker populations should receive
               periodic health evaluations.

         *     The application of carbaryl should be timed to avoid
               effects on non-target species.

         *     Carcinogenicity studies that meet modern standards should
               be conducted.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    Structural formula

    CHEMICAL STRUCTURE 1

    Molecular formula: C12H11N02

    Common name:       Carbaryl (BSI)

    CAS chemical name: 1-naphthalenylmethylcarbamate (9CI)

    CAS registry number:         63-25-2

    RTECS registry number:       FC5950000

    Common synonyms:

         alpha-naftyl- N-methylkarbamat, alpha-naphthalenyl
         methylcarbamate, alpha-naphthyl methylcarbamate, alpha-naphthyl
          N-methylcarbamate, carbamic acid, methyl-, 1-naphthyl ester,
          N-methyl-alpha-naphthyl-urethan,  N-methyl-1-naftyl-
         carbamaat,  N-methyl-1-naphthyl-naphthyl carbamate,
          N-methyl-1-naphthyl-carbamat,  N-methylcarbamate de
         1-naphtyle,  N-metil-1-naftil-carbammato, 1-naphthol
          N-methyl-carbamate, 1-naphthyl methylcarbamate, 1
         naphthyl- N-methyl-karbamat

         The most commonly used chemical name is 1-naphthyl- N-
         methyl-carbamate.

    Common trade names:

         Arilat, Arilate, Arylam, Atoxan, Bercema, Caprolin, Carbacine, 
         Carbatox, Carbavur, Carbomate, Carpolin, Denapon, Dicarbam, 
         Dyna-carbyl, Karbaryl, Karbatox, Karbosep, Menaphtam, Monsur,
         Mugan, Murvin, Oltitox, Panam, Pomex, Prosevor, Ravyon,
         Seffein, Sevimol, Sevin, Vioxan

         The most commonly used trade name is Sevin.

    Previous codes:

         Compound 7744, ENT 23,969, ENT 23969, Experimental insecticide
         7744, Germain's HSDB 952, NAC, NMC 50, Union Carbide 7744

    Purity:

         The technical product is principally manufactured in the USA; 
         however, there are other minor sources in other parts of the 
         world.

         The technical product manufactured in the USA is produced to a
         minimum purity of 99% w/w carbaryl with a <0.05% w/w content
         of the 2-naphthyl carbamate isomer (sometimes known as
         "beta-carbaryl").

         FAO specifies a minimum purity of 98% w/w carbaryl with <0.05%
         w/w content of the 2-naphthyl carbamate isomer.

    2.2  Physical and chemical properties

         Some of the physical properties of carbaryl are listed in
    Table 1.

         Pure carbaryl is a white crystalline solid without odour.

         The explosion limit for dust (finely divided particles) in air
    is 20.3 g/m3 (approximately 2500 ppm). It is non-corrosive
    (Weston, 1982).

         The volatility may increase 4-fold when the relative humidity
    is increased from 8 to 80%.

    Table 1.Physical properties

                                                              

    Melting point (°C)                 142

    Boiling point (°C)                 decomposing

    Solubility in water (30 °C)        40 mg/litre

    Specific density (20 °C)           1.23

    Relative vapour density             -

    Vapour pressure                    1.17 x 10-6-3.1 x 10-7
                                       mmHg at 24-25 °C

    Flash point                        193 °C

    Octanol/water partition            1.59-2.3
    coefficient (log Kow)

    Flammability (explosive) limits     -

    Relative molecular mass            201
                                                              

         The solubility of carbaryl increases with temperature (Bowman &
    Sans, 1985). In sea water at 18 °C, the solubility is 31 mg/litre
    (Karinen  et al., 1967). Carbaryl is soluble to some extent in most
    organic solvents, and it is soluble in corn oil. It is lipophilic
    (Kanazawa, 1981).

         It is stable to light and heat (up to 70 °C) and acids, but
    easily hydrolysed by alkaline materials (Dittert & Higuchi, 1963).
    It is a strong oxidizer.

         The quality of carbaryl depends upon the purity of the
    precursor, 1-naphthol. The amount of the 2-naphthylcarbamate isomer
    found as a contaminant in the final product is directly related to
    the purity of this precursor. 1-Naphthol, free of 2-naphthol
    (undetectable), is produced in the USA today through the catalytic
    conversion of naphthalene. However, 1-naphthol produced by other
    manufacturing processes may contain 2-naphthol as a byproduct.

         High pressure liquid chromatography (HPLC) has been used to
    determine 1- and 2-naphthol in their mixtures in ratios 500:1, in
    order to check for traces of contamination in samples of a
    commercially important insecticide. The results have been summarized
    in Table 2 (Argauer & Warthen, 1975).

    Table 2.2-Naphthol recovered from carbaryl samplesa

                                                                  

    Sample and size          Amount of 2-naphthyl      Amount of
                             methylcarbamate added    2-naphthol
                              for recovery check         found
                                                                  

    USA produced

      250 mg Union Carbide
      99.66% active                  None            Undetectable

      500 mg Ortho Sevin
      50% wettable powder            None            Undetectable

      570 mg Union Carbide
      44% aqueous slurry             None            Undetectable

      310 mg Union Carbide
      80% wettable powder            None            Undetectable

      310 mg Union Carbide
      80% wettable powder           2.5 mg              1.7 mg

      310 mg Union Carbide
      80% wettable powder           0.50 mg             0.33 mg

    Foreign origin

      250 mg Sample A-
      technical                      None               2.3 mg

      250 mg Sample B-
      technical                      None                14 mg

      500 mg Sample C-
      50% wettable powder            None               12.4 mg

      500 mg Sample D-
      50% wettable powder            None               1.3 mg
                                                                  

    aFrom: Argauer & Warthen (1975).

    2.3  Conversion factors

         1 ppm = 8.22 mg/m3 of air;
         1 mg/m3 = 0.12 ppm.

    2.4  Analytical methods

         The methods used to determine carbaryl are summarized in
    Table 3. They vary considerably in relation to the equipment used.
    As an alternative to chemical analysis, Bowman  et al. (1982) used
    a simple bioassay system procedure to determine foliar residues for
    a safe re-entry period and to screen food for residues.  Daphnia
    and  Hyalella were used as highly sensitive test organisms.

         The Joint FAO/WHO Codex Alimentarius Commission has given
    recommendations for the methods of analysis to be used for the
    determination of carbaryl residues (FAO/WHO 1986a).


    
    Table 3.  Methods of analysis

                                                                                                                                             

    Medium             Sampling preparation   Analytical              Detection limit         Comments                  Reference
                                              methods
                                                                                                                                             

    Meat               extraction by          paper test based        0.5 mg/kg                                         Filatov & Brytskov
                       acetone                on ChE determination;                                                     (1972)
                                              butyryl choline
                                              as a substrate and
                                              phenol red as an
                                              indicator

    Air                                       thin-layer              0.2 ng qualitative                                Wagner (1973)
                                              chromatography          0.5-50 ng
                                                                      quantitative

    Air (carbaryl      absorption in          UV spectro-             1 mg/kg                 carbaryl lambda max.      Klisenko (1965)
    and                methanol               photometry                                      281 nm 1-naphthol 
    1-naphthol)                                                                               lambda max. 296 nm

    Soil plant         extraction by          thin-layer              0.1 µg                  recovery 80-95%           Kovaleva &
                       hexane, acetone,       chromatography                                  sensitivity 0.02 mg/kg    Talanov (1978a)
                       chloroform

    Cow's milk and                            spectrophotometry       0.002 mg/litre - milk   recovery 79-81%           Hurwood (1967)
    tissues                                    p-nitro-benzene
                                              diazonium fluoborate    0.02 mg/kg - tissues    fortification 9.5-5 µg
                                              coupling method

    Urine 1-naphthol   extraction with        gas chromatography      0.02 mg/litre           recovery 89-95%           Shafik et al. (1971)
                       benzene                tritium detector
                                                                                                                                             

    Table 3 (continued)

                                                                                                                                             

    Medium             Sampling preparation   Analytical              Detection limit         Comments                  Reference
                                              methods
                                                                                                                                             

    Air of working     absorption in sodium   gas chromatography,                                                       Krechniak & Foss
    environment        hydroxide solution     electron capture                                                          (1981)
                       with simultaneous      detector
                       hydrolysis to
                       1-naphthol;
                       derivatization by
                       1-fluoro-2-4
                       dinitro-benzene

    Spinach Chicory    sulfuric acid for      electron capture        0.2 mg/kg in fortified                            Tilden & van
                       hydrolysis to          for chromatography      crop extract; 20 pg for                           Middelem (1970)
                       methylamine salt;                              pure standards
                       4-bromobenzoyl
                       chloride used to
                       produce derivative
                       4-bromo-N-methyl
                       benzamide

    Water carbaryl     extraction with        gas chromatography      0.2 µg/litre            recovery for carbaryl,    Deuel et al. (1985)
    and 1-naphthol     dichloromethane        H-3 source electron                             100%; for naphthol, 90%
                                              capture detector or
                                              63Ni detector

    Soil carbaryl      extraction with                                0.01 mg/kg for          recovery for carbaryl,
    and 1-naphthol     20% diethylester                               fortified soil          89.8%; for 1-naphthol,
                       in dichloromethane                             samples                 79.4%
                                                                                                                                             

    Table 3 (continued)

                                                                                                                                             

    Medium             Sampling preparation   Analytical              Detection limit         Comments                  Reference
                                              methods
                                                                                                                                             

    Air ambient        series of gas          HPLC with ultraviolet                                                     Currier et al. (1982)
                       scrubbers charged      detection at 220 nm
                       with methanol;
                       particulate deposit
                       on Teflon discs

    Pads               methanol ethanol       HPLC                    50 ng/pad (103.2 cm2)   sensitive, inexpensive    Bogus et al. (1985)
                       extraction; selective                                                  procedure
                       absorption and
                       elution of reversed
                       phase solid support

    Post-mortem        extraction procedure   HPLC ultraviolet                                recovery: blood and       Duck & Woolias (1985)
    specimens          on Extrelut column;    detection reversed                              urine 99%; liver and
                       protein precipitation  phase                                           stomach tissue 95%
                       with acetonitrile

    Foliage            surface extraction     HPLC                    recovery: at 5 ng/kg    Pieper (1979)
                       by trichloromethane                            fortification level

    Grass, etc.        extraction by CH3CN                            grass 89.5%;
                                                                      geranium 86.5%

    Water              extraction by CH2Cl2                           aspen 75%;
                                                                      Douglas fir 49.8%;
                                                                      at 0.1 mg/litre level
                                                                                                                                             

    Table 3 (continued)

                                                                                                                                             

    Medium             Sampling preparation   Analytical              Detection limit         Comments                  Reference
                                              methods
                                                                                                                                             

    Soil               extraction by                                  soil 103%;
                       acetonitrile + water                           stream water 99.7%;
                                                                      sediment 101%

    Water, soil,       extraction by          thin-layer              0.5 mg/kg qualitative   carbaryl and 1-naphthol   Klisenko et al. (1972)
    cow's milk,        benzene ( n-hexane,     chromatography
    tissue (liver,     diethyl ether)
    kidney, heart,
    lungs, etc.)

    Vegetables and     extraction by          HPLC                                            Recovery 83-97% at        Ting et al. (1984)
    fruits             methanol (10% in                                                       0.5 mg/kg fortification
                       petroleum ether) or                                                    level. Detailed
                       acetonitrile clean-up                                                  description of the
                       on a florasil column                                                   method is given

    Water and Serum    single extraction by   HPLC                    0.5 ng/ml               Analysis time is          Strait et al. (1991)
                       methanol after 1 ml                                                    10 min Recovery in
                       of C18 solid-phase                                                     water > 99%
                       extraction columns

    Plants             methanol and           liquid chromatography   0.01 mg/kg              Recovery varies from      Krause (1985a,b)
                       mechanical             reverse phase; LC                               86 to 121%
                       ultrasonic             column using
                       homogenizer used       acetonitrile - water
                       for extraction         mobile phase
                                                                                                                                             

    Table 3 (continued)

                                                                                                                                             

    Medium             Sampling preparation   Analytical              Detection limit         Comments                  Reference
                                              methods
                                                                                                                                             

    Marion-berries     extracted by Luke      chemical ionization                             Recommended when GC       Cairns et al. (1983);
                       procedure (Luke et     mass spectrometry                               retention data are
                       al., 1975, 1981)       with both methane                               inconclusive
                       cited by Cairns        and ammonia as
                       (1983); eluted         reagent gases
                       through florisil
                       using 50% mixed
                       petroleum ethers

    Honey-bees         extraction by          gas chromatography,     0.03-0.10 mg/kg         Recovery 95-100%          Kendrick et al. (1991)
                       diethyl ether          nitrogen-phosphorous
                       clean-up using         ionization detector
                       silica cartridge
                                                                                                                                             


    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         Carbaryl was first synthesized in 1953 and, in 1958, the Union
    Carbide Corporation began its commercial production. Carbaryl is now
    processed by more than 290 formulators into 1537 different
    registered products (Harry, 1977, unpublished report). Carbaryl is
    formulated as a 50 and 85% wettable powder, 1.75-50% dust, oil-and
    water-based 4% liquid suspension, and 5 and 10% granules and baits.
    Annual production is of the order of 10 000 tonnes. It is produced
    by the reaction of 1-naphthol with methylisocyanate.

         Carbaryl is widely used, in many countries, as a broad spectrum
    contact and ingestion insecticide with some systemic properties, and
    is recommended for use at 0.25-2.7 kg active ingredient per hectare
    to control various insect pests. Up to 10 kg/ha per season can be
    used on tree fruits. In the USA, carbaryl is registered for the
    control of about 560 different pests. It is used on more than 115
    food and fibre crops, trees, and ornamentals. About 40% of the
    quantity used is applied to cotton (Kuhr & Dorough, 1976; Mastro &
    Cameron, 1976; Payne  et al., 1985). In combination with other
    substances, or alone, carbaryl is used as a plant regulator for
    apple thinning (Looney & McKellar, 1984; Looney & Knight, 1985).

         In veterinary practice, carbaryl is used on cattle, poultry,
    and pets, especially to control flies, mosquitos, ticks, and lice,
    some of which are vectors of disease.

         Carbaryl (5% formulation Carbacide) is used to treat human body
    louse infestation (Sussman  et al., 1969).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Volatilization and air transportation

         Carbaryl has a low volatility and a low air-water partition
    coefficient. Thus, only limited evaporation can be anticipated after
    treatment. Some traces of carbaryl in the air and in fog, resulting
    from spray drift, may be detected at a certain distance from the
    treated areas. A maximum level of 0.09 mg/m3 in the air has been
    reported.

         The dimensionless air-water partitioning constant (Henry's Law
    Constant) for carbaryl has been evaluated to be 5.3x10-6
    (Schomburg  et al., 1991).

         Deuel  et al. (1985) studied the persistence of carbaryl in
    paddy water. Results indicated that no measurable dissipation could
    occur as a result of volatilization. In contrast to the results from
    Deuel, using the BAM model, Lee  et al. (1990) calculated that 50
    days after treatment, 0.63% of the carbaryl applied to soil could
    have been volatilized and 78.84% degraded.

    4.2  Water

    4.2.1  Hydrolysis

         In pure, sterilized water, kept in the dark, the persistence of
    carbaryl is pH-dependent. Carbaryl is rather stable in acidic
    conditions. Its half-life at pH 7 is 10-16 days, and at pH 8 it is
    1.3-1.9 days only. At pH levels higher than 8, its half-life is in
    the range of a few hours, or even less (Aly & El Dib, 1971a).

         Carbaryl is an example of an N-substituted carbamate that
    hydrolyses readily in water. In this mechanism, an acid-base
    equilibrium is established and the conjugate carbamate undergoes an
    elimination type reaction to give an unstable carbamic acid that
    decomposes to the primary amine and CO2. Initially, the principal
    non-biological degradation pathway of carbaryl in water, however,
    involves base-catalysed hydrolysis to 1-naphthol (Khasawinah, 1977).

         Aly & El Dib (1971a,b, 1972) conducted studies to determine the
    physical factors that may influence the degradation of carbamates,
    including carbaryl, in aquatic systems. Hydrolysis of carbaryl in
    alkaline medium was a function of hydroxyl ions in solution and was
    first order with respect to these ions. Carbaryl was so sensitive to
    hydroxide ions that, at high base concentrations, the liberation of
    1-naphthol was too fast (few minutes) to be measured by conventional
    methods. Carbaryl was stable to hydrolysis at the acid pH range of
    3-6. At pH 7, a rise in the hydrolysis rate was observed, which
    increased with increase in pH. Carbaryl was very susceptible towards
    hydrolysis in aqueous solutions at neutral and alkaline pH values. A

    series of kinetic studies was carried out at different temperatures
    (3-33 °C) to study the temperature dependence of the rate of
    hydrolysis. Results showed that an increase in temperature resulted
    in an increase in the reaction velocity.

         Wauchope & Haque (1973) reported that, in weak acidic
    solutions, carbaryl and 1-naphthol were stable for several weeks, in
    the dark or under laboratory light. In basic solutions, the basic
    form of 1-naphthol (1-naphthoxide) was light sensitive.
    1-Naphthoxide ion was transformed into 2-hydroxy-1,4-naphthoquinone;
    this was confirmed by mass spectrometry.

         Khasawinah (1977) carried out the hydrolysis of carbaryl in the
    dark, in aqueous buffer solutions at temperatures of 25 and 35 °C.
    Increasing the pH and temperature of the buffer accelerated the
    disappearance of carbaryl and the formation of 1-naphthol.

         Rate constants (at 20 °C) were determined for the purely
    chemical hydrolysis of carbaryl in water containing solvents at pH
    values ranging from 4 to 8 (Chapman & Cole, 1982). The solvent
    composition (water/ethanol = 99/1) was close to pure water and the
    solutions were sterilized to ensure that only chemical reactions
    were taking place. The half-lives for carbaryl were calculated from
    pseudo-first order disappearance rate constants (Table 4).

         Fisher & Lohner (1986) conducted tests on the environmental
    fate of carbaryl as a function of pH. In both a microcosm and
    abiotic studies, greater amounts of carbaryl were detected in water
    at pH 4, than at pH 6 or 8.

         Hydrolysis of labelled carbaryl in aqueous solution was
    conducted by Carpenter (1990) under dark conditions. When
    degradation occurred, the major degradation product of significance
    was 1-naphthol. No other degradation product accounted for more than
    2% of the radioactivity and no volatile products were generated
    during the hydrolysis reaction. The test systems were sterile and
    the transformation/degradation mechanism was purely chemical
    hydrolysis.

         Carbaryl half-lives in aqueous solution observed by different
    authors are summarized in Table 4.


    
    Table 4.  Half-life of carbaryl at different pH values and temperatures in aqueous solution (days)

                                                                                                                                 
                                  pH                                               Temperature   References
                                                                                 
      3        4         5         6         7         8         9        10          (°C)
                                                                                                                                 

                                           10.5      1.3       0.1       0.01                    Aly & El Dib (1971a, 1972)

                                                               0.12      0.01          25°       Wauchope & Haque (1973)

    stable                       stable                        0.14                    25°       Khasawinah (1977)
    stable                       29                            0.02                    35°

                       1500                15                  0.15                    27°       Wolfe et al. (1978)

             2100a               406       14        1.9                               20°       Chapman & Cole (1982)

             104                 71.6                1.4                                         Fisher & Lohner (1986)

                                 171.4     16.5                                        25°       Larkin & Day (1986)

                       stable              11.6                0.13                              Carpenter (1990)
                                           12.5
                                                                                                                                 

    a pH 4.5


    
    4.2.2  Photolysis

         There is sufficient evidence to suggest that photodecomposition
    will account for some loss of carbaryl in clear surface waters
    exposed to sunlight for long periods. In turbid waters, light
    penetration is greatly reduced, thus photolysis will play only a
    minor role in the decomposition of carbaryl.

         The primary effect of ultraviolet light radiation (UVR) seems
    to be cleavage of the ester bond, however, other modifications in
    the carbaryl molecule occur. Crosby  et al. (1965) studied the
    photodecomposition of carbaryl and found several other
    cholinesterase inhibitory substances, in addition to 1-naphthol,
    indicating that these substances retained the intact carbamate ester
    group, and that irradiation resulted in changes at other positions
    in the molecule. Both UVR and natural sunlight caused decomposition
    of carbaryl, however, the extent of photodecomposition was not the
    same under the different conditions of irradiation. Intense UV
    irradiation generally resulted in the formation of a greater number
    of degradation products. It is expected that the effects of natural
    sunlight UVR (292-400 nm) on the photodegradation rate and the
    nature of the degradation products would differ from those of the
    shorter wavelength irradiations used above.

         The effect of UVR on the photodegradation of carbaryl was
    studied by Aly & El Dib (1971b, 1972). Generally, the concentration
    of carbaryl decreased with time, however, the photolysis rate
    gradually decreased. Photodecomposition proceeded at increasing
    rates as the pH values of solutions increased. After an exposure
    time of 60 min, the decomposition rates of carbaryl at pH 5, 7, and
    8 were 50, 57, and 78%, respectively. The half-life at pH 8 was
    <20 min while, at pH 5, it was approximately 80 min. The main
    decomposition product after 5 min of exposure in all irradiated
    solutions was 1-naphthol. However, its concentration also decreased
    as the irradiation time was increased, indicating that 1-naphthol
    also underwent photolysis, as soon as it appeared in solution. The
    photodecomposition of 1-naphthol was also affected by the pH of the
    medium. The half-lives of carbaryl and 1-naphthol were 39 and
    60 min, respectively, at pH 7 and 8, and 43 min at pH 8.

         The photochemistry of carbaryl was studied by Addison  et al.
    (1975) in aerated and pure ethanol, cyclohexane, isopropyl alcohol,
    and  tert-butanol. Irradiation of carbaryl produced 1-naphthol and
    small amounts of naphthamides, naphthalene, and
    ß-napthyl-1-naphthol. In cyclohexane, 1-naphthol was the only
    decomposition product.

         Khasawinah (1977) conducted a photolysis study on labelled
    carbaryl in an aqueous solution buffered at pH 6. The study
    terminated before the actual half-life was reached. The half-life
    was calculated to be 40-50 days. The author stated that under field

    conditions it is expected that carbaryl will photodegrade slowly and
    that photodegradation does not play a major role in the
    environmental degradation of carbaryl.

         The direct photolysis half-life of carbaryl in sunlight was 6.6
    days in distilled water (Wolfe  et al., 1978). On the basis of the
    results of the methods of Zepp  et al. (1976) and Zepp & Cline
    (1977), the calculated half-life for direct photolysis was about
    50 h in a clear water body, near the surface. The annual variation
    of the photolysis half-life of carbaryl according to season of the
    year was calculated. As the intensity of the sunlight increases, so
    do photolysis rates. Carbaryl absorbs UV-B radiation most strongly,
    and, thus, can also be photolysed under overcast conditions (cloudy
    days). UVR is absorbed by water, and the photolysis rate decreases
    as the water deepens. In spring and summer, when carbaryl is
    applied, the rate of photolysis is about four times that in winter
    months. In distilled water under the June midday sunlight at pH 5.5,
    the half-life of carbaryl was 45 h.

         Deuel  et al. (1985) studied the photodecomposition of
    carbaryl in deionized water. They confirmed that carbaryl could be
    photodecomposed in an aquatic environment.

         The influence of different aqueous systems (rivers, lakes, and
    seawater) on the photochemical degradation of some carbamate
    insecticides in Greece was studied by Samanidou  et al. (1988). In
    lake and sea water, carbaryl was almost completely degraded by
    sunlight within 4 and 2 days, respectively, in the presence of
    oxygen. One day of UV irradiation in river, lake, and sea water,
    respectively, resulted in 98%, 87%, and 99% degradation. The high
    concentration of suspended matter in river and lake water influences
    the absorption of sunlight and consequently the degradation of
    carbaryl.

         Das (1990a) exposed sterile water, buffered at pH 5, with
    labelled carbaryl to artificial sunlight (548.8 watts/m2) for
    360 h; 65% of the carbaryl had disappeared by the end of the 360-h
    period. The major degradation product was 1-naphthol. In control
    test solutions, incubated in the dark, changes in carbaryl
    concentrations were insignificant.

    4.2.3  Degradation by microorganisms

         A review of the chemical and microbial degradation of carbaryl
    in aquatic systems has been published by Paris & Lewis (1973).

         The rate of hydrolysis of carbaryl in neutral and slightly
    basic conditions was so rapid that differences reported between
    sterilized and non-sterile water were usually were minor. Thus, it
    is generally considered that the microbial degradation of carbaryl

    in natural water plays only a secondary role in comparison with
    chemical hydrolysis.

         The bacterial decomposition of 1-naphthol by ring cleavage was
    reported in farm pond water (Hughes & Reuszer, 1970). They studied
    bacterial populations in pond water containing drainage water from
    carbaryl-treated fields. Their data were the earliest to show that
    bacteria can adapt to live on carbaryl and that when this occurs one
    strain dominates. They also showed that there may be a minimum
    period of time before bacteria can degrade carbaryl and a minimum
    concentration below which bacteria will not multiply rapidly enough
    to cause degradation.

         Ahlrichs  et al. (1970) found bacteria that could break the
    ring structure of carbaryl, however data concerning the role of
    microorganisms in the elimination of insecticides from surface water
    were variable.

         In a study by Hughes (1971) a bacterium ( Flavobacterium sp.)
    was isolated from pond water, which degraded 1-naphthol to
     o-hydroxycinnamic acid, salicylic acid, and an unidentified
    product. In this study, the bacteria cleaved the naphthalene ring,
    since both hydroxycinnamic acid and salicylic acid each have only a
    single phenol ring.

         Aly & El Dib (1972) studied the biodegradation of carbaryl in
    Nile River water in 5-gallon containers, which was buffered to
    maintain a pH of 7.2 and held at 25±2 °C under aerobic conditions.
    The concentration of carbaryl in water decreased progressively with
    time and 89% of the added amount of carbaryl (4.75 mg/litre)
    degraded in 6 days. 1-Napthol, which appeared as a degradation
    product, did not result only from the chemical hydrolysis of
    carbaryl, since a sterile buffered solution showed negligible
    hydrolysis. 1-Naphthol was produced mainly as a result of the
    biological activity of microorganisms in river water. Subsequent
    additions of increasing concentrations of carbaryl disappeared in
    shorter periods of time, and there was no build-up of 1-naphthol.
    Carbaryl disappeared more rapidly in Nile River water containing
    sewage. Thus, the authors considered that natural waters and sewage
    contain microorganisms capable of degrading carbaryl and 1-naphthol.

         A number of marine microorganisms, including algae, bacteria,
    fungi, and yeasts, were tested by Sikka  et al. (1973, 1975) for
    their ability to metabolize carbaryl or 1-naphthol. None of them was
    able to degrade carbaryl to a significant extent. Only a very small
    amount of carbaryl was metabolized to form water-soluble metabolites
    by the algae  Cyclotella nana and  Dunaliella tertiolecta.
    1-Naphthol was degraded to water- and ether-soluble metabolites by
     Culcitalna achraspora, Halosphaeria mediosetigera, Humicola
     alopallonella, Aspergillus fumigatus, Serratia marina, Spirillum
    sp., and  Flavobacterium sp. The organisms differed greatly in

    their ability to convert carbaryl to water-soluble products, and
    also in their ability to degrade 1-naphthol. Overall, 1-naphthol
    appeared more susceptible to degradation than carbaryl, and
    filamentous fungi appeared to possess a greater ability to degrade
    1-naphthol than bacteria or yeast.

         Bacteria isolated from river water were also capable of
    degrading 1-naphthol (Bollag  et al., 1975; Czaplicki & Bollag,
    1975). After 60 h of incubation with 14C-labelled 1-naphthol, it
    was possible to trap 44% as CO2 and 22% was recovered. The release
    of labelled CO2 clearly indicated that complete biodegradation of
    carbaryl had taken place via rupture of the naphthyl ring. However,
    15-20% of radioactivity remained in the growth medium. This suggests
    that at least 2 different pathways may be involved in the
    degradation of 1-naphthol by these bacteria. The radioactivity in
    the growth medium was partitioned and the dominant product was
    identified as 4-hydroxy-1-tetralone, which suggests an alternative
    pathway that involves hydroxylation of the naphthyl ring in the
    4-position and conversion of an aromatic ring to an aliphatic cyclic
    compound. Walker  et al. (1975a) confirmed this pathway with a soil
    pseudomonad.

         Paris  et al. (1975) found that, in heterogeneous bacterial
    cultures in water, bacteria did not significantly degrade carbaryl
    but did utilize 1-naphthol, produced from hydrolysis, as a carbon
    source. Products of the bacterial degradation of the 1-naphthol were
    1,4-naphthoquinone and 2 unidentified compounds. Hydrolysis and
    photolysis contributed significantly to the degradation of carbaryl,
    since half-lives were short compared with those of biolysis.

         Within 7 days of incubation in river water, 92% of carbaryl or
    1-naphthol disappeared (Prima  et al., 1976); 68% was removed by
    biochemical degradation, and 24% by a physico-chemical process.

         Liu  et al. (1981) measured the rate of carbaryl degradation
    at pH 6.8 both with, and without, bacteria obtained from lake
    sediment. Without the lake sediment inoculum, the half-life of
    carbaryl was 8.3 days under aerobic conditions and 15.3 days under
    anaerobic conditions. With bacterial metabolism, half-lives of 6.8
    and 5.8 days, respectively, were measured. After the addition of
    cometabolites (glucose and peptone), the half-lives were further
    reduced to 3.8 and 4.2 days, respectively. Thus, bacterial
    degradation played a much greater role in the degradation of
    carbaryl under anaerobic conditions.

         Microbial activity was an important factor in the breakdown of
    carbaryl in water from a pond and creek (Szeto  et al., 1979).
    Autoclaving prior to the addition of carbaryl and incubating for 50
    days increased the recovery from 39 to 57% (creek water) and from 28
    to 58% (pond samples containing sediment).

         Boethling & Alexander (1979) studied the degradation of
    carbaryl in stream water (pH 7.5-8.6) at extremely low
    concentrations. They reported that, at initial concentrations of 30
    and 300 mg/litre, more than 60% of the carbaryl was degraded to
    CO2 within 4 days, but 10% or less was converted to CO2 at
    0.3 mg/litre and 0.0003 mg/litre. At these two latter
    concentrations, CO2 was generated at rates not exceeding 3% of the
    starting material per day. The authors concluded that laboratory
    tests on bio-degradation are usually conducted with concentrations
    of chemicals higher than those found in rivers, lakes, and marine
    waters and, therefore, will not accurately predict the environmental
    behaviour of microorganisms.

         Sharom  et al. (1980) compared the persistence of carbaryl in
    natural water, distilled water, sterilized natural water, and
    sterilized distilled water. Carbaryl disappeared from all four types
    of water, which was considered to show that chemical processes
    played a major role, and biological processes, a secondary role, in
    the degradation of carbaryl in water.

         Chaudhry & Wheeler (1988) maintained a  Pseudomonas sp.
    isolated from a pesticide waste disposal site on a medium containing
    normal and radiolabelled carbaryl.  Pseudomonas sp. degraded
    carbaryl and the authors concluded that  Pseudomonas sp. may have
    potential as biological treatments for waste and groundwater.

    4.2.4  Persistence in surface water

         The agricultural use of carbaryl may indirectly produce
    residues in surface water and in sediment, following application, as
    result of drift or from soil-bound particles. In general, carbaryl
    is not expected to persist in the aquatic environment. Although it
    is stable to hydrolysis in acidic water, at the pH of most surface
    fresh waters (7-8.2), it is highly susceptible to hydrolysis.
    Biologically-mediated degradation and photolysis are secondary
    mechanisms; sediment and humic substances also influence the
    persistence of carbaryl in aquatic systems.

         Half-lives of carbaryl in natural water, calculated from
    experimental results, are summarized in Table 5. In one case, with
    exceptionally cold and acidic conditions, the half-life was in the
    range of 70 days. In most cases, half of the carbaryl degraded in a
    few days, or even in less than one day.


    
    Table 5.  Percentage of carbaryl degraded in water, a certain number of days after treatment,
              and the corresponding approximate half-lives
                                                                                                

    Origin of water         Days        %         Half-life    References
                            after                  (days)
                          treatment
                                                                                                

    laboratory               7         95            1         Eichelberger & Lichtenberg (1971)

    pond                                           < 0.5       Romine & Bussian (1971)

    containers               6         89            2         Aly & El-Dib (1972)

    microcosm                                      < 5         Kanazawa (1975)

    river                    7         92            2         Prima  et al. (1976)

    lab. pond water         42        80-82         18         Szeto  et al. (1979)

    lab. + sediment                                < 2

    lab. creek water        42        60-63         30

    lab. + sediment                                < 7

    lab. drainage           28         100           4         Sharom  et al. (1980)

    field, drainage          6         100           1         Osman & Belal (1980)

    brooks, rivers,                                  1         Stanley & Trial (1980)
    streams

    stream                  17         100           3         Ott  et al. (1981)
                                                                                                

    Table 5.  Contd

                                                                                                

    Origin of water         Days        %         Half-life    References
                            after                  (days)
                          treatment
                                                                                                

    lab. sewage             42         100          11         Odeyemi (1982)

    lab. fresh water        60         100        < 15

    rice irrigation         10         80            4         Thomas  et al. (1982)

    pond 1                  60         100           8         Gibbs  et al. (1981, 1984)

    pond 2                 138         77          2-3         rice fieldDeuel  et al. (1985)

    microcosm (pH 4-8)       7        31-73       13-4         Fisher & Lohner (1986)

    stream                                         < 0.1       Sundaram & Szeto (1987)

    stream                 1-3         100         < 1         Springborn (1988b)

    rice irrigation                                < 1         Springborn (1988a)

    ponds (18 °C)            4         100           1         Hanazato & Yasuno (1989)

    ponds (4 °C)            10         30           20
                            45         95           10

    ponds (4-20 °C)                               0.4-0.9      Hanazato & Yasuno
                                                               (1990a,b)
                                                                                                
    aRounded.


    
         The behaviour and persistence of carbaryl in water from a pond
    and creek, with and without sediment, were studied under simulated
    conditions in the laboratory by Szeto  et al. (1979). At 9 °C,
    carbaryl was less persistent in pond water (pH 7.5-7.8) than in
    creek water (pH 7-7.1). Carbaryl degraded to 18-20% of the initial
    amount after 42 days in pond water samples and to 37-40% of the
    initial amount in creek water samples after 50 days. The higher pH
    of pond water compared with creek water may have contributed to this
    effect. The presence of sediment did not affect the rate of loss of
    carbaryl, but approximately 50% of the remaining carbaryl was found
    in the sediment. Microbial activity was a major factor in the
    degradation of carbaryl in this study.

         Eichelberger & Lichtenberg (1971) measured the persistence of
    carbaryl in river water at room temperature and pH 7.3-8. From an
    initial concentration of 10 µg/litre, only 5% could be detected
    after 1 week and none was detected at 2 weeks. At the time of
    disappearance of carbaryl, 1-naphthol could not be detected.

         In Egypt, Osman & Belal (1980) mentioned that residues present
    in irrigation and drainage canals following application of carbaryl
    disappeared from the water 6 days after spraying.

         The persistence of carbaryl was tested by Odeyemi (1982) who
    incubated water samples treated wtih 45 mg/kg under tropical
    greenhouse conditions (Nigeria). According to colorimetric
    measurements, carbaryl disappeared after 42 days of incubation in
    sewage water, and after 60 days in fresh water samples.

         The impact of an experimental aerial application of carbaryl
    (Sevin-4-oil) on woodland ponds in Northern Maine (USA) was studied
    by Gibbs  et al. (1981, 1984). Carbaryl was applied at the rate of
    840 g/ha. Maximum residues levels of 734 µg/litre were detected in
    the water, and about 4860 µg/kg (dry weight) in the sediment. In one
    pond, carbaryl was not found after 62 days. Data from another pond
    showed residues equivalent to 23% of the initial residue after 138
    days, and 13% of the initial residues persisting after 375 days.
    Investigators noted a rapid movement of carbaryl into bottom
    sediments with persistence up to 16 months in this compartment,
    compared with 14 months in the water. The anaerobic state of the
    organic substrate and acidic conditions in one pond may have
    contributed to greater persistence. The lower residue levels in the
    other pond were attributed to a greater flow of water.

         Hanazato & Yasuno (1990a,b) conducted studies in experimental
    outdoor concrete ponds in Japan. Water received three treatments
    with carbaryl in order to produce a minimal concentration of
    0.5 mg/litre on 12, 19, and 20 October. The water temperature, which
    was 20 °C at the start of the experiment, declined steadily to 4 °C
    in early December and then did not change. The pH increased from 7.3
    on the third day after the start of the experiment to about 9 on the

    13th day. It remained between 8-9 until the end of the experiment.
    The concentration of carbaryl in water decreased exponentially and
    it was no longer detected 4 days after the first and second
    treatments and 11 days after the third treatment. The half-lives for
    the three treatments were respectively 0.36, 0.40, and 0.86 days.
    The corresponding times for 90% degradation were, respectively,
    1.18, 1.32, and 2.84 days.

         Carbaryl was added to 60 litres of water and 15 kg of soil held
    in 110-litre, plastic, garbage containers, buried partially in open
    ground (Junk  et al., 1984). Carbaryl was studied at the high and
    low concentrations of 4 g/litre and 0.2 g/litre, respectively.
    Additional variables studied included aeration (1 litre/min) and
    peptone nutrients (0.1% by weight). Data obtained from this
    experiment demonstrated that soil and water in an inexpensive
    container provide satisfactory conditions for the containment of
    pesticides so that chemical and biological degradation can occur.
    Hydrolysis of carbaryl was rapid.

         Deuel  et al. (1985) studied the persistence of carbaryl and
    the 1-naphthol metabolite in paddy water under flooded rice
    cultivation conditions. Persistence was evaluated with respect to
    time, application rates (1.1 and 5.6 kg/ha), and irrigation scheme
    (intermittent or continuous). Results showed that application rate
    and time of sample collection had a significant influence on the
    carbaryl residues recovered in paddy water during the 3-year study.
    They were found to be greater in plots under intermittent
    irrigation, but only in 2 of the 3 years. Carbaryl residues in water
    were greatest in years when rainfall occurred within 24 h of foliar
    application. Using intermittent treatment data, carbaryl was
    determined to dissipate to half the initial residue level within
    48-59 h.

    4.2.5  Removal from water

         As already mentioned, Chaudhry & Wheeler (1988) proposed that
     Pseudomonas sp. may have potential as a biological treatment for
    waste and groundwater.

         According to Miles  et al. (1988a,b), the degradation rates of
     N-methylcarbamate insecticides, including carbaryl and its
    metabolite 1-naphthol, were more rapid in chlorinated water than in
    pure water. Half-lives of carbaryl were as follows:

             carbaryl control pH 7:10.3 days
             carbaryl control pH 8: 1.2 days
             carbaryl chlorinated pH 7: 3.5 days
             carbaryl chlorinated pH 8: 0.05 days.

         A separate experiment with 1-naphthol in chlorinated water
    showed that this product is highly unstable with a half-life of the

    order of minutes. A water source contaminated with carbaryl and
    treated by chlorination will have lower concentrations of the
    insecticide in the effluent.

         Mason  et al. (1990) studied the removal of carbaryl from
    drinking-water by the disinfectants, Cl2, ClO2, and O3.
    Carbaryl did not react with chlorine or with ClO2, but reacted very
    rapidly with O3. Therefore removal/degradation of carbaryl can be
    achieved using ozonization.

    4.2.6  Persistence in sea water

         Under laboratory conditions, the persistence of carbaryl in sea
    water is slightly higher than that in freshwater and, according to
    temperature, lighting, and microbial presence, its half-life varies
    from a few days to about one month. The salt content of natural
    waters (ionic strength) may affect the rate of hydrolysis of
    carbamates (Christenson, 1964). Thus, carbaryl is expected to be
    more stable to hydrolysis in waters with a high salt content than in
    freshwater.

         Carbaryl may enter marine systems when it is used to control
    oyster pests and predators, such as oyster drills, mud shrimp, ghost
    shrimp, and star fish (Loosanoff  et al., 1960a,b; Lindsay, 1961;
    Loosanoff, 1961; Snow & Stewart, 1963; Haydock, 1964; Haven  et al.,
    1966). However, Hurlburt  et al. (1989) stated that tidal action
    diluted the insecticide rapidly and that larvae are unlikely to be
    subjected to high concentrations of carbaryl for more than several
    hours.

         The persistence of carbaryl in estuarine water was studied in
    the laboratory by Karinen  et al. (1967). Samples of water
    containing 5, 10, or 25 mg carbaryl/litre and 3% NaCl were buffered
    at pH 8 and kept in aquaria at 8 °C. In the absence of mud, the
    concentration of carbaryl decreased 50% in 38 days, with most of the
    decrease accounted for by the production of 1-naphthol. In another
    experiment, naphthyl-14C and carbonyl-14C carbaryl (6.8-8.7 mC)
    were used with cold carbaryl at total concentrations of 15 and
    25 mg/litre, respectively, and maintained at 20 °C. About 50% of the
    carbaryl was hydrolysed in 4 days and, after 17 days, the carbaryl
    had almost disappeared with 43% converting to 1-naphthol.
    Fluorescent light slightly accelerated the hydrolysis of carbaryl to
    1-naphthol. When mud was added to the aquarium system, both carbaryl
    and 1-naphthol in sea water declined to less than 10% of the initial
    concentration in 10 days. Both compounds were adsorbed by the mud,
    where decomposition continued at a slower rate than in sea water.
    1-Naphthol persisted in mud for a short period of time, but carbaryl
    could be detected for approximately 3 weeks. The naphthol moiety of
    the carbaryl molecule was converted to more persistent products. The
    experiment with labelled carbaryl demonstrated degradation by
    hydrolysis of carbamate and oxidation of the naphthyl ring to

    produce 14CO2 and 14CH4. In a preliminary field study,
    estuarine mud flats were treated with carbaryl at 11.2 kg/ha (dose
    used to control pests in oysters beds); carbaryl could be detected
    in the mud for up to 42 days. 1-Naphthol concentrations were found
    only after the first day, which may indicate that hydrolysis
    proceeds slowly in mud.

         The fate of 1-naphthol was studied in simulated marine systems
    by Lamberton & Claeys (1970). 1-Naphthol was unstable in the
    alkaline environment of sea water, since light and microorganisms
    enhanced its degradation to CO2 and other products. 1-Naphthol was
    relatively stable in an oxygen-free aqueous solution.

         Odeyemi (1982) incubated water samples treated with 45 mg
    carbaryl/litre under tropical greenhouse conditions (Nigeria).
    According to colorimetric measurements, about 77% of the insecticide
    had disappeared after 63 days of incubation in seawater, whereas it
    had completely disappeared after 42 days of incubation in sewage
    water, and after 60 days in freshwater samples.

    4.2.7  Bioaccumulation/biomagnification

         Because of its low persistence in water, and its even faster
    degradation by living organisms, carbaryl has very low
    bio-accumulation properties and presents no risk of biomagnification
    under practical conditions.

         Kanazawa (1975) studied the uptake and excretion of carbaryl by
     Pseudorasbora parva. Fish were reared for 30 days in an aquarium
    containing carbaryl at about 1 mg/litre. In water, 95% of the
    carbaryl was degraded in 6 days. One day after treatment, residues
    of carbaryl in  P. parva reached 7.5 mg/kg, which was the maximum
    uptake.

         Kanazawa  et al. (1975) studied the distribution and
    metabolism of 14C-1-naphthyl-labelled methylcarbamate (carbaryl)
    in an aquatic model ecosystem containing 10 kg soil, 80 litre water,
    and catfish ( Ictalurus punctatus), crayfish ( Procambarus sp.),
    daphnids ( Daphnia magna), snails (Physa sp.), algae ( Oedogonium
     cardiacum) and duckweed ( Lemna minor). After 20 days, 31% of the
    radioactivity was lost, 67.85% remained in the soil (about 45%
    unextractable residues), 1.1% was present in water, and only 0.1%
    was recovered in organisms. Bioaccumulation ratios were calculated
    from radioactivity recovery and were likely to be low in the case of
    animals. In the case of plants, they were apparently higher, but as
    they are based only on radioactivity, including normal synthesis
    reutilizing 14CO2 and not on real carbaryl measurement, they
    should be considered as an overestimation of the true
    bioconcentration factor for carbaryl (Table 6).

         A flow-through bioconcentration study was conducted with
    bluegill sunfish ( Lepomis macrochirus) exposed to 0.093 mg
    carbaryl/litre for 28 days followed by a depuration phase in which
    bluegill were held for 14 days in untreated water (Chib, 1986a; Chib
     et al., 1986). Analysis of fillet, whole fish, and visceral
    portions indicated a rapid uptake of carbaryl. Bioconcentration
    factors ranged from 14x to 75x, for fillet and viscera,
    respectively. Data suggest that fish stopped accumulating carbaryl
    after day 7 of uptake, indicating that a steady state had been
    reached.

    
    Table 6.  Accumulation of 14C radioactivity expressed as carbaryl
              equivalenta by various aquatic organismsb
                                                                       

                                              Carbaryl
                                                                       

    Concentration in water                  1.66 (1 day)

    µg/litre                                9.45 (22 days)

    Concentration in soil                   2.43 (start)

    mg/kg                                   2.55 (22 days)

                                                                       

    Organisms                      mg/kg                        BARc
                                                                       

    Algae                          37.9                         4000

    Duckweed                       34.2                         3600

    Snail                           2.81                         300

    Catfish                         1.33                         140

    Crayfish                        2.48                         260
                                                                       

    aCarbaryl not actually measured.
    bFrom: Kanazawa  et al. (1975).
    cBioaccumulation ratio calculated by dividing mg/kg of dried
     tissues by mg/litre in water at harvest.
    
    By the end of the 14-day depuration period, over 90% of the
    accumulated carbaryl was eliminated.

         The persistence and accumulation of radiolabelled carbaryl
    (technical, 99%), administered in either food or water
    (flow-through), was studied in catfish ( Ictalurus punctatus) over
    a 56-day period (Korn, 1973). Fish were removed periodically for
    whole-body residue analysis. Intact carbaryl was not distinguished
    from 1-naphthol. Accumulation from dietary carbaryl (2.8 mg/kg per
    week) was 11 and 9 mg/kg tissue at 3 and 56 days, respectively. Fish
    accumulated 1% or less of the available pesticide via dietary
    exposure. The mean total accumulation of carbaryl (and/or metabolite
    residues) after 56 days of exposure to water containing 0.25 mg
    carbaryl/litre was 11 mg/kg. Fish exposed via the water retained
    0.0001% carbaryl. Fish exposed to 2.8 mg/kg per week via diet
    eliminated residues rapidly after they were placed on a
    carbaryl-free diet for 28 days. However, residues remained constant
    for 28 days in fish previously exposed to 0.25 mg carbaryl/litre
    water for 56 days. The authors speculated that the greater
    persistence of carbaryl residues from the water might be due to the
    persistence in fish of 1-naphthol.

         The low accumulation and rapid elimination of carbaryl in fish
    were confirmed in other laboratory work (Kanazawa, 1975, 1981).

         The biodegradation of carbaryl, was studied by Bogacka & Groba
    (1980) in a model system simulating the river-water and aqueous
    ecosystem conditions. The rate of pesticide decay in water depended
    on the initial concentration, temperature, and the kind of model.
    Lowering the temperature inhibited this process. The accumulation of
    carbaryl in bottom sediments or in aquatic organisms (algae, snails,
    and fish) was not observed at concentrations of 10 or 50 µg/litre.
    Trace quantities of 1-naphthol could be detected occasionally.

    4.3  Soil

    4.3.1  Adsorption, desorption

         Carbaryl is adsorbed on soil. Most Koc values were in the
    range of 100-600, which corresponds to medium to strong adsorption.
    Only in some soils from Eastern Australia was carbaryl apparently
    less tightly bound (Koc 90-220). Taking into account both the
    adsorption/desorption properties and the short persistence of
    carbaryl in soil, it can be calculated that the compound has low to
    moderate mobility in soil and will remain in the top layers, when
    applied under actual agricultural conditions (normal dose rates).
    Leenheer & Ahlrichs (1971) stated that fast adsorption rates for
    carbaryl on soil particles were related to organic matter (OM) and
    were of the order expected for physical adsorption.

         Carbaryl desorption and movement in the soil was studied in 1-m
    soil columns in glass tubes, which had a drain (LaFleur, 1976a).
    Desorption by added water was rectilinear for carbaryl (soil range
    1-200 µmol/kg). The movement of carbaryl in the column was a
    function of the percentage of the organic matter. In soil containing
    5.16% organic matter, carbaryl reached the 40-cm section of the
    column only. When the organic matter content of the soil was low
    (0.22-0.57%), about one-half of the added carbaryl moved through the
    column and was found in the effluent, after addition of a volume of
    water that was equal to six months' rainfall. Briggs (1981) also
    reported that increasing levels of organic matter in soils resulted
    in an increase in the adsorption of carbaryl.

         On the basis of the comparative mobility of carbaryl on soil
    thin-layer chromatography (TLC) plates using 4 US soils (silt loam,
    loam, Norfolk sandy loam, and silty clay loam), Chib & Andrawes
    (1985) concluded that the mobility of carbaryl is low to moderate.
    With water elution equivalent to about 580 mm of rainfall, the major
    portion of carbaryl was in the top 10 cm of soil, thus exhibiting
    low mobility. Only 0.6% of the applied 14C was eluted with the
    water. Approximately 70% of the applied carbaryl was degraded to
    volatile gases during the 30-day incubation.

         Aly  et al. (1980) studied the adsorption of carbaryl at
    different temperatures on Ca-bentonite and on two Egyptian soils
    (Nile alluvial and a highly calcareous soil). Carbaryl adsorption
    increased as the temperature decreased. Ca-bentonite exhibited the
    highest degree of adsorption followed by the Nile alluvial soil and
    the calcareous soil. The factors that contributed most to the total
    adsorption of carbaryl were the soil contents of clay, calcium
    carbonate, and organic matter.

         The adsorption-desorption and mobility of carbaryl in 3 soils,
    and in a stream sediment were studied by Sharom  et al. (1980). The
    order of adsorptive capacity was organic soil (75.3% OM, pH 6.1) >
    sediment (2.8% OM, pH 6.6) > sandy loam (2.5% OM, pH 6.8) > sand
    (0.7% OM, pH 7). Desorption occurred in greatest amounts from sand
    > sandy loam > sediment. Leachability studies were consistent with
    the adsorption/desorption results and a water solubility of
    40 mg/litre. Carbaryl leached more from the sand than from the
    organic soil.

         In another adsorption/desorption study on carbaryl on sand,
    sandy loam, silt loam, silty clay loam, and on aquatic sediment
    using batch equilibrium techniques, Chib (1985a) concluded that
    carbaryl binds strongly to soil/sediment matrices. This depends on
    the carbaryl concentration in solution (the more in solution, the
    more on soil) and on the organic content of soil. Desorption
    isotherms for carbaryl at low concentrations were nearly flat with
    all soils, indicating that carbaryl was tightly bound to the
    substrates and difficult to move.

         The transport of carbaryl in the soil was also studied under
    natural conditions. High-volume rainfall occurring shortly after
    carbaryl has been applied to a field can generate the low-level
    transport of the pesticide to non-target areas (Caro  et al.,
    1974). Carbaryl is adsorbed on soil surfaces to a great extent.
    Laboratory measurements of absorption isotherms gave a Freundlich k
    value of 2.2. Of the 4 kg of carbaryl applied in a watershed, only
    5.77 g (0.16%) were found in run-off water and sediment during the
    season; (75 and 25% of the seasonal loss, respectively). The
    distribution coefficient between sediment and water was 0.33.
    Carbaryl had completely disappeared from the sediment by day 70, but
    still remained in the water at low concentrations.

         Carbaryl could still be found in the soil, 1-2 years after
    application at 2 kg 85% WP/ha. It is carried by rainfall and
    cultivation from the surface layers of the soil into the deeper
    layers. During the first few days after application, it was found in
    the root zone. After 3 months, 90% of the carbaryl was present in
    the surface layers, and, after 300 days, it was found in the soil at
    a depth of 60-70 cm. Rainfall was not specified (Molozhanova, 1968).

         Carbaryl was applied to a sandy loam field plot at a dose of
    25.4 kg/ha. A shallow water table was present at 1.1 m depth
    (LaFleur, 1976b). Rainfall during the following 16 months was
    182 cm. After this length of time, the upper 1 m contained 6% of the
    applied carbaryl. No carbaryl was found in the 0-20 cm layer after
    the fourth month. The half-life of carbaryl in the upper 1 m was >1
    month. Carbaryl appeared in the underlying groundwater within 2
    months following treatment and could be detected through the eighth
    month. The maximum groundwater concentration occurred at the end of
    the second month (about 60 µg/litre). The dose rate was more than 10
    times the usual one and the persistence was overestimated, as well
    as the residues that might be present in shallow groundwater.

         Norris (1991) reported a terrestrial field soil dissipation
    study conducted with carbaryl under actual use conditions. Carbaryl
    was applied to broccoli in California at 2.24 kg/ha, five times, on
    a weekly schedule. It was also applied once to sweet corn in North
    Carolina at a rate of 7.12 kg a.i./ha. The half-life in soil was
    estimated to be 6-12 days at the California site and about 4.8 days
    at the North Carolina site. Carbaryl residues were found mainly at a
    depth of 0-15 cm, which indicates that carbaryl has a low potential
    for leaching through the soil profile under typical agronomic
    practices.

    4.3.2  Transformation

         Degradation of carbaryl in soil occurs as a result of the
    activity of microorganisms, and through physical and chemical
    effects. It undergoes hydrolysis, oxidation, and other chemical
    processes and, on the surface of the soil, is subjected to

    photolysis. When applied at the usual doses, carbaryl has a short
    persistence in soil. In the field, under temperate and warm climatic
    conditions, the half-life of carbaryl in the soil does not exceed
    one month (Table 7).

    4.3.2.1  Photolysis in soil

         Studies have been conducted on the photolysis of carbaryl in
    soil. In one study, volatile substances were first identified and
    quantified and then soil TLC plates were used over a 30-day period
    to quantify degradation products (Chib, 1986b). The calculated
    half-life of carbaryl in sandy loam soil on TLC plates irradiated
    with a high-pressure mercury vapour lamp (200 watt, Hanovia) at
    25 °C was 2.5 days. In controls kept in the dark, labelled carbaryl
    degraded with a half-life of >30 days. CO2 was the only major
    volatile degradation product from all treatments. The other soil
    degradation products identified were 5-hydroxy carbaryl,
     N-hydroxymethyl carbaryl and 1-naphthol. Only carbaryl and
    1-naphthol were present in control soil extracts. The degradation
    products in the irradiated soil extracts suggest that hydrolysis and
    oxidation are the main mechanisms in the degradation of carbaryl
    under soil photolysis conditions.

         Das (1990b) also studied the photolysis of carbaryl in soil.
    Labelled carbaryl was applied to a sandy loam on plates
    (9.8±0.3 mg/kg) and maintained in artificial sunlight,
    intermittently (12 h irradiation + 12 h darkness) for 30 days. The
    measured irradiance of the artificial sunlight (502.6 watts/m2)
    was comparable to the natural sunlight (545.8 watts/m2). The
    evolution of volatile substances was also monitored. Controls were
    incubated in the dark. The calculated half-life of irradiated
    samples was 41 days (each day 12 h irradiation + 12 h darkness). No
    major metabolites were formed under irradiated conditions.

    4.3.3  Biotransformation in soil

         The persistence and metabolism of 14C-carbaryl (200 mg/kg)
    was studied in 5 different soil types by Kazano  et al. (1972).
    Persistence was influenced by soil type, and the production of
    14CO2 varied from 2.2% (loamy sand) to 37.4% (clay loam) of the
    initial radioactivity during 32 days of incubation at 25 °C. The
    amount of radioactivity left in the soil after extraction was
    proportional to the soil organic matter content. A significant
    amount (17-57%) of the remaining radiolabel could not be extracted
    with organic solvents. Analysis of the extractable residues
    indicated the presence of 1-naphthyl  N-hydroxymethylcarbamate,
    4-hydroxy-1-naphthyl methylcarbamate and 5-hydroxy-1-naphthyl
    methylcarbamate, but these were not confirmed. The main pathway of
    degradation in soil was probably hydrolysis of the carbamate
    linkage, producing CO2 and the corresponding phenol, though it is
    possible that hydroxylation of the ring or the methyl carbon

    precedes hydrolysis. 1-Naphthol decomposed more rapidly in clay than
    in sandy loam. Most of the radioactivity (83-92%) was recovered in
    the soils after 60 days of incubation. 1-Naphthol was immobilized on
    humic substances in the soil, not by mechanical adsorption, but by
    chemical bonding. Four metabolites (coumarin, the others not
    identified) were also produced by a soil  Pseudomonas.

         Gill & Yeoh (1980) studied the degradation of carbaryl in an
    extract of flooded paddy field soil (pH 3.7-4.8, organic matter
    content 0.5-3%, very high clay content) extract and in the paddy
    fish ( Trichogaster pectoralis). Under flooded conditions, the soil
    half-life of carbaryl was about 7 weeks. The major significant
    metabolite was 1-naphthol. Soil moisture plays an important role in
    the extent of degradation since, under flooded conditions and 100%
    field capacity, the degradation of carbaryl was more extensive than
    under 0 and 50% field capacity, providing more evidence that
    microorganisms play an important role in carbaryl degradation in
    paddy-field soil. Where sufficient moisture is available, oxidative
    mechanisms become important giving rise to ring and  N-methyl
    hydroxylation in addition to cleavage of the carbonyl moiety, a
    common pathway of carbaryl metabolism. Carbaryl was also found to be
    more persistent in acidic soil than in alluvial soil.

         Rajagopal  et al. (1983) measured the residues of carbaryl and
    of the 1-naphthol metabolite in 3 flooded soils (organic matter
    0.54-1.61%, pH 6.2-9.5) following three applications of the test
    substance. Samples received either 1, 2, or 3 applications of
    carbaryl in aqueous solution. The concentration of carbaryl
    decreased with incubation time in all soils. The disappearance of
    the first 50% of the substance in all soils ranged from 10 to 15
    days. Subsequent samplings provided evidence for the enrichment of
    carbaryl-degrading microorganisms in retreated soils. Thus, the
    disappearance time for 75% of the compound was 20-26 days for 3
    applications, 28-30 days for 2 applications, and >30 days for 1
    application. It appears that carbaryl degradation under flooded
    conditions does not follow a clear kinetic pattern (e.g., first
    order). However, the first order degradation rates were similar for
    the first, second, and third applications for 0-10 days. Degradation
    proceeded by hydrolysis with 1-naphthol as the major product, the
    amounts formed decreasing with incubation time in 2 out of the 3
    soils. The disappearance of 1-naphthol was faster in retreated soils
    and may not be attributed only to degradation, because significant
    amounts of 1-naphthol may be bound to humic substances, especially
    in soils with a high organic matter content.

         The persistence of carbaryl was studied in 4 soils under
    flooded conditions by Venkateswarlu  et al. (1980). They recovered
    a substantial portion of carbaryl from all soils 15 days after
    application. The recovery ranged from 37% in an alluvial soil to 73%
    in an acid sulfate soil. They concluded that flooded conditions
    enhance carbaryl degradation.

         The metabolism of 14C-carbaryl and 14C-1-naphthol in moist
    and flooded soils was studied by Murthy & Raghu (1989) in a
    continuous flow-through system, over a period of 28 days, permitting
    a 14C-mass balance. The percentage distribution of radiocarbon in
    organic volatile compounds, CO2, and extractable and
    non-extractable (bound) fractions of soils was determined. Organic
    volatile compounds could not be detected in either carbaryl- or
    1-naphthol-treated soils. More 14CO2 (25.6%) was evolved from
    moist than from flooded soil (15.1%), treated with carbaryl. The
    mineralization of14C-1-naphthol was negligible. The level of
    extractable radiocarbon was higher (5.5%) in flooded soil treated
    with carbaryl. Less than 1% was the parent compound, and carbaryl
    was mainly metabolized to 5-hydroxycarbaryl in moist soil and to
    4- and 5-hydroxycarbaryl in flooded soil. The extractable
    radiocarbon amounted to 18.2% and 24.3% in moist and flooded soils,
    respectively, and there was less than 1% of the parent compound with
    1-naphthol treatment. Most of the 14C was found as soil-bound
    residues, levels being higher with 1-naphthol treatment than with
    carbaryl. The humus fraction of the soil organic matter contributed
    most to soil-bound residues of both carbaryl and 1-naphthol.

         Aerobic and anaerobic soil metabolism studies were conducted
    with carbaryl applied to sandy and clay loam soils in the dark
    (Wilkes  et al., 1977; Khasawinah, 1978). Under aerobic conditions
    at room temperatures (23-25 °C), the half-life of carbaryl was
    approximately 9-17 days in sandy loam soil (Texas) and 21-27 days in
    clay loam (California). Lower temperature (15 °C) nearly doubled its
    half-life. The only solvent-extractable apolar material was parent
    carbaryl. A major proportion of the radioactivity initially applied
    to the soil was lost as CO2. It appears that, under aerobic
    conditions, carbaryl was degraded so that 1-naphthol carbon was lost
    as CO2, or it was incorporated into the organic matter of the soil
    (1-naphthol was not detected). After 112 days, carbaryl levels
    declined to 3.6% (average in Texas soil) and 15% (average in
    California soil) of the initial application.

         In an aerobic, soil study conducted by Miller (1990) with a
    sandy loam soil from North Carolina, soil was incubated with
    labelled carbaryl in the dark and maintained at 25±1 °C. The
    concentration of the parent compound rapidly decreased to a mean
    value of 11.9% of the applied dose by day 14. A significant amount
    of radioactivity was recovered as CO2. The average maximum value
    of CO2 was 59.8% by day 14. The only other major degradation
    product was 1-naphthol (maximum concentration of 34.9% of applied
    dose by day 1). Base hydrolysis released 41% of the unextractable
    residue. Carbaryl rapidly degraded under aerobic conditions with a
    half-life of 5.5 days.

         Murthy & Raghu (1991) studied the fate of carbaryl in the soil
    environment as a function of pH, with respect to the formation of
    extractable and non-extractable (soil-bound) residues. Soil samples

    (sandy clay, sandy loam, and clay) containing C14-carbaryl
    (10 mg/kg) were incubated at 28-30 °C for periods ranging from 7 to
    56 days. More 14C-residues could be extracted from sandy clay and
    sandy loam than from clay soil, under both moist and flooded
    conditions. In general, flooding had no influence on the extractable
    14C-residues. Thin-layer chromatography of chloroform extracts
    revealed the presence of carbaryl and 1-naphthol. At the end of 56
    days, the percentage of carbaryl recovered was 32.1, 6.4, and 1% in
    sandy clay (pH 4.2), sandy loam (pH 6.8), and clay soils (pH 8.3),
    respectively. The authors considered that there appeared to be a
    correlation between soil pH and soil-bound residue formation as an
    increase in soil pH was reflected in increased bound residues. The
    humin portion of soil organic matter accounted for most of the
    14C-residues. Low recoveries in sandy clay and in sandy loam soils
    may stem from the possible mineralization of carbaryl.

         Carbaryl persistence in the soil was studied under normal
    conditions of application (Caro  et al., 1974) of 5.03 kg/ha in
    granules applied in corn seed furrows. About 135 days were required
    for 95% of the carbaryl to disappear (Fig. 1). The pesticide
    remained stable in the soil for 25 days (in some cases, more than
    116 days) and then decayed rapidly. This decay is an indirect
    indication of microbiological degradation.

         This hypothesis is sustained by the finding that the stability
    of carbaryl in the soil is affected by the nature of the treatments
    applied during the period preceding its application. In soil that
    had been treated with carbaryl 6 months before sampling, more than
    70% of the added radiolabelled carbaryl was degraded after 4 days,
    measured by the disappearance of radioactivity. Only 10% was lost in
    orchard soil that had been treated for 15 years with various
    pesticides, and only 3% was lost in soil that had never been treated
    with pesticides. It appeared that soil that was treated with
    carbaryl for 6 months increased the ability of the microorganisms to
    degrade carbaryl (Rodriguez & Dorough, 1977).

         Carbaryl was applied in soil at an agricultural rate and
    incorporated to a depth of 6 inches (15 cm) (Heywood, 1975). At 28
    days after treatment, 63% of the applied dose appeared as CO2 and
    the identifiable residual carbaryl was about 6% of that applied.

    FIGURE 1

         In India, degradation of carbaryl was studied in a greenhouse
    by Brahmaprakash & Sethunathan (1984, 1985). Since a soil planted
    with crops may be more dynamic and complex than unplanted soil,
    because of increased microbial activity, they studied carbaryl
    persistence in soil (pH 6.2, organic matter 1.6%) planted with rice
    in a greenhouse, under flooded and non-flooded conditions. Carbaryl
    disappeared more rapidly from soils planted with rice than from
    those without rice, under both flooded and non-flooded conditions.
    The amount of carbaryl decreased to between 30.2 and 32.1% of the
    original level within 30 days in unplanted soil under both flooded
    and non-flooded conditions. During this same period, the carbaryl
    concentration decreased to 17-18% of the original level in planted
    soil under both water regimes. Degradation occurred by hydrolysis,
    but there was no appreciable difference in the rates of degradation
    between flooded and non-flooded soils. The rate of degradation of
    carbaryl was little affected by moisture. Further degradation of
    1-naphthol was slow in both planted and unplanted systems. A
    significant portion of the ring-14C accumulated in the soil as
    1-naphthol and soil-bound residues. Evolution of 14CO2 from the
    labelled side-chain and ring was negligible, even in soil planted to
    rice.

    4.3.4  Degradation by microorganisms

         Many studies have demonstrated the great ability of
    microorganisms to degrade carbaryl in the soil, and for some of
    them, to use it as a sole source of carbon. The most frequently
    identified organisms are bacteria ( Pseudomonas phaseolicola, P.
     cepaphia, Rhodococcus sp.,  Nocardia sp.,  Xanthomonas sp.,
     Achromobacter sp.) and fungi ( Aspergillus niger, A. terreus,
     Fusarium solani, Gilocladium roseum, Rhizoctonia solani, R.
     practicola, Penicillium sp.,  Mucor sp.,  Rhizopus sp.). In many
    cases, it was demonstrated that the persistence of carbaryl in the
    soil decreased after a first application, which was interpreted as
    the selection and build-up of strains more capable of degrading the
    product. The same process may also explain that, in some studies,
    the rapidity of degradation suddenly rose after a lag period during
    which only minor amounts of carbaryl degraded.

         Tewfik & Hamdi (1970) mentioned that carbaryl was decomposed
    into 4 distinct compounds by a soil bacterium designated as S-1.
    They considered that this soil bacterium might utilize carbaryl in a

    similar way to  Pseudomonas sp., which metabolize naphthalene via
    the salicylate pathway.

         Zuberi & Zubairi (1971) also reported that carbaryl is degraded
    by soil microflora.  Pseudomonas phaseolicola and  Aspergillus
     niger hydrolysed carbaryl to 1-naphthol. In the case of  P.
     phaseolicola, an unidentified minor metabolite was also detected.

         Larkin & Day (1986) reported that 2 bacteria isolated from
    garden soil,  Pseudomonas sp. (NCIB 12042) and  Rhodococcus sp.
    (NCIB 12038), could grow on carbaryl as the sole source of carbon
    and nitrogen at pH 6.8, but failed to metabolize carbaryl rapidly.
    Both could use 1-naphthol as the sole source of carbon and
    metabolize it via salicylic acid. Strain NCIB 12038 produced also
    gentisic acid.  Pseudomonas sp. (NCIB 12043), in a soil perfusion
    column enrichment at pH 5.2, metabolized carbaryl rapidly to
    1-naphthol and methylamine. 1-Naphthol itself was metabolized via
    gentisic acid. A possible pathway for the catabolism of carbaryl and
    1-naphthol was proposed.

         Walker  et al. (1975a), working with  Pseudomonas sp.,
    observed degradation of 1-naphthol and suggested that carbaryl could
    serve as the sole source of nitrogen and carbon for bacteria. It was
    also noted that the presence of another nitrogen source in the media
    seemed to have a delaying effect on metabolism of carbaryl.

         Bacterial communities of at least 12 and 14 members were
    selected in continuous culture using carbaryl as the sole source of
    carbon and nitrogen at pH 6. These communities were supported by the
    slow formation of hydrolysis products and no carbaryl-degrading
    bacterium was selected after more than 83 days. When using equimolar
    1-naphthol and methylamine as the sole source of carbon and
    nitrogen, a bacterial community of at least 8 members was selected.
    After a lag of 10-50 days, soil perfusion columns (pH 5.2) and
    continuous culture enrichments (pH 5) led to the selection of a
     Pseudomonas sp. that could utilize carbaryl as its sole carbon and
    nitrogen source (Larkin & Day, 1985).

         Sud  et al. (1972) showed that  Achromobacter sp. also
    utilized carbaryl as the sole source of carbon in a salt medium.
    Four degradation products of carbaryl were 1-naphthol, hydroquinone,

    catechole, and pyruvate. The organism also grew well in the first 3
    degradation products.

         The rate of degradation of carbaryl after 1, 2, and 3
    applications to 3 submerged soils was examined by Rajagopal  et al.
    (1983). Soils that had been pretreated with carbaryl were able to
    degrade carbaryl more rapidly than those without pretreatment. The
    enrichment culture was inactivated upon autoclaving. The
    concentration of carbaryl decreased in the mineral medium inoculated
    with the enrichment cultures from the 3 soils, especially when it
    served as the sole source of both carbon and nitrogen.

         Rajagopal  et al. (1984) studied the metabolism of side-chain
    and ring 14C-labelled carbaryl in a mineral salts medium by soil
    enrichment cultures. Hydrolysis was the major route of microbial
    degradation. During carbaryl degradation by enrichment cultures and
     Bacillus sp., 1-naphthol and 1,4-naphthoquinone accumulated in the
    medium.

         Rajagopal  et al. (1986) also observed that carbaryl
    disappeared more rapidly from a laterite soil pretreated with
    1-naphthol than from a control soil never exposed to 1-naphthol. The
    accumulation of 1-naphthol and bound residues formed from
    added14C-carbaryl was greater in soils pretreated with 1-naphthol
    than in untreated soils.

         In experiments with the soil fungus  Rhizoctonia practicola,
    Bollag  et al. (1976) found that it could transform 1-naphthol from
    an ether-extractable to a water-soluble product. It was also
    observed that, after removal of the fungal cells, the growth medium
    possessed the ability to transform 1-naphthol, indicating activity
    of an extracellular enzyme. Attempts to analyse the labelled
    material in the aqueous phase indicated that the radioactivity was
    associated with a compound of comparatively high relative molecular
    mass.

         Czaplicki & Bollag (1975) exposed 1-naphthol to  Rhizoctonia
     solani, isolated from soil, and found that it was completely
    transformed to a compound not extractable with ether.

         Working with the soil fungus  Aspergillus terreus, Liu &
    Bollag (1971b) investigated the metabolic transformation of carbaryl

    through 1-naphthyl- N-hydroxymethylcarbamate and tried to clarify
    the pathway of the side-chain. The next intermediate in biological
    transformation was 1-naphthyl carbamate, which was further degraded
    to 1-naphthol. Within one week, approximately half the amount of
    carbaryl was transformed to these other metabolic products. No
    attempt was made to clarify whether the formation of 1-naphthol was
    the result of the biological or the chemical degradation of
    1-naphthylcarbamate, but there were clear indications that
    1-naphthol was metabolized further in the presence of  A. terreus.

          In vitro studies were carried out to investigate the
    degradation of carbaryl by soil microorganisms. Three isolates from
    soil, including  Fusarium solani, a Gram-negative coccus, and a
    Gram-positive rod, accelerated the hydrolysis of carbaryl to
    1-naphthol and other intermediates.  Fusarium solani was the most
    effective in decomposing the 14C-labelled compound. Radioactivity
    decreased by 24% during the first 5 days and by 82% during 12 days
    in a growing culture after inoculation. A mixture of two or three of
    the microorganisms was more effective in decomposing carbaryl and
    1-naphthol (Bollag & Liu, 1971).

         Bollag & Liu (1972a) studied the biological degradation of
    14C-1-naphthol during growth, with replacement cultures and cell
    extracts of  Fusarium solani. The radioactivity of 1-naphthol
    disappeared partially during growth, but it was completely
    dissipated by cell extract activity. The cell extract of  F. solani
    degraded more than 80% of the 1-naphthol to form CO2 within 60 min
    of incubation, but it was not possible to identify intermediates.
    This implies rupture of the naphthol ring. No difference in activity
    could be observed between cell-free extracts from the spores or the
    mycelium of the fungus at pH 5.7 and 7.2. The enzyme system was
    relatively stable since there was no decrease in activity after the
    cell extract was stored at -10 °C during 4 months. The enzyme that
    participated in the degradation reaction was constitutive (always
    present) as shown by cell extracts prepared from cells grown in a
    medium with, or without, carbaryl as substrate.

         The fungus  Gliocladium roseum, isolated from soil by Liu &
    Bollag (1971a), metabolized carbaryl to 3 metabolites which were
    identified as 1-naphthyl- N-hydroxy methylcarbamate,
    4-hydroxy-1-naphthyl methylcarbamate, and 5-hydroxy-1-naphthyl

    methyl-carbamate. It was therefore considered that  N-alkyl- and
    aromatic ring-hydroxylation of carbaryl were important detoxication
    reactions of  G. roseum. About 70% of the radioactivity was
    recovered as carbaryl from an 11-day-old culture. The decrease in
    radioactivity from the growth medium containing side-chain labelled
    carbaryl indicated that a further degradation of the formed
    metabolites occurred, or that an additional pathway was involved in
    the degradation of carbaryl by  G. roseum.

         Bollag & Liu (1972b) reported that most soil fungi
    ( Penicillium sp.,  Mucor sp.,  Rhizopus sp., and  Aspergillus
    sp. except  A. fumigatus), could hydroxylate carbaryl at different
    positions, but that the products differed qualitatively as well as
    quantitatively with the various fungi.

         In a different study, the enzyme or protein fraction
    (extracellular phenol oxidase) of the culture filtrate from
     Rhizoctonia practicola as chromatographed on a column of Sephadex
    G-200 and fractions were obtained that were able to transform
    1-naphthol as a substrate (Sjoblad  et al., 1976). The enzyme
    catalysed the polymerization of 1-naphthol to several products.

         Biological oxidation and coupling of phenols are key reactions
    in nature, that result in the formation of products such as lignins,
    melanins, tannins, alkaloids, and humus compounds. Thus, it can be
    assumed that enzymes interact with xenobiotic phenols that are
    incorporated into soil or sediment organic matter.  Rhizoctonia
     practicola (and an extracellular enzyme) was able to polymerize
    1-naphthol (dimers, trimer, tetramer) (Bollag  et al., 1978).

         Rodriguez & Dorough (1977) studied the persistence of carbaryl
    in culture media in the presence of mixed and pure cultures of
    bacteria and fungi isolated from soil. All fungi ( Fusarium,
     Penicillium, Aspergillus, and one unidentified species), isolated
    from a soil treated with carbaryl six months before sampling,
    produced at least one metabolite from carbaryl. After 14 days of
    incubation, 54-79% of the carbaryl was recovered intact, and there
    was little formation of carbon dioxide by the fungi. In contrast,
    related experiments with bacterial isolates ( Arthrobacter,
     Nocardia, Pseudomonas, Xanthomonas, and  Bacillus) from the same
    soil showed that only 1-9% of the added carbaryl remained
    unconverted ( Arthrobacter was the exception with 59.1% remaining
    carbaryl). Controls showed that non-biological degradation also

     occurred. Bacteria, like fungi, metabolized carbaryl qualitatively
    in the manner observed with natural soil populations. However,
    quantitative differences were so great that the use of isolates may
    be of little value in estimating the degradation rate of carbaryl
    and other pesticides in field soil. This is important to note when
    conducting microbial degradation studies in the laboratory.

         Bollag (1979) summarized the transformations of carbaryl by
    microbial activity. It was possible to isolate several
    microorganisms capable of hydrolising carbaryl to 1-naphthol. In
    addition,  Gliocladium roseum showed the formation of:

         4-hydroxy-1-naphthyl  N-methylcarbamate
         5-hydroxy-1-naphthyl  N-methylcarbamate
         1-naphthyl  N-hydroxy-methylcarbamate.

    Other terrestrial fungi hydroxylated carbaryl at different
    positions, but the products differed quantitatively and
    qualitatively with the various fungi. Subsequent metabolic
    transformation of the hydroxylated products differed considerably.
    With  A. terreus, the following products were obtained:

         1-naphthyl  N-hydroxy-methylcarbamate -->
            1-naphthyl-carbamate --> 1-naphthol

         Several bacteria isolated from river water were capable of
    degrading 1-naphthol. At least two different pathways were involved.
    The first was a complete degradation with the release of CO2, the
    second produced principally 4-hydroxy-1-tetralone, which may involve
    hydroxylation of the naphthyl ring in the 4 position and conversion
    to an aliphatic cyclic compound. Such a pathway has also been
    described with a soil  Pseudomonas by Walker  et al. (1975a) and
    Davis & Evans (1964).

    4.3.5  Persistence in soil

         Carbaryl is not usually applied as a soil treatment, therefore,
    the amounts of carbaryl that may reach the soil come principally
    from spray drift, or from washing off treated crops by rain.

         When applied at the usual doses, in the laboratory, carbaryl
    has a short persistence (half-life <40 days and usually from 6-20
    days), but this may increase when the soil is flooded, or when the
    dose is increased. In field studies, the half-life of carbaryl,
    applied at the usual dose rates, in warm or temperate climatic
    conditions, did not exceed one month in the soil. The results of
    laboratory and field studies on the persistence of carbaryl in soil
    are summarized in Table 7.


    
    Table 7.  Half-life of carbaryl in soil, calculated from experimental laboratory
              and field results
                                                                                                            

    Origin of soil             Number      Degradation    Half-life    References
                               of days         (%)         (days)
                                                                                                            

    Laboratory                   40            100            8        Johnson & Stansbury (1965)

    Laboratory 0.5 mg/kg         45            77            20        Molozhanova & Kanevskij (1971)

    Laboratory 1 mg/kg           45            53            40

    Laboratory 10 mg/kg          45            13

    Laboratory                   30           55-63         < 20       Flores-Ruegg et al. (1980)

    Laboratory (flooded)         15           63-27         10-40      Venkatesvarlu et al. (1980)

    Laboratory                   53            100           < 8       Odeyemi (1982)

    Orchard                     184            99            30        Ivanova & Molozhanova (1973)

    Corn                        135            95            30        Caro et al. (1974)

    Pretreated soil               4            70            < 3       Rodriguez & Dorough (1977)

    Grain cropa                  30           53-31         27-55      Gangwar et al. (1978a)

    Corn soilb                    5           42-56           5        Kavadia et al. (1978)

    Potatoes                     50           < 99           < 7       Kovaleva & Talamov (1978b)

      -                          30            96             6
                                                                                                            

    Table 7 (continued)

                                                                                                            
    Origin of soil           Number        Degradation    Half-life    References
                            of days            (%)         (days)
                                                                                                            

    Unspecified                                              90        Czaplicki (1979)

    Tropical                                                  7        Rajukkannu et al. (1985)

    Sesamum                      60            56            50        Yadav et al. (1985)

    Bare soil                                                < 4       Davis (1986a)

    Bare soil                                               1-13

    Forest                                                   1.5       Sundaram & Szeto (1987)

    Forest                       90           < 78          < 38       Springborn (1988b,c)

    Forest                       90           < 90          < 24

    Flooded rice                180           (56)                     Springborn (1988a)

    Flooded rice                180           (52)

    Broccoli                                                6-12       Norris (1991)

    Sweet corn                                                5
                                                                                                            

    a20-60 kg/ha.
    b15-45 kg/ha.


    
         Johnson & Stansbury (1965) calculated a half-life of
    approxi-mately 8 days in an agricultural soil (sandy loam, pH 5.5)
    treated at 3 concentrations. Residues of carbaryl appeared to be
    completely degraded within 40 days.

         The considerable influence of the dose rate on the persistence
    of carbaryl in soil was demonstrated by Molozhanova & Kanevskij
    (1971). The percentages of the initial quantities that were degraded
    45 days after treatment are shown in Table 8.

    Table 8.  Degradation rate of carbaryl in relation to the dose

                Initial dose              Degradation (%)
                   (mg/kg)
                                                                 
                     0.5                      77

                     1                        53

                     1.5                      37.3

                     2                        30

                     2.5                      27

                     3                        23

                     4                        20

                     6                        16.7

                     8                        15

                    10                        13.2
                                                                 

         The same authors also demonstrated the influence of the type of
    soil on the degradation of carbaryl. Forty-five days after
    treatment, about 50% degradation was observed in light grey forestry
    soil, and only about 20% in peat. The ability of soils to degrade
    carbaryl could be ranked as follows: light grey > grey forestry >
    turf podzol > southern chernozeme > ordinary chernozeme > meadow
    > peat.

         Ivanova & Molozhanova (1973) calculated that application of
    1.36 kg carbaryl/ha in an orchard resulted in 19.7% being retained
    in the soil; 99% of the carbaryl present in soil disappeared within
    184 days.

         Czaplicki (1979) conducted studies in Poland. The soil
    half-life of carbaryl was about 3 months and 90% degradation

    occurred within 18 months. From October to March, when the soil
    temperature was <5-8 °C, the disappearance of the insecticides in
    the soil almost stopped.

         Rajukkannu  et al. (1985) studied the persistence of 4
    products in the red and black soils of Tamil Nadu (India), where the
    tropical climate in conjunction with the soil properties shortened
    the persistence of insecticides. The half-life of carbaryl was 6.7-7
    days and 95% degradation was achieved after 90 days.

         It was reported by Odeyemi (1982) that carbaryl disappeared
    from soil samples treated with 45 mg/kg after 53 days incubation in
    a greenhouse under tropical conditions (Nigeria).

    4.3.6  Interaction with other physical, chemical, or biological
           factors

         Nitrogen fertilizers (ammonium sulfate and urea) increased the
    persistence of carbaryl in flooded laterite soil with a low native
    content of nitrogen (0.04%). In the alluvial soil with 0.11% total
    nitrogen, the persistence of the insecticides was little affected.
    The rates of degradation in the two soils treated with nitrogen
    fertilizers were almost identical. The authors speculated about the
    mechanism of this effect, which was possibly due to the preferential
    utilization of inorganic nitrogen by microorganisms, or to the
    inhibition of soil hydrolase activity (Rajagopal & Sethunathan,
    1984).

    4.3.7  Vegetation

    4.3.7.1  Uptake and transformation in plants

         Carbaryl from soil treated at about 50 times the usual dose
    penetrated into apple trees and couch-grass (Molozhanova, 1968).
    Three months after application of carbaryl (85%) to soil at a dose
    of 100 mg/kg, residues of carbaryl were detected in the roots and
    stems in apples (39-13 mg/kg) and in couch-grass (50-38 mg/kg).
    Under the same conditions, no residues were detected in tomato
    fruits or in wheat grain, but 5.9 mg/kg were detected in potatoes
    (Table 9).

        Table 9.  Migration of carbaryl from the soil into apple trees at
              different times following applicationa

                                                                       

    Experimental           Sampling day   Carbaryl content of samplesb
    conditions                 after      (mg/kg)
                           application
                                          Soil      Foliage     Fruits
                                                                       

    85% WP carbaryl              5         9.3        0            -
    applied under each
    tree at a rate of           12         6.8        0            -
    10 mg a.i./kg soil
                                19         6.0        5.0          -

                                56         4.4        0.04        4.4

                               138         2.1        0            -
                                                                       

    aFrom: Molozhanova (1968).
    bAverage data from 18 samples are given for each case.
    
         Huque (1972) reported that 14C-labelled carbaryl was readily
    taken up from granules by 2-week-old rice plants. After 3 days, a
    level of about 100 mg/kg was determined in the plant (excluding the
    roots). Residues then decreased to about 15 mg/kg after 18 days.

         Ferreira & Seiber (1981) studied the uptake and distribution of
    carbaryl in rice seedlings following exposure of the roots to the
    insecticide. Carbaryl was rapidly absorbed and transported upwards
    to the leaves and stems. After exposure was terminated, the major
    route of loss of carbaryl was through root exudation (22%) rather
    than volatilization from the leaves (4.2%). However, since most of
    the remaining carbaryl in the plant was present on the leaf
    surfaces, the authors surmised that volatilization might play a
    greater role in pesticide loss over longer periods of time.

         14C-carbaryl and 14C-1-naphthol from soil-bound residues
    were partially released when barley was grown (Murthy & Raghu,
    1988). 14C-residues could be detected in both shoots and roots in
    the case of carbaryl treatment, while only roots showed
    14C-residues in the case of 1-naphthol.

         The rate of decomposition of carbaryl in plants depends on the
    climatic conditions. It is more rapidly decomposed in hot climates,
    at high temperatures, and by intensive ultraviolet radiation. Thus,
    residual levels in feed plants were lower in regions with a hot
    climate than in other regions (Atabaev, 1972).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

         Ambient air concentrations of carbaryl were measured before and
    after a treatment of a large area of forest in Maine, USA, to
    control spruce budworm. Concentrations in air ranged from less than
    0.0035 to 0.107 µg/m3 several miles away (Shehata  et al., 1984).

         Room concentrations of airborne carbaryl were measured
    following application for pest control as a 5% dust at an
    undetermined rate. The levels detected on the day of application,
    and 1, 2, or 3 days after application were 1.3, 0.2, 0.1, and 0.01
    µg/m3, respectively (Wright  et al., 1981).

    5.1.2  Water

         Carbaryl concentrations in water from different sources in the
    USSR were studied by Molozhanova (1970). Data are presented in Table
    10.

        Table 10.  Concentrations of carbaryl in watera

                                                                        

    Type of sample           Number of samples               Mean
                       Total      Carbaryl-containing   concentrations
                                      samples (%)         (mg/litre)
                                                                        

    Well               114                87                0.13

    Artesian water      64                70                0.16

    Ground water        24                75                0.27

    Dam                 90                47                0.02

    River               77                62                0.044

    Lake                84                85                0.03
                                                                        

    aFrom:  Molozhanova (1970).
    
         According to an earlier report by Molozhanova (1968), carbaryl
    was present in trace amounts up to a maximum level of 1 mg/litre in
    well water and reservoirs during carbaryl application (6 kg/ha, 85%
    WP).

         Water irrigation channels, situated at a distance of 200-300 m
    from a carbaryl-treated cotton field, contained from 0.01 to
    0.25 mg/litre up to 18 days after spraying at a dose of 2kg/ha
    (Guseynov, 1970).

         Residues of pesticides were monitored in the aquatic system of
    Ioannina basin (Greece) and its natural outlet, Kalamas River, for
    the period September 1984-October 1985 (Albanis  et al., 1986). The
    carbaryl concentration in water was found to follow a seasonal
    fluctuation with maxima during summer and minima during winter
    months. Mean and range values are summarized in Table 11.

        Table 11.  Mean and range values of carbaryl (ng/litre) on different
               sampling dates in the Ioannina basin
                                                                       

    Month of sampling     River         Canal         Lake
                                                                       

    September              0.5

    November              NDa                         NDa

    March                 NDa

    May                   ND

    June                                              NDa

    July                  23.7                        21.7

    August                                             2.3

    September              1.7                        NDa

    April                               NDa

    July                                8.8
                                                                       

    aND = not detected.
    
         An oil-based, carbaryl formulation (Sevin-2-oil) was applied
    twice to a coniferous forest in New Brunswick (Canada). At a dose
    rate of 280 g/ha, the highest concentration in stream water was
    0.314 mg/litre and only 0.123 mg/litre 0.5 h after spraying. More
    than 50% of the initial residues dissipated within 1 h (Sundaram &
    Szeto, 1987).

         Carbaryl was applied aerially as Sevin-4-oil (1.12 kg/ha) to
    aforest in Montana. Field samples of water were collected to study
    persistence. Residue levels in 4 streams sampled were variable
    (3-6, 3-175, 2-260, 4-108 µg/litre) 1.3-2.8 h after application
    (Pieper & Roberts, 1978; Pieper, 1979). Local accumulations of
    floating oil-based spray may have caused this variation. Grantham
    (1980) reported that carbaryl (Sevin-4-oil) levels were generally
    highest directly after spraying, but increased at some stream sites
    for 1-2 days after application. This was attributed to light rains,
    which washed the spray residue off the foliage and into the stream
    channel. However, Brown (1980) concluded that carbaryl enters
    streams in periodic doses and that rainfall dates are not related to
    the presence of residues in streams. Maximum residues of
    26.32 µg/litre were found in water 12 h after spraying, with no
    residues detectable in samples taken hourly until 36 h. Residues
    were found again in samples taken 2.5-3 days and 5.5-6.5 days after
    spraying.

         In a study where carbaryl (Sevin-4-oil) was applied aerially
    (0.84 kg/ha) to a forest in Maine, in 1978, samples were collected
    in 9 streams (Stanley & Trial, 1980). Peak concentrations occurred
    shortly after spraying and maximum residue levels ranged from 0.93
    to 7.8 µg/litre in brooks and from 0.44 to 2 µg/litre in rivers. In
    one stream, the maximum concentration was 16 µg/litre. Ott  et al.
    (1981) reported that carbaryl levels were highest on the day of
    spraying (2.7 µg/litre), declined to about 0.7 µg/litre by the third
    day, but increased again to about 1.2 µg/litre on day 5. No residues
    were detected in stream water samples taken on the 17th day.

         Thomas  et al. (1982) treated planted rice fields with
    carbaryl at rates of 0.63, 0.94, and 1.85 kg a.i./ha, either as a
    high volume spray (500 litre/ha) or as a low volume spray (150
    litre/ha), and monitored the residues. In irrigation water sampled
    one hour after treatment, carbaryl levels amounted to 0.15-0.30 and
    0.07-0.18 mg/litre, under high and low volume spraying,
    respectively. During the first 24 h after spraying, the
    concentration in the irrigation water remained fairly constant, but,
    by the fourth day, it had decreased significantly. By the tenth day
    after spraying the residues in water had decreased to 0.02-0.05 and
    0.03-0.04 mg/litre, respectively.

         A rice field dissipation study was conducted in Arkansas (USA)
    by Springborn (1988). Carbaryl (Sevin XLR) was applied 3 times at
    14-day intervals to an irrigated field plot in which rice was
    planted. In irrigation water, carbaryl residues disappeared with a
    half-life of <1 day after each treatment. The maximum concentration
    in water was 1466 µg/litre and, by day 3 following each treatment,
    the concentration was <121 µg/litre. In a similar study conducted
    in California, Springborn (1988a) found that carbaryl dissipated
    rapidly in irrigation water with a half-life of <1 day. The maximum
    concentration in water was 648 µg/litre. By day 3 following each
    treatment, the concentration was <27 µg/litre.

         Residues of 1-naphthol were found in the water collected from
    wells and ponds in and around Bhopal (India). The residues of
    1-naphthol in well water (near a manufacturing plant) ranged from
    0.002 to 0.024 mg/litre. In pond waters, the levels were found to be
    between 0.036-0.098 mg/litre. The level of 1-naphthol in soil
    samples was of the order of 0.153-0.656 mg/kg (Dikshith  et al.,
    1990).

    5.1.3  Soil

         Contamination of the soil occurs when carbaryl is used in
    agriculture. During the treatment period, levels of 1-3 mg
    carbaryl/kg were measured in the surface layer of the soil in the
    USSR (Molozhanova, 1968). Concentrations of 0.03-0.35 mg/kg were
    found in the surface layer of the soil up to 52 days after a single
    application of carbaryl at a rate of 2 kg/ha (Guseynov, 1970).
    Carbaryl levels in the soil varied depending on the type of soil
    (Table 12).

         Potatoes were sprayed with carbaryl at 4.25 kg/ha (5 kg Sevin
    WP, 85%/ha). One day, 10 days, and 2 months after treatment,
    residues in the soil under the potatoes were, respectively, 1.9,
    9.55, and 0.02 mg/kg (Kovaleva & Talamov, 1978b). When the soil was
    sprayed before sowing, the residues in the soil 1 day, 1 month, 4
    months, and 15 months after treatment were 1.5-2, 0.05-0.07,
    0.02-0.08, and 0.06 mg/kg, respectively. Within 100 and 150 days
    following soil incorporation of carbaryl (Sevin, 10 kg/ha), residues
    in non-planted soil decreased to 0.05 and 0.02 mg/kg, respectively
    (Kovaleva & Talanov, 1980).

    Table 12.  Carbaryl content in different types of soil during
               harvestinga
                                                                 

    Type of soil           Number of    Carbaryl concentration
                            samples             (mg/kg)
                                                                 

    Meadow-chernozem          200             2.22 ± 0.5

    Chernozem southern        766             1.01 ± 0.23

    Chernozem ordinary        288             1.09 ± 0.26

    Chenozem podzol           100             0.15 ± 0.04

    Turf-podzol               150             0.04 ± 0.01

    Grey-woodland             246             0.0
                                                                 
    aFrom:  Molozhanova (1970).

         Yadav  et al. (1985) detected 0.22 mg carbaryl/kg in the soil
    at harvest time, when sesamum ( Sesamum indicum) was sprayed twice
    with carbaryl (0.2%) on days 45 and 60 of crop growth (21 August and
    5 September). As residues in the soil after the first spray were
    about 0.65 mg/kg, the rate of reduction of residues in soil was 56%
    within 2 months. Shilova  et al. (1973) measured about 0.1 mg
    carbaryl/kg soil one month after treatment with carbaryl (5 kg/ha)
    against blood sucking insects in the subarctic.

         Gangwar  et al. (1978b) applied a 4% granular formulation to
    sandy loam planted with a grain crop (bajra) at very exaggerated
    application rates of 20, 40, and 60 kg a.i./ha. Initial residues of
    140-354 mg/kg decreased by a total of 31 to 53% within 30 days and
    95 to 98% within 90 days. Residues at 90 days were 2.68-17.49 mg/kg.

         Application of carbaryl granules at very high doses of 15, 30,
    and 45 kg/ha resulted in deposits of 232, 397, and 525 mg/kg,
    respectively, in soils cultivated with corn, and in 104-109,
    168-217, and 304-422 mg/kg, respectively, in clay loam soils
    cultivated with root crops (beet, radish, carrot). The dissipation
    rate of carbaryl residues from clay loam soil, in 5 days following
    the treatment, was 42-56% during autumn and 55-69% during spring.
    The highest residue levels sampled from all plots decreased to
    229.7, 142.9, 73.8, 33.8, 6.7, and 1.3 mg/kg on days 5, 10, 15, 30,
    60, and 100, respectively. Residues were below detectable levels in
    several plots by day 60 and in most plots by day 100 (Kavadia
     et al., 1978).

         According to Kuhr  et al. (1974), the dissipation of carbaryl
    in the soil of apple orchards is rapid. Soil residues of carbaryl
    had almost completely disappeared from the top 2 inches of soil in 2
    weeks. They were 13.8 mg/kg immediately after application and
    3 mg/kg, 1-2 days later.

         An oil-based carbaryl formulation (Sevin-2-oil) was applied
    twice by a fixed-wing aircraft to a coniferous forest in New
    Brunswick (Canada). Initial residue levels 1 h post-spray in litter
    and soil for both applications were, respectively, 1.21 and
    0.86 mg/kg and 0.78 and 0.48 mg/kg (Sundaram & Szeto, 1987).
    Relative to the amount sprayed, only a small amount of the chemical
    reached the litter and soil, probably because of canopy filtration.
    Within 1 day, an average of 40-45% of the initial residues was lost
    from litter and soil, respectively, indicating a rapid dissipation
    time of 1.5 days for the disappearance of 50% of the initial maximum
    concentration. Beyond 5 days, an average of 12% of the initial
    concentration remained in both the substrates.

         As already reported, two field dissipation studies were
    conducted by Springborn (1988b,c) with carbaryl (Sevin-4-oil)
    applied twice with a seven-day interval to forest. The first study
    was conducted in a coniferous Oregon forest. In soil from the
    treated site, carbaryl levels decreased from 0.196-3.877 mg/kg
    following the first application to 0.130-1.87 mg/kg, 3 days after
    treatment, and from 0.079-5.323 mg/kg following the second
    application to 0.242-1.187 mg/kg at 90 days. The second study was
    conducted in Pennsylvania. Carbaryl levels in soil decreased from
    0.022-0.068 mg/kg following the first application to
    <0.012-0.075 mg/kg, 3 days after treatment, and from
    0.11-0.932 mg/kg following the second application to
    0.01-0.099 mg/kg at 90 days.

         A rice field dissipation study was conducted in Arkansas (USA)
    by Springborn (1988a). Carbaryl (Sevin XLR) was applied 3 times, at
    14-day intervals, to an irrigated field plot in which rice was
    planted. In flooded soil, the concentration of carbaryl varied from
    <11 to 309 µg/kg throughout the study and was not directly related
    to application date. The carbaryl level was <11-309 µg/kg in soil
    following the first application and <11-129 µg/kg following the
    third application; 180 days later, carbaryl concentrations in the
    soil were 11-56 µg/kg.

         In a similar study conducted in California, under the same
    conditions, Springborn (1988) found that carbaryl dissipated rapidly
    in flooded soil. The concentration of carbaryl ranged from <11 to
    198 µg/kg throughout the study. Carbaryl was <11-23 µg/kg in soil
    at sampling intervals following the first application, and increased
    to <11-180 µg/kg following the third application; 180 days after
    the third application, carbaryl concentrations in the soil were
    11-88 µg/kg.

         A soil dissipation field study was conducted in 1985/1986 in
    California (sandy loam, pH 6.3) and Iowa (silt loam, pH 6.5) with
    carbaryl 80 S formulation (Davis, 1986a). Carbaryl was applied to
    strip plots of bare soil, 6 weeks later, 7 applications were made
    with intervals of about 5 days between applications. Soil sampling
    was performed before treatment, during treatment, and up to 6 months
    after the last application. No carbaryl residues were found in
    California pretreatment samples. After the last application,
    residues reached a maximum of 1.61 and 0.29 mg/kg in the 0-15 and
    15-30 cm samples, respectively. Fourteen days after the last
    application, carbaryl residues below the 15-cm level were less than
    the limit of quantification.

         It took 28 days for residues to dissipate completely from the
    top 15 cm. The half-life in California soil was calculated to be
    2.7-3.8 days.

    5.1.4  Food and animal feed

    5.1.4.1  Fruit, vegetables, and grain

         Contamination of vegetation by carbaryl occurs, either during
    spraying, or, by its migration through contaminated soil into the
    roots of plants.

         Residual levels of carbaryl after the spraying of plants depend
    on the type and species of the plants sprayed. Carbaryl levels of up
    to 30 mg/kg have been found in plants during the treatment period
    (Molozhanova, 1968). It has been found to be rather persistent in
    vegetables and fruits. Concentrations of 0.6-3.9 mg/kg were measured
    in lettuces 1 week after single or repeated sprayings, and levels up
    to 1 mg/kg were found in tomatoes treated according to requirements
    (Antonovich, 1970). In cabbage, initial residues after spraying
    ranged from 14.8 to 33.9 mg/kg, depending on the concen-tration
    used. After 7 days, the residues decreased to 2.5-5.13 mg/kg. In
    eggplant, the initial concentrations were 8.3-16.9, and 7 days
    later, 3.05-5.4 mg/kg. After washing, the concentrations decreased
    considerably to less than 3 mg/kg after day 7 (Mann & Chopra, 1969).

         Following application of carbaryl on cauliflower, in the form
    of dust (10%) at 1.5-2 kg a.i./ha or wettable powder (50%) at 0.75-1
    kg a.i./ha, the residues of carbaryl declined to 3.64-9.59 mg/kg
    within 8 days of treatment. The carbaryl deposits on leaves were
    between 19.45 and 42.08 mg/kg. Washing of cauliflower with plenty of
    water reduced the residues of carbaryl by 36-95%. A waiting period
    of 8 days has been suggested for cauliflower (Singh  et al., 1978).

         Persistence of carbaryl in brinjals and peas after spraying at
    1 and 2 kg a.i./ha was found to be 3.42 and 5.03 mg/kg respectively.
    Washing of vegetables with water within one hour and after a day of
    spraying reduced the level of deposits of carbaryl to about

    1.0 mg/kg level. In the case of pea pods, the levels of residues
    dropped to 0.20 mg/kg within 5 days. In pea seeds, the residue
    levels ranged between 0.03 and 0.09 mg/kg, after 8 days (Krishnaih
     et al., 1978).

         Measurements of carbaryl in different fruits were taken at
    intervals of 5-10 days after plants had been treated with a 0.2%
    suspension of carbaryl at 1000 litre/ha during the vegetation period
    (Bogomolova, 1968, 1970). The initial amount of carbaryl, 2 days
    after the treatment, varied in different fruits from 2.3 to
    2.7 mg/kg. Ten days later, the concentrations were reduced by
    50-70%, and, after 20 days, the levels were within the range of
    0.2-0.8 mg/kg, depending on the species (Table 13). According to
    Mann & Chopra (1969), the dissipation of carbaryl from plants after
    the first day of spraying was about 40-45% of the initial residue.

         In apples, concentrations of 2.5-2.9 mg/kg, 0.4-2.4 mg/kg, and
    0.15 mg/kg were found on days 7, 10, and 38, respectively, after
    spraying. One to two months after spraying apples with a 0.1%
    suspension at a dose of 2000 litre/ha, residues of 0.08-0.10 mg/kg
    were measured (Antonovich, 1970). Four months after spraying with a
    0.06% suspension at a dose of 9 kg a.i./ha, levels in the range of
    0.09-0.24 mg/kg were found in apples, depending on the spraying
    procedure. Fine-droplet spraying resulted in residue levels 2.5-3
    times lower levels than those with coarse-droplet sprays (Atabaev,
    1972).

    Table 13.  Carbaryl levels in different fruits after spraying
               during vegetation (mg/kg)a
                                                                

    Kind of fruit                Day after spraying

                             2           10           20
                                                                

    Strawberries           2.3          1.25

    Gooseberries           2.5          0.90        0.6

    Blackcurrants          2.4          1.10        0.8

    Cherries               2.7          1.90        0.2-0.4

    Plums                  2.4          1.40        0.2-0.4
                                                                

    aFrom:  Bogomolova (1968).

         A survey of apples grown in Ontario, Canada, between 1978 and
    1986 showed that out of 22% of carbaryl-treated apples (1.67 kg/ha)
    sold, 3.6% had detectable carbaryl residues (detection limit of
    0.01 mg/kg), and that the average residue level was 0.03 mg/kg, with
    a maximum of 0.04 mg/kg (Frank  et al., 1989).

         Prolonged storage of apples reduced the carbaryl residues only
    slightly (Bogomolova, 1968). The initial level (2.4-2.8 mg/kg)
    changed little during the first 3 months of storage at a temperature
    of +5 to +10 °C. A slight reduction was observed during the fourth
    month of storage. During the process of storage, carbaryl migrated
    inwards from the surface, so that the concentration in the skin was
    reduced, while that in the pulp was increased (Table 14).

         Residues on lemon foliage on day 0 of treatment were
    4.6±0.3 µg/cm2. Five days after treatment, levels of 2.4 µg/cm2
    and 5.6 µg/cm2 were found on lemon and orange foliage,
    respectively; on the 60th day, the residual values were 0.41 and
    0.36 µg/cm2, respectively. Persistence half-lives were 22 days
    (lemons) and 14 days (oranges) (Iwata  et al., 1979).

         Carbaryl is persistent, particularly in citrus fruits and
    grapes. Residues of 3-6 mg/kg were measured in lemons and oranges
    2.5-3 months after treatment of trees with 3-10 kg carbaryl/ha, and
    amounts of 3.6, 1.9, and 0.4 mg/kg were found in grapes on days 7,
    14, and 40, respectively, after repeated spraying of vineyards with
    a 0.12% suspension. The half-life of carbaryl in grapes was 29 days,
    compared with 2-9 days in cherries and cabbage (Antonovich, 1970).

         Washing and peeling reduced carbaryl levels in fruits and
    vegetables by 40%; thermal processing by 45-90%, and preparation of
    juices by 53% (Molozhanova, 1970). Canning also reduced carbaryl
    residues. Thus, canning of different fruits (strawberries, black
    currants, gooseberries) containing carbaryl in the range of
    0.25-0.45 mg/kg, resulted in a reduction to 0.17-0.29 mg/kg; when
    the initial contents were higher (3-7 mg/kg) the levels after
    canning dropped to 1.4-2.2 mg/kg and 2.1-2.5 mg/kg, respectively,
    i.e., from 30 to 70%. Storage of canned fruit further reduced
    carbaryl residues by 2-3 times after 12 months (Bogomolova, 1968).

         Boiling vegetables (e.g., cabbage) reduced carbaryl residues by
    approximately 50%; however, the residues in pickled cabbage, 5
    months after preparation, were only 25% less than the initial amount
    (Antonovich, 1970).


    
    Table 14.  Carbaryl content in apples during storage (mg/kg)a
                                                                                                               

    Part of apple                                    Day of storage

                       10        20        30        40        50        70        80        100       110
                                                                                                               

    Skin              2.40      1.80      2.00      1.80      1.92      1.72      1.60      1.45      1.22

    Pulp              0.35      1.00      1.02      1.10      1.00      1.10      1.34      1.42      1.30

    Total             2.75      2.80      3.02      2.90      2.92      2.82      2.94      2.87      2.52
                                                                                                               

    aFrom:  Bogomolova (1968).


    
         Elkins (1989) reported that washing during the commercial
    processing of produce removed 97, 87, and 77% of the carbaryl
    residues from tomatoes, spinach, and broccoli, respectively.
    Blanching (short treatment with hot water) was stated to result in
    68% removal of carbaryl from green beans, while blanching, in
    addition to washing, resulted in the removal of over 97% of carbaryl
    from both spinach and broccoli.

         After a single application of carbaryl (Sevin 50 at 2.5 kg/ha),
    residues in cauliflower decreased from 16.75 mg/kg on the day of
    application to 0.87 mg/kg, 15 days afterwards (Yadav & Jaglan,
    1982). Washing further reduced the detectable residues at 15 days to
    0.67 mg/kg, while no detectable residues were present after boiling.

         Carbaryl was found in vegetation adjacent to treated fields.
    Grass growing at a distance of 250 m from a carbaryl-treated cotton
    field contained 0.18-0.25 mg carbaryl/kg wet weight up to 45 days
    after spraying (Gusseynov, 1970).

         The results of the 1989 Pesticide Residue Monitoring Programme
    in California showed that carbaryl was detected in 2 samples of
    grape from 26 in quantities less than the accepted tolerance level.
    It was not found in oranges (Okumura  et al., 1991). Summaries of
    residue data on different plants are given in Tables 15 and 16.
    Carbaryl residues were not detected in 44 samples of wheat in the
    United Kingdom analysed by the multiresidue method (Osborne  et al.,
    1989).

        Table 15.  Comparison of carbaryl residues with different
               formulationsa
                                                                       

    Formulation use      Plant         Mean residues    Day after last
    (kg a.i./ha)                       value (mg/kg)    application
                                                                       

    44% SC 2x0.5         apple              0.25              7
                         pears              0.16              7
    50% WP 2x0.5         apple              0.15              7
                         pears              0.09              7

    44% SC 2x2           spinach            4.44              -
    50% WP 2x2                              2.38             14

    44% SC 2x2           lettuce leaf       2.72             14
    50% WP 2x2                              1.55

    44% SC 2x2           barley             7.87             14
    50% WP 2x2                              4.63

    Table 15 (continued)
                                                                       

    44% SC 2x2           wheat         0.96             14
    50% WP 2x2                         0.99

    44% SC 2x2           oats          0.22             14
    50% WP 2x2                         0.26
                                                                        

    aFrom:  Davis (1987).
    
         Davis (1987) studied the impact of different types of
    formulation on food residues, including carbaryl (44% w/w) oil-based
    liquid formulation containing a "sticker", in order to prevent bees
    from carrying carbaryl particles back to the beehive. The 50 W
    formulation was a "standard" wettable powder formulation. The
    results are given in Table 15. This work showed that the addition of
    a "sticker" increased levels of food residues to some extent.

         Studies on the removal of carbaryl residues from tomatoes,
    green beans, spinach, and broccoli by commercial and home
    preparation procedures (Elkins  et al., 1968; Farrow  et al.,
    1968, 1969; Lamb  et al., 1968) showed a considerable decrease in
    the residues with treatment (Table 17).

         For pre-harvest use on grain, the rate of application of
    carbaryl ranges from 2 to 9.5 kg/ha, depending on the degree of
    infestation, density of foliage, and the stage of the life cycle of
    the pest. Carbaryl, usually applied at a rate of 5 mg/kg, is also
    used to protect stored grain. Studies on stored wheat, barley, oats,
    and rice indicated that carbaryl residues on grain have a half-life
    of between 26 and 80 weeks, depending on the temperature (FAO/WHO,
    1976). Residues of carbaryl in baked bread are then of the order of
    1-1.5 mg/kg.

    5.1.4.2  Animal products

         Technical carbaryl was fed to dairy cows of the Brown Swiss,
    Jersey, Holstein, and Ayrshire breeds at 50, 150, and 450 mg/kg of
    their average total daily roughage intake (dry weight) for a period
    of 2 weeks. Samples of milk were taken at regular intervals and the
    cream was analysed for carbaryl by means of the
     p-nitrobenzene-diazonium fluoborate coupling method. The
    concentration of carbaryl, if present, was below the sensitivity of
    the analytical method (0.01 mg/kg) (Gyrisco  et al., 1960).


    
    Table 16.  Carbaryl residues following different applications
                                                                                            

    Formulation use     Plant          Mean value       Day after     Reference
    (kg a.i./ha)                        residues          last
                                         (mg/kg)       application
                                                                                            

    44% SC              barley             5.4             14         Davis & Thomas (1987)

    44% SC              sugar beet      0.07-1.04          14         Thomas (1986)
                        roots

    44% SC              pasture         59.7-183            3         Davis (1986b)
    aerial ground       grass

    Carbaryl            sweet             0.33                        Frank et al. (1987a)
                        cherries

    Carbaryl            tomato             1.2              0         Frank  et al. (1991)
                                           0.5              3
                                          0.03             6-8

                        tomato            0.47              0
                        juice             0.24              3
                                          0.08             6-8
                                                                                            

    Table 17.  Removal of carbaryl after preparation procedures
                                                                                                                

    Vegetable      Initial                         Percentage removal                      References
                   residues                                                             
                   (mg/kg)        Commercial procedure               Home procedure
                                                                                                                

    Tomatoes         5.2       washing             82-99       washing              77     Farrow et al. (1968)
                               canning             98-99       canning              92
                               juicing             98          juicing              77

    Green beans      7.6       blanching           68-73       washing              52     Elkins et al. (1968)
                               & canning                       blanching            81
                                                               freezing             94
                                                               canning             100

    Spinach         20.8       washing             66-88       washing              70     Lamb et al. (1968)
                               blanching           96-97

    Broccoli        12.4       washing             77          washing & cooking    55     Farrow et al. (1968)
                               blanching           82-97       washing,             90
                                                               blanching,
                                                               & freezing
                                                                                                                


    
         Residues resulting from a single application and repeated
    applications of carbaryl spray on cattle were rapidly eliminated
    from body tissues. On days 1 and 3 after application, carbaryl was
    detected in the liver (0.05 mg/kg), muscles (0.04 mg/kg), and
    perirenal fat (0.16 mg/kg). Seventy-two hours after treatment, no
    residues were found in the tissues studied. The excretion in milk
    persisted for at least 69 h after spraying, the highest
    concentration being 0.075 mg/litre, 5 h after exposure (Hurwood,
    1967).

         Data concerning the composition and levels of milk and tissue
    residues in cows after continuous feeding with 100 mg
    14C-carbaryl/kg diet are shown in Tables 18 and 19.

        Table 18.  Metabolites in tissues after continuous 28-day feeding
               of 100 mg 14C- carbaryl/kg dieta
                                                                       

    Metabolite (mg/kg)               Kidney      Liver      Muscle
                                                                       

    carbaryl                          0.03       0.04        0.02

    5,6-dihydrodihydroxycarbaryl      0.05       0.01        0.04

    5,6-dihydrodihydroxynaphthol      0.02       0.02         0.0

    naphthyl sulfate                  0.29       0.02         0.0

    water-soluble unknowns            0.43       0.13        0.03

    unextractable unknowns            0.18       0.19        0.01
                                                                       

    aFrom:  Dorough (1971).

    Table 19.  Composition of milk residues after continuous 28-day
               feeding with 100 mg 14C-carbaryl/kg dieta
                                                                        

                                              Percentage     mg/kg
                                                                        

    Organic phase

    5,6-dihydrodihydroxycarbaryl                 38.5        0.11

    carbaryl                                      8.4        0.02

    3,4-dihydrodihydroxycarbaryl                  4.0        0.01

    Table 19 (continued)

                                                                        

                                         Percentage      mg/kg
                                                                        

    5,6-dihydrodihydroxynaphthol                  1.0        0.01

    Water soluble

    5-methoxy-6-hydroxycarbaryl                  25.6        0.07

    unknowns                                     10.6        0.03

    1-naphthol                                    5.5        0.02

    5-hydroxycarbaryl                             3.1        0.01

    carbaryl                                      1.2        0.01
                                                                        

    aFrom:  Dorough (1970a).
    
         Effective horn fly control for a period of 15 days was obtained
    by spreading carbaryl down a cow's back. Results indicated that, if
    applications of a 0.5% spray or a 50% dust were made immediately
    after the morning or evening milking, no residues of carbaryl would
    result in subsequent milkings (Eheart  et al., 1962). The results
    obtained by Petrovski (1970) were similar. After treating cows with
    a 0.85-1% suspension of carbaryl, residues of from 0.1 to
    0.3 mg/litre were found in milk, 20 h after application. On the
    third day, only trace amounts of carbaryl were found. After
    treatment with a 0.5% suspension of carbaryl, no traces were found
    in the milk.

    5.1.4.3  Animal feed crops

         Generally, animal feed crops contain less carbaryl than fruit
    and vegetables. Mean levels of 0.82 mg/kg were found in 80 samples
    of animal feed plants (Molozhanova, 1970). Levels of 0.3 mg/kg were
    found in maize stems at harvest, 70 days after spraying (Antonovich,
    1970).

         Studies on the carbaryl content of animal feed plants in hot
    climates showed that carbaryl can be detected 3-3.5 months after
    treatment, depending on the dose and the number of applications.
    Thus, after repeated applications of 50% carbaryl dust at a rate of
    0.5 g/m2, the carbaryl content in animal feed plants was in the
    range of 1-1.8 mg/kg wet weight, but, after a single application of

    0.7 g/m2, concentrations of 0.10-0.31 mg/kg were found (Atabaev,
    1972).

    5.1.5  Other products

         Measurement of carbaryl residues in tobacco plants showed that,
    15 days after field spraying with 950 g/ha, the content of carbaryl
    in green tobacco leaves was 10.1 mg/kg. Drying leaves by hot air
    decreased carbaryl residues by only 10% (Antonovich, 1970).

         Application of carbaryl at a rate of 2.2 kg/ha resulted in
    carbaryl residues on cotton foliage of 7.2 µg/cm2 on the day of
    spraying (Estesen  et al., 1982). Levels decreased to 5.9, 0.58,
    and 0.26 µg/cm2 after 3, 6, and 8 days, respectively.

         Carbaryl was found in the foliage of cotton plants in
    concentrations of 0.03-1 mg/kg from 10 days to 2.5 months after
    treatment. Carbaryl penetrated the plant through foliage and roots
    and contaminated the cotton and the seeds. Cotton harvested from
    treated fields 2 weeks to 1 month after treatment contained
    0.015 mg/kg. Trace amounts of carbaryl were found in cotton oil
    (Guseynov, 1970).

         After treatment with a 2% suspension of carbaryl against
    mountain pine beetle, residues in bark disks after 1 year were
    359 mg/kg. In another case, residues in bark disks were
    890±146 mg/kg, after spraying, and 531±178 mg/kg 16 months later
    (Page  et al., 1985).

    5.1.6  Terrestrial organisms

         The quantities of carbaryl that were absorbed by songbirds,
    either by contact or by eating food from a sprayed area, were
    studied by Kurtz & Studholme (1974). Towhees (American finches) were
    collected 3 days after the forest had been sprayed for gypsy moths
    at a rate of 1.1 kg/ha. The amounts of carbaryl found in the towhees
    were small, even though the samples were taken close to the spraying
    time. Trace amounts of carbaryl were found in three samples out of
    five, compared with two samples out of five control birds. The
    minimum level of detection was 0.1 µg/g. The low levels of carbaryl
    found in "sprayed" birds were explained by the fact that towheeds
    are groundfeeders and that only a small amount of carbaryl might
    have passed through the trees to the ground.

    5.2  General population exposure

    5.2.1  Exposure through the food

         The daily intake of carbaryl was studied for several years in
    the USA (see Table 20).

        Table 20.  Carbaryl daily intake in the USA
                                                                        
    Year     Positive samples     Daily Intake   References
                    (%)              (mg/day
                                   per person)
                                                                       

    1964-65        7.4                0.15       Duggan et al. (1971);

    1965-66        2.7                0.026      Duggan & Corneliussen
                                                 (1972)
    1966-67        1.1                0.007

    1968-69        0.8                0.003

    1969-70        0                  -

                             Infant    Toddler

    1978             -       0.088      0.05     Gartrell et al. (1986)

    1979             -       -          0.049

    1980             -       0.06       0.035    Reed et al. (1987)

    1981-82          -       0.129      0.127

    1982             -      -           0.012

    1982-84          -       0.117      0.017-   Gunderson (1988)
                                        0.0315
                                                                        
    
         Carbaryl residues in total diet samples in the USA are
    relatively low (Table 21). Carbaryl is found in potatoes, leguminous
    vegetables, root vegetables, and fruit. In foods processed in the
    usual manner, i.e., by peeling, stripping outer leaves, and cooking,
    when appropriate, carbaryl residues usually decreased to
    undetectable levels or traces (Manske & Corneliussen, 1974).


    
    Table 21. Carbaryl residues in food in the USA
                                                                                                      

    Number of composites        Number of       Number of      Range in       References
    analysed                    composites      composites       mg/kg
                               with residues    with traces
                                                                                                      

    270, from 30 grocery          20                15          trace to      Manske & Corneliussen
    stores in 27 cities                                            0.5        (1974)
    June 1970-April 1971

    420, from 35 market           6                  5            0.02        Manske & Johnson
    baskets, 6 June 1971-                                                     (1975)
    July 1972

    360, 12 August 1972-          12                10          0.05-1.10     Johnson & Manske (1976)
    July 1973

    360, August 1973-             8                  2         0.001-0.284    Manske & Johnson (1977)
    July 1974

    1044, 1978-82                 11 (1%)            a              a         Yess et al. (1991a)

    3744, 16 market              135 (4%)            a              a         Yess et al. (1991b)
    basket collections
    1982-86
                                                                                                      

    aNo figures given.


    
         During a 5-year period, from 1982 to 1986, the Los Angeles
    District Laboratory analysed 19 851 samples of domestic and imported
    food and feed commodities for pesticide residues. A single, rapid,
    multiresidue method was used. Carbaryl was detected in 164 samples
    from the total 19 851 samples analysed. Not one sample exceeded the
    US Federal tolerance levels (Luke  et al., 1988). In another
    publication, the same authors reported comparative studies on US and
    imported food. Carbaryl was found in 21 samples from a total 6391 US
    samples in quantities ranging from 0.1 to >2.0 mg/kg, but less than
    10 mg/kg. From 12 044 imported agricultural commodities 132 were
    contaminated by carbaryl, and levels in 14 of them exceeded the
    tolerance levels (Hundley  et al., 1988).

    5.2.2  Exposure during insect control

         Exposure to carbaryl, used to control the gypsy moth in camping
    and picnic areas, was monitored on the day of application and then
    weekly for 3 weeks. Carbaryl was applied from the air at a rate of
    1.12 kg/ha. Exposure was measured using dermal pads.

    Extrapolating from the most contaminated group of pads (they
    contained an average of 279 µg/pad), the authors calculated a "worst
    case" exposure of 0.54 mg/kg on the day of spraying. The authors
    concluded that the risk to those who use public areas during, and
    after, carbaryl application to trees is negligible (Cameron  et al.,
    1985).

         A 5% spray of carbaryl 85% wettable powder (WP) was applied for
    insect control in homes (Vandekar, 1965), as a surface application,
    at the rate of 2 g/m2. Urine samples taken from villagers 1 week
    after spraying showed a significant increase in 1-naphthol levels
    from 30.5 µg/ml baseline to 50.3 µg/ml. Inhibition of plasma ChEA
    was found in 48 out of 63 subjects, 1 week after spraying.

         During a monitoring study carried out from 1976 to 1980 in the
    USA, 1-naphthol was found in 1.4% of the urine samples from persons
    between 12 and 74 years old. The source was thought to be carbaryl
    and naphthalene (Carey & Kutz, 1985).

    5.3  Occupational exposure during manufacture, formulation,
         or use

         Harry (1977) estimated that about 13 million people in the USA
    were potentially exposed to carbaryl during its manufacture,
    formulation, packing, transportation, storage, and during and after
    application, and while working with treated crops or during harvest.

         Best & Murray (1962) published a survey on the exposure of
    plant workers during the production of carbaryl. Air concentrations
    varied from 0.23 to 31 mg/m3. Urine samples contained an excess of

    1 mg total 1-naphthol per 100 ml of urine. During air blast spraying
    of orchards, Jegier (1964) found air concentrations of 0.6 mg/m3
    (0.18-0.81 mg/m3). The mean respiratory exposure, measured by the
    respirator pad technique was 0.29 mg/h (0.24-0.53 mg/h) and mean
    dermal exposure, measured by skin pads, was 25.3 mg/h
    (18.5-30.3 mg/h). The maximum total exposure was 31 mg/person per h,
    or 0.025% of the toxic dose. Simpson (1965) estimated that the
    amount of dermal exposure was less than 0.1% of the toxic dose in
    orchard sprayers. During cotton spraying by aircraft, Yakim (1965)
    found 4 mg carbaryl dust/m3 in the breathing zone of flagmen,
    1 mg/m3 during preparation of the solution, and 0.7 mg/m3 in the
    pilot's cabin. Adylov (1966) reported the following air
    concentrations found during the aerial application of a water
    solution: flagmen's breathing zone 1.92 (0.64-2.84) mg/m3; pilot
    cabin, trace amounts, workers on the ground (preparation of
    solution, etc.,) 6.28 (0.48-19.2) mg/m3. In the urine samples of
    carbaryl formulators, 1-naphthol levels varied from 6.2 to
    78.8 mg/litre. Agricultural workers who used carbaryl for pest
    control excreted from 0.07 to 1.7 mg/litre in their urine (Shafik
     et al., 1971).

         Exposure studies were completed for pesticide application and
    formulating plant workers by the biological monitoring of 1-naphthol
    in the urine, dermal pads, and respirator filter pads (total 480
    samples of dermal pads and 73 respirator pads). Workers operating
    tractor-drawn airblast equipment applied carbaryl at 0.045-0.06% as
    spray (Comer  et al., 1975). An estimate of the amount of dermal
    and respiratory exposure that could occur was made using the
    procedures described by Durham & Wolfe (1962). The results are
    presented in Table 22.

         The concentration of 1-naphthol in the urine varied from 0.2 to
    65 mg/litre with a mean of 9 mg/litre. The rate of excretion per
    hour varied from 0.004 to 3.4 mg with a mean of 0.5 mg/h. The
    maximum level during the working day was reached by late afternoon.
    An approximate calculation of the excreted carbaryl (0.5 mg
    1-naphthol/h = 0.7 mg/h excretion of carbaryl), and potential
    exposure, 75 mg/h, shows great differences. About 1/100 part of
    possible absorption occurs.

         Exposure to carbaryl during agricultural application was
    studied by Leavitt  et al. (1982). WP 80 carbaryl was used (0.45 kg
    in 200 litre water) to spray trees, lawns, and gardens. The mean
    dermal exposure was 128 mg/h and the mean inhalation exposure was
    0.1 mg/h. The maximum percentage of the toxic dose that the
    applicators received was 0.12%/h. No symptoms or inhibition of ChE
    were reported. In another group of applicators, the mean dermal
    exposure was 59.4 mg/h and inhalation exposure 0.1 mg/h.

        Table 22.  Potential dermal and respiratory exposure of formulating
               plant workers and field spraymen to carbaryla,b
                                                                        

    Subject           Route of       Exposure      Exposure (mg/h)
                      exposure      situations
                                     studied     Range           Mean
                                                                        

    Formulating       dermal            48       0.80-1209.30    73.90
    plant workersc
                      respiratory       48       0.03-4.10        1.90

    Field             dermal            32       1.70-211.80     59.00
    spraymend

                      respiratory       25       0.01-1.08        0.09
                                                                        

    aFrom:  Comer  et al. (1975).
    bCalculated on the basis of the worker wearing a short-sleeved,
     open-necked shirt, no gloves or hat, with his clothing protecting
     the areas covered.
    cWorkers on mixing and bagging operations (4 and 5% dust).
    dOperating power air-blast spray machines in fruit orchards
     (0.045-0.06% solution spray).
    
         Dermal exposure is influenced by the type of spray equipment.
    The dermal deposit and respiratory intake of carbaryl in humans was
    monitored during home garden spray operations using compressed air
    or garden hose-end sprayers (Puech, undated). The greatest mean
    dermal deposit in cm2/min was received on the feet. When the spray
    target was above shoulder height the next highest dermal spray was
    received on the forearm (Table 23). Exposure through inhalation was
    insignificant.

         A study of the urban application of carbaryl was performed by
    Gold  et al. (1982). The maximum dermal exposure recorded in this
    study was 2.86 mg/kg per h. The maximum air concentration was
    0.28 µg/litre. An insignificant decrease in ChEA in serum and
    erythrocytes was found in some of the applicators. The mean dermal
    carbaryl exposure of the applicator, expressed as a percentage of
    toxic dose per h, was 0.01%, with a maximum of 0.08%. This exposure
    rate is below the risk rate for applicators. No symptoms of
    intoxication were reported by the authors. During the urban
    application of carbaryl to trees and ornamental shrubs using
    hand-held equipment, air concentrations measured at the breathing
    zone in full-shift samples, of 0.010-0.070 mg/m3, were detected in
    only 30% of the samples (Leonard & Yearly, 1990).

    Table 23.  Human exposure during spray operations
                                                                 

    Type of spray equipment      Mean deposit      Total exposure
                               (µg/cm2 per min)    (µg/kg per min)
                                                                 

    Compressed air sprayer

       below waist                   0.030               4.3

       above shoulder height         0.096               5.6

    Hose-end sprayer

       below waist                   0.154              18.3

       above shoulder height         0.353              24.4
                                                                 

         Dermal exposure to carbaryl in harvesters of strawberries was
    studied by Zweig  et al. (1984, 1985). They observed dermal
    exposure on the hands and forearms, and to a much lesser degree, on
    the lower legs. The first day, 3 mg carbaryl/h was found on cotton
    gloves, 0.66 mg/h on pads on the forearms, and 0.07 on the lower
    legs. The following day, the values were 1.23, 0.41, and 0.07 mg/h
    for gloves, forearms, and lower legs, respectively. The ratio of
    dermal exposure to dislodgeable foliar residues (DFR) was 4.34,
    2.82, and 6.17, for 3 consecutive days. The half-life of carbaryl on
    strawberry leaves was 4.1 days. Dislodgeable carbaryl residues on
    cotton foliage, expressed as µg/cm2 of cotton leaf (one surface
    only), following application by man-pulled ground rig were 7.2, 5.9,
    0.58, and 0.26 at 0, 72, 144, and 192 h after application,
    respectively (Estesen  et al., 1982). Approximate dermal exposure
    rates may be calculated using the following expression, proposed by
    Zweig  et al. (1985). Dermal exposure rate (mg/h) = 5x103xDFR
    (in µg/cm2). This method is suggested to obtain the exposure rate
    of fruit harvesters, in order to establish safe re-entry periods
    without human studies.

         Factors affecting the levels of exposure during the
    agricultural application of pesticides were analysed by Wolfe  et
    al. (1967). Wind is the most important environmental condition. The
    type of activity, equipment used, the duration of exposure,
    formulation, individual protection, including attitude, are also
    discussed. Carbaryl deposits from air jet application on orchards
    were found at 500 m downwind in the presence of inversion, and at
    300 m, in its absence. Ground application results gave deposits at
    150 and 50 m, respectively (MacCollom  et al., 1985, 1986). Air
    concentrations were 17.88 µg/m3 during spraying above the orchard

    downwind edge, 9.5 µg/m3, 30 min after spraying, and 8.17 µg/m3,
    1 h after spraying.

         Airborne and deposit levels of carbaryl were measured after
    three applications by air to an apple orchard (Currier  et al.,
    1982). Samples of air were taken at distances of from 12.2 to 3994 m
    from the target orchard. At a distance of 12.2 m, the concentration
    in air was between 3.3 and 76.2 µg/m3. One hour later it was
    between 2.5 and 11.3 µg/m3. At a distance of 3.2-3.3 km, the
    initial concentration was between 9 and 28.8 µg/m3 during spraying
    and 0.9-14.4 µg/m3, one hour after treatment. Because the area of
    the study was one of concentrated agriculture, it is possible that
    carbaryl could have been used on other orchards and gardens near to
    the sampling point.

    6.  KINETICS AND METABOLISM

    6.1  Absorption

         When only 0.1 ml of carbaryl solution (0.025-0.05 mmol/litre)
    was administered into the lungs of anaesthetized rats, it was
    rapidly absorbed. About 50% of the dose was absorbed in 2.6 min. The
    amount of carbaryl absorbed per unit time was directly proportional
    to the administered dose (Hwang & Shanker, 1974). Blase & Loomis
    (1976) demonstrated that carbaryl could be taken up and metabolized
    by the isolated perfused rabbit lung. Retention by rats of
    14C-labelled carbaryl, inhaled as vapours during a 1-h exposure
    period, was 75.4% of the total dose inhaled, which did not exceed
    50 µg (Dorough, 1982).

         When a dose of 7.5 µmol radiolabelled carbaryl/kg body weight
    was administered intragastrically to fasted, anaesthetized, female
    rats, 22 and 67 min after dosing, the proportions absorbed were
    52.6±14.1% (n=3) and 81.7±15.7% (n=3), respectively; 89.3% of the
    radiolabelled material in the collected portal blood was
    [1-naphthyl-1-14C] N-methyl carbarmate (Casper  et al., 1973).

         Absorption from the small intestine was studied in
    anaesthetized rats with a ligature around the pylorus and an
    ileocecal junction with major blood vessels not occluded. A
    concentration of carbaryl of 0.005-0.1 mmol/litre was used. The
    absorption half-time was 6.4 min (Hwang & Schanker, 1974).

         On the basis of ligation studies on mice, Ahdaya & Guthrie
    (1982) determined that the absorption of carbaryl from the stomach
    was relatively low compared with that from the entire
    gastrointestinal tract (29%), but was relatively high in comparison
    with that of other pesticides.

         Variation in the digestive absorption kinetics, according to
    the vehicle used, was reported in studies on female Wistar rats
    (Cambon  et al., 1981). The results indicated that carbaryl was
    absorbed more rapidly in the intestine when either DMSO or
    tragacanth was used as a vehicle. It seems that milk does not
    facilitate carbaryl absorption. Inhibition of ChEA was closely
    related to the absorption rate.

         The rate of dermal penetration of carbaryl (in acetone
    solution) into mammals, birds, amphibia, and insects was studied by
    Shah
     et al. (1983). The half-time of penetration of 14C-labelled
    carbaryl was 317 min in Japanese quail, 12.8 min in mice, 6.4 min in
    grass frogs, 4576 min in American roaches, and 791 min in tobacco
    horn worms.

         In an  in vitro study, only about 1% of an applied dose of
    carbaryl penetrated through the skin of the rat over an 8-h period
    (MacPherson  et al., 1991). Using two different methods, Shah &
    Guthrie (1983) measured the half-time for penetration of carbaryl,
    applied dermally at a rate of 4 µg/cm3, and found 10.34 h and
    4.75 h, respectively. Shah  et al. (1987) compared the rate of
    dermal penetration of carbaryl in young, versus adult, Fischer 344,
    female rats and did not find any consistent age-related differences.

         Percutaneous absorption of carbaryl in rats was also studied by
    Knaak  et al. (1984). Carbaryl dissolved in acetone was applied to
    back skin (not occluded) at 43.4-48 µg/cm2. Recovery studies
    indicated that 57.7% of the applied carbaryl was absorbed.
    Approximately 5.8% of carbaryl penetrated the skin within 1 h, the
    rate of absorption being 0.18 µg/h per cm2. The half-life of
    absorption by blood was 1.26 h, and that for elimination, 67 h.

         Carbaryl labelled with radioactive carbon (14C), dissolved in
    acetone, was applied to the skin of six volunteers, in order to
    study percutaneous penetration (Maibach  et al., 1971; Feldmann &
    Maibach, 1974). The results showed almost complete penetration of
    carbaryl on the forearm and jaw angle. After a 24-h application, the
    cumulative urinary excretion over 5 days was 74%. According to other
    authors using the same data, the estimated cumulative absorption
    over 5 days, as a percentage of the applied dose, was 63% (Fisher
     et al., 1985), 45% of this occurring 8 h after the onset of
    penetration, which had a lag of 3.5 h.

         Comparing the different studies, it is clear that some solvents
    can facilitate the dermal penetration of carbaryl.

    6.2  Distribution

         Plasma levels of carbaryl in rats were compared after iv,
    intraduodenal, or hepatic portal administration of 0.5 mg/kg

    (Houston  et al., 1974). In Fig. 2, it is shown that plasma
    concentrations were lower after intraduodenal application, when
    carbaryl was subjected to the liver's first pass metabolizing
    effect. Plasma concentrations following portal application were also
    lower (approximately 80% of the concentration after the systemic
    route of application).

    FIGURE 2

         The distribution of carbaryl in rat tissues after a single oral
    administration of 144.2 mg/kg body weight (0.2 LD50) was studied
    (Klisenko & Yakim, 1966) at 5 and 30 min, and 1, 2, 4, 24, 48, and
    72 h. Carbaryl and 1-naphthol were identified by thin-layer
    chromatography with a sensitivity of 0.5 µg/g. At 5 min, carbaryl
    was found in all organs. Thirty min after administration of
    carbaryl, peak concentrations found were: muscle, 35 µg/g, brain,
    16 µg/g, spleen, 25 µg/g, and erythrocytes, 120 µg/g; at 60 min, a
    level of 45 µg/g was found in the liver. After 24 h, levels of only
    1-4 µg carbaryl/g were detected in the liver, kidney, muscles, and
    skin. At 48 h, no residues were found. The authors suggested that

    carbaryl is rapidly distributed and excreted. 1-Naphthol was found
    in the liver, stomach, intestines, kidneys, and lungs. Other
    non-identified metabolites were present in the liver and lungs.

         Levels of carbaryl in the tissues of rats poisoned with oral
    doses of 800 and 1200 mg/kg, respectively, were as follows: liver,
    7-58 and 52-80 µg/g; heart, 3.5-31.3 and 40.6-45.9 µg/g; brain,
    3-26.8 and 25.9-30.9 µg/g. Higher concentrations were found in
    animals that died from poisoning than in animals killed, even though
    they were treated with the same doses (Mount  et al., 1981).

         Yakim (1970) studied the distribution of carbaryl and
    1-naphthol after 6-month oral administration of 0.2, 0.1, or 0.05
    LD50 carbaryl in rats. Carbaryl was found in the intestines (20-40
    µg/g), liver (4-20 µg/g), and kidneys and lungs (in trace amounts);
    1-naphthol was found in the kidneys (20-50 µg/g), and in the liver
    (5-10 µg/g) in groups treated with 0.2 LD50. The carbaryl level
    was <1 µg/g in the organs studied in the group treated with
    0.1 LD50; no traces of carbaryl were found in the group treated
    with 0.05 LD50. The author suggested that a higher quantity of
    carbaryl is found 30 min after a single oral application, which
    corresponds to the highest percentage of ChE inhibition.

         Two to 6 h after a single dermal application of 500 mg
    carbaryl/kg to cats, the compound was found in plasma at 15 µg/ml
    and in erythrocytes at 25 µg/ml. Inhalation studies were also
    performed on cats (Table 24). The author stressed that carbaryl was
    present in smaller amounts in plasma than in erythrocytes because of
    the more active metabolism by blood proteins. More 1-naphthol and
    other unidentified metabolites were present in plasma. Elimination
    of carbaryl and normalization of ChE activities occurred in 48-70 h
    with all routes of administration of carbaryl. Carbaryl has a low
    cumulation capacity.

         In a study in which the abilities of several pesticides to bind
    to potential carriers isolated from human blood were compared,
    carbaryl was much more effectively bound by albumin than by either
    high- or low-density lipoproteins (Maliwal & Guthrie, 1981).


    
    Table 24.  Relation between carbaryl inhalation and resulting cholinesterase (ChE) inhibitiona

                                                                                                                                   

    Experimental                   Carbaryl and 1-naphthol                             ChE inhibition in %
    conditions               Plasma                   Erythrocytes              Plasma                 Erythrocytes
                                                                                                                                   

    Single 6 h exposure      2.5-5 µg/ml after        5-10 µg/ml                39-80 (after 4 h)      52-84 (after 4 h)
    to 80 mg/m3              exposure; no traces      (after exposure)
    8 cats                   4 h later                10-15 µg/ml (4 h later)
                                                      2-2.5 µg/ml (24 h later)

    Single 6 h exposure                               0-10 µg/ml                                       28-44 in blood
    to 20 mg/m3                                       in single animal                                 (after 4 h);
    8 cats                                            0 after 48 h                                     0 (after 48 h)

    4-Month exposure to                               traces in single animal
    16 mg/m3                                          in blood
    4 cats

    1-Month exposure to      5-15 µg/ml, 0 on the     5-15 µg/ml, 0 on the      44 on the day of       62 on the 7th day of
    63 mg/m3                 6th day after the end    6th day after the end     exposure               exposure
    4 cats                   of exposure              of exposure

    4-Month exposure to      5 µg/ml on the third     10 µg/ml on the third          -                      -
    38 mg/m3                 day of exposure          day of exposure
    4 cats
                                                                                                                                   

    aFrom:  Yakin (1979)


    
         Levels of carbaryl in some tissues of male, albino, Fisher
    Strain 344 rats, after single and multiple oral administration
    (Table 25) were reported by Hassan (1971).

        Table 25.  Tissue levels of carbaryla
                                                                                   

    Treatment                    Time after        Concentration of carbaryl
                               administration   Whole blood     Heart     Brain
                                                (µg/ml)         (µg/g)    (µg/g)
                                                                                   

    Single dose 80 mg/kg            2 h           16.2            2.6       3.45

    Rats fed 700 mg/kg diet       90 days          4.8            0.85      0.68

    Rats fed 100 mg/kg diet       90 days          2.7          < 0.5     < 0.5
                                                                                   

    aFrom:  Hassan (1971).
    
         Andrawes  et al. (1972) studied the 14C residues in hen
    tissues following the feeding of 1-naphthyl-14C-carbaryl at
    70 mg/kg for 4 days (Table 26).

         Radiolabelled carbaryl naphthyl 14C (6600 dpm/µg) and
    carbaryl carbonyl 14C (4000 dpm/µg) were administered
    intratracheally to rats as aerosols for 15 seconds. The maximum
    concentration in blood occurred after 2-5 min. Distribution of the
    residues in the organs, 1 h after inhalation, was highest in the
    lung (9.2-10.5%), liver (4.7-9.2%), bladder (2.7-5.9%), and kidney
    (2.5-3.7%) (Nye & Dorough, 1976).

         Distribution of 14carbon after intraperitoneal and oral
    administration of 7.4 µmol carbaryl/kg body weight to rats was
    studied by Krishna & Casida (1966) (Table 27). Carbaryl was found in
    all tissues analysed. No marked differences with sex and
    administration route were noted. On the basis of the rate of
    excretion of radioactivity following an intraperitoneal injection of
    labelled carbaryl, Shah & Guthrie (1983) calculated a half-time for
    clearance of label of 6.46 h.

    Table 26.  Concentration of14C residues in hen tissues after
               feeding 1-naphthyl-14C carbaryl at the level of
               70 mg/kg for 4 daysa
                                                                 

    Sample                       µg/kg at indicated times after
                                         last treatment

                                   16 h                   7 days
                                                                 

    Brain                          17.3                     6.8
    Heart                          47.5                    20.9
    Kidney                        405.5                    80.7
    Pancreas                       69.6                    15.6
    Skin                           86.6                    22.4
    Fat                            25.2                     5.2
    Gizzard                        43.0                    13.9
    Thigh                          28.6                    10.1
    Breast                         25.9                    12.7
    Leg muscle                     29.1                     9.0
    Blood                         197.2                   152.2
    Lung                          138.5                   122.5
    Liver                         332.6                    33.4
    Spleen                        108.7                    74.2
    Intestine and contents        300.1                   < 5.0
    Intestinal wall                44.0                    11.1
    Oviduct                        50.5                     6.7
    Developing egg (small)        534.3                     7.4
    Developing egg (large)        508.1                    35.5
    Remaining carcass              35.5                   < 5.0
                                                                 

    aFrom: Andrawes  et al. (1972).

         Distribution of carbaryl was studied in 7 Sprague-Dawley rats
    and Swiss mice on day 18 of pregnancy. Whole-body auto-radiography
    was performed after oral application of 13.5 µCi carbaryl methyl
    14C/kg. The transfer to the placenta began in the first hour.
    Distribution of the carbaryl occurred in the excretory organs,
    fetus, digestive tract, and the bone marrow and brain. The major
    portion was quickly eliminated. A more stable localization occurred
    in highly active protein-building organs, such as the fetus,
    digestive tract, and bone marrow. The 14carbon concentration in the
    eye, liver, and brain of the fetus was relatively constant from 8 to
    96 h (Declume & Derache, 1976, 1977; Declume & Benard, 1977a,b,
    1978).


    
    Table 27.  Distribution of 14carbon in various tissues in rats, 48 h after ip administration of carbaryl and its hydrolysis product,
               in µmol equivalent/kg of fresh tissue, based on total 14Ca
                                                                                                                                              

    Labelled position             Blood         Bone     Brain      Fat       Heart    Kidney     Liver     Lung     Muscle    Spleen   Testes
                                              
                          Corpuscle   Plasma
                                                                                                                                              

    Carbonyl 14C             0.38      0.16     0.26      0.33      0.16      0.39      0.47      0.63      0.32      0.18      0.33

    Methyl 14C               0.51      0.22     0.47      0.67      0.19      1.23      1.37      1.78      0.97      0.47      0.97

    1-Naphthyl-1-14C         0.02      0.19     0.19      0.03      0.18      0.06      0.17      0.09      0.05      0.03      0.26     0.09

    1-Naphthol-1-14C       < 0.01      0.06     0.03      0.01      0.04      0.01      0.05      0.14      0.02      1.16      0.13
    (hydrolysis product)
                                                                                                                                              

    aAdapted from:  Krishna & Casida (1966).


    
         Fernandez  et al. (1982) determined that the elimination of
    label following intravenous administration of 20 mg 14C
    carbaryl/kg to rats could be best described by a three compartment
    model, with 73% of the label excreted within 24 h.

         Strother & Wheeler (1976, 1980) reported that 14C-carbaryl
    rapidly crossed the rat placenta and was distributed in all fetal
    tissues. Fetal brain, heart, and lung contained more 14C on a
    weight basis than the maternal counterpart.

    6.3  Metabolism

         The metabolism of carbaryl has been studied extensively, and
    its complexity and the need for additional studies are recognized.
    As with other carbamates (WHO, 1986), the principal metabolic
    pathways are hydroxylation, hydrolysis, and epoxidation, resulting
    in numerous metabolites subjected to conjugation, forming
    water-soluble sulfates, glucoronides, and mercapturates (Carpenter
     et al., 1961; Dorough  et al., 1963; Dorough & Casida, 1964;
    Knaak  et al., 1965; Menzie, 1969; Bend  et al., 1971).

         Hydrolysis of carbaryl results in the formation of 1-naphthol,
    carbon dioxide, and methylamine (Fig. 3) (Carpenter  et al., 1961;
    Sakai & Matsumura, 1971).

         The first evidence for carbaryl hydroxylation was reported by
    Hodgson & Casida (1961). Carbaryl is metabolized by a rat liver
    microsome system, requiring NADPH2 and oxygen, to form a
    formaldehyde-yielding derivative.

    FIGURE 3

         The use of 14carbon-labelled carbaryl (Fig. 4) and thin-layer
    chromatography contributed to further studies on carbaryl metabolism
    (Skraba & Young, 1959; Krishna  et al., 1962). Chin  et al. (1974)
    used  in vitro techniques on tissues from animals and human beings.

    FIGURE 4

         Reviews on carbamate and carbaryl metabolism have been
    published (Lykken & Casida, 1969; Kuhr, 1970; Knaak, 1971; Kuhr,
    1971; Ryan, 1971; Fukuto, 1973; Dorough, 1973; Kuhr & Dorough,
    1976).

    6.3.1  In vitro studies on animal tissues

         An investigation of the individual metabolism of carbaryl in
    the liver, lung, and the kidney of rat was conducted using the
    tissue explant maintenance technique. Hepatic tissue of the rat,
    incubated with carbaryl, actively performed demethylation,
    hydrolysis, hydroxylation, and oxidation, followed by sulfate and
    glucuronide conjugations (Chin  et al., 1979b).

         Rat liver microsomes fortified with reduced nicotineamide-
    adenine dinucleotide phosphate were used to study the hydroxylated
    products of carbonyl 14C, methyl 14C, and naphthyl 14C
    carbaryl (Dorough & Casida, 1964). The metabolites were identified
    as  N-hydroxymethylcarbaryl, 4-hydroxycarbaryl, and
    5-hydroxycarbaryl. At least 2 unidentified metabolites had the
    C-O-C(O)-N-C structure intact. 1-Naphthol and at least two
    unidentified metabolites without the carbamyl groups were formed as
    a product of hydrolysis. The nature of carbaryl metabolites in liver
    microsomes in mice, rats, and rabbits was studied by Leeling &
    Casida (1966) and in guinea-pigs and rats by Knaak  et al. (1965).

    Two more metabolites were identified (Table 28): 5,6-dihydro-5,6-
    dihydroxycarbaryl, and 1 hydroxy-5,6-dihydro-5,6-dihydroxy-
    naphthalene. It was suggested that hydrolysed metabolites are
    probably conjugated as glucoronides and sulfates (Knaak  et al.,
    1965; Hassan  et al., 1966; Leeling & Casida, 1966). A study on rat
    liver microsomes and small intestine later showed (Mehendale &
    Dorough, 1971) that about 90% of 1-naphthol and
     N-hydroxymethylcarbaryl and about 40% of 5-hydroxycarbaryl and
    4-hydroxycarbaryl were conjugated as glucuronides. The presence of
    thioether conjugates in incubation mixtures of mouse liver
    homogenates with carbaryl has been confirmed (Bend  et al., 1971;
    Ryan, 1971).

         The  in vitro technique for metabolic studies using liver
    tissues qualitatively reflects the  in vivo metabolic processes of
    carbaryl in animals and human beings (Sullivan  et al., 1972) and
    their similarity (Matsumura & Ward, 1966).

         Methylmercury hydroxide pretreatment in rats (10 mg/kg daily
    for 2 days) decreased the hepatic microsomal cytochrome P-450
    content and aminopyrine demethylase by 50%, as well as the
    microsomal hydroxylation reaction  in vitro of carbaryl to form
    4-hydroxycarbaryl and  N-hydroxymethylcarbaryl. Chlordane
    pretreatment increased both cytochrome P450 and hydroxylation
    (Lucier  et al., 1972). However, there were no quantitative changes
    in the metabolite pattern.

         When the metabolism of carbaryl in rat intestine was studied
     in vitro, hydrolysis and the synthesis of 1-naphthyl glucuronide
    were reported to occur mainly in the first third of the intestine
    (Pekas & Paulson, 1970; Pekas, 1972).

         MacPherson  et al. (1991) studied the metabolism of carbaryl
    using a rat skin preparation  in vitro. A post-mitochondrial
    fraction was able to catalyse hydrolysis and sulfation and
    glucuronidation conjugation reactions, but not ring hydroxylation.
    The activities were very small in comparison with activities in
    liver microsomes.

         The degradation of carbaryl by an esterase of the American
    cockroach ( Periplaneta americana) was reported by Matsumura &
    Sakai (1968).


    
    Table 28.  Carbaryl naphthyl-1-14C metabolism by liver microsomes from mice, rabbits, and rats, in the presence of NADPH2a

                                                                                                                                    

    Substance determined                                               Total radiocarbon (%) using liver microsomes from:

                                                                              Mice             Rabbits         Rats
                                                                                                                                    

    Ether extract

      Carbaryl                                                                32.1              19.4           46.9

      Hydroxylated metabolites
        1-naphtyl  N-hydroxymethylcarbamate                                    11.9               6.3           11.7
        4-hydroxy-1-naphthyl methylcarbamate                                   6.7               8.1            6.1
        5-hydroxy-1-naphthyl methylcarbamate                                   2.4               1.7            1.3
        5,6-dihydro-5,6-dihydroxy-1-naphthyl methylcarbamate                   5.3               9.1            3.8
        1-hydroxy-5,6-dihydro-5,6-dihydroxy-naphthalene                        1.9               2.7            1.5

      1-Naphthol                                                               7.2               6.3            5.8

      Unidentified metabolites
        Metabolite A                                                           4.0               4.5            3.5
        Metabolite C                                                           0.6               2.0            0.8

    Aqueous fraction                                                          28.5              39.6           19.4
                                                                                                                                    

    aFrom:  Leeling & Casida (1966).


    
    6.3.2  In vivo studies on animals

         The metabolism of carbaryl has been studied in a variety of
    mammals including rat, rabbit, guinea-pig, monkey, sheep, cow, pig,
    and dog. Although many organs have been shown to be able to
    metabolize carbaryl, the most important one is the liver.

         The metabolism of 1-naphthyl-14C carbaryl was studied in male
    and female Beagle dogs following a single, oral administration of
    2.5 or 25 mg/kg. The metabolic pathways identified involved
    hydrolysis,  N-methyl oxidation, ring hydroxylation, and
    conjugation. No significant qualitative differences were found
    between male and female dogs or between high and low dosage levels.
    Faecal elimination accounted for 30-66% of the applied dose and was
    found to be primarily the result of incomplete absorption from the
    intestinal tract of the solid material and subsequent elimination of
    unchanged carbaryl. The metabolic pathway defined is illustrated in
    Fig. 5 (Andrawes & Bailey, 1978c).

         The metabolism of 1-naphthyl-14C carbaryl was studied in male
    and female Sprague-Dawley rats following a single, oral
    administration of 2.5 mg/kg. The metabolic pathways identified in
    the rat involved hydrolysis, N-methyl oxidation, ring hydroxylation,
    and conjugation. New metabolites identified, previously unknown in
    the rat, were: 1,5-naphthalenediol, 1,6-naphthalenediol,
    3,4-dihydro-3,4-dihydroxy-1-naphthol, and 3-hydroxy-1-naphthyl
    methylcarbamate. These new metabolites had been previously
    identified in the dog. The metabolic pathway defined is illustrated
    in Fig. 5. Faecal elimination accounted for only 2-7% of faecal
    14C as carbaryl, indicating more complete absorption of the test
    material than in the dog (Andrawes & Bailey (1978a).

         Conjugated metabolites of 1-naphthyl-14C carbaryl excreted in
    rat and dog urine, after similar single oral treatments of
    2.5 mg/kg, were separated and compared as intact conjugates using
    gel permeation and thin layer chromatography. The metabolic products
    were found to be qualitatively similar in the two animal species,
    with evidence of glutathione conjugation in the dog. Urinary
    metabolites only differed quantitatively between species. The rat
    appeared to be considerably more active in hydrolysing carbaryl to
    1-naphthol followed by conjugation, whereas, in the dog, the
    principle urinary metabolites were formed through direct conjugation
    of carbaryl itself. A significant amount of urinary radioactivity in
    both species remained unidentified, i.e., 27 and 34% in the rat and
    dog, respectively (Andrawes & Bailey, 1978b). Tables 29 and 30
    illustrate the quantitative urinary metabolic differences in rats
    and dogs. Note that "Free" refers to unconjugated metabolites
    whereas "Acid" and "Enzyme" refer to acid- and enzyme-hydrolysed
    conjugates.

    FIGURE 5

    Table 29.  Metabolic products present in a 24-h sample of urine of a
               rat treated orally with 2.5 mg 1-naphthyl-14C
               carbaryl/kg in corn oil
                                                                       

    Products                 Percentage of total radioactivity in urine
                                                                       
                                Free      Enzyme      Acid     Total
                                                                       

    1-Naphthol                  0.26      15.86       0.49     16.61

    Carbaryl                    0.14       0.45       4.22      4.81

    Methylol                     NDa        NDa      0.64b      0.64

    1,5-Naphthalenediol         0.17       1.12       0.08      1.37

    1,6-Naphthalenediol         0.03       0.42        NDa      0.45

    5-Hydroxy carbaryl          7.76       3.07       0.24     11.07

    5,6-Dihydrodihydroxy
      naphthol                  1.16       4.99          b      6.15

    5,6-Dihydrodihydroxy
      carbaryl                  5.66       7.75          b     13.41

    1,4-Naphthoquinonec         0.03       1.12       0.10      1.25

    4-Hydroxy carbaryl          2.30       2.76       0.19      5.25

    3-Hydroxy carbaryl           NDa        NDa       0.06      0.06

    3,4-Dihydrodihydroxy
      naphthol                  0.71       1.53          b      2.24

    Unknown 1                   0.25       2.95       0.06      3.26

    Unknown 2                    NDa       3.46        NDa      3.46

    Other unknowns              0.37       1.92       0.38      2.67

    Highly polar
      materials                  NDa       6.99      20.31     27.30
                                                                      

    aND = none detected.
    bAcid hydrolysis degrades the methylol to desmethyl carbaryl and
     the dihydrodihydroxy derivatives to phenols.
    cA decomposition product of 1,4-naphthalenediol during work-up.

    Table 30.  Metabolic products present in a 24-h sample of urine of a
               female dog treated orally with 25 mg 1-naphthyl-14C
               carbaryl/kg
                                                                      

    Products                 Percentage of total radioactivity in urine

                                Free      Enzyme      Acid     Total
                                                                      

    1-Naphthol                  0.38       2.74       1.47      4.59

    Carbaryl                    1.71       0.16       9.90     11.77

    Methylol                     NDa        NDa       0.22      0.22

    1,5-Naphthalenediol         0.21       1.83       1.14      3.18

    1,6-Naphthalenediol          NDa       1.62        NDa      1.62

    5-Hydroxy carbaryl          1.61       1.67       0.20      3.48

    5,6-Dihydrodihydroxy
      naphthol                  1.12       9.79        NDa     10.89

    5,6-Dihydrodihydroxy
      carbaryl                  3.80       3.09        NDa      6.89

    1,4-Naphthoquinoneb          NDa       1.24       1.36      2.60

    4-Hydroxy carbaryl          0.64       5.30       0.44      6.38

    3-Hydroxy carbaryl           NDa       0.04       0.01      0.05

    3,4-Dihydrodihydroxy
      naphthol                   NDa       0.50        NDa      0.50

    Unknown 1                    NDa       0.20       0.62      0.82

    Unknown 2                    NDa       1.30        NDa      1.30

    Other unknowns               NDa       1.26       0.43      1.69

    Highly polar materials       NDa       9.06      34.96     44.02
                                                                       
    aND = none detected.
    bA decomposition product of 1,4-naphthalenediol during work-up.

         The above work supersedes the work by Knaak & Sullivan (1967),
    who mistakenly concluded that the Beagle dog metabolic pathway was
    qualitatively different from that of the rat, because of poor
    absorption of solid/slurry test material. The marked emphasis on
    differences in metabolic pathways between species, together with the
    analytical techniques available at the time of the study contributed
    to their conclusions.

         Studies on the nature of the biliary, water-soluble metabolites
    of carbaryl were conducted by Bend  et al. (1971) on 19 male Wistar
    rats, using a technique with the bile duct cannulated. Water-soluble
    conjugates of carbaryl with sulfur-containing amino acid were found
    in the urine as well as the bile of treated rats:  S-(4-hydroxy-1-
    naphthyl) cysteine and  S(5-hydroxy-1-naphthyl)-cysteine. Biliary
    secretion of 5,6-dihydro-5,6-dihydroxycarbaryl glucuronide following
    an infused dose was found to be greatly reduced, from 10% to less
    than 1%, by pretreatment with antibiotics (Struble  et al., 1983b).
    This indicates that bacteria play a role in the enterohepatic
    circulation and bilary secretion of this metabolite of carbaryl.

         The functional activity of the reticulo-endothelial system
    (RES) can influence carbaryl metabolism (Pipy  et al., 1980). The
    elimination of carbaryl from the blood decreased significantly in
    rats (24 male Sprague-Dawley) with RES inhibited by colloidal
    carbon, and increased in those in which the RES was activated with
    glyceryl trioleate. Correlation of the activity of RES with the
    enzyme activity of monoxygenases of the hepatic microsomal fraction
    could possibly explain this effect of the RES in the toxicokinetics
    of carbaryl.

         An intravenous injection of colloidal carbon, which inhibits
    liver microsomal metabolism, reduced biliary excretion of an iv dose
    of carbaryl given 18 h later (Pipy  et al., 1981). Pretreatment of
    rats with 75 mg phenobarbital/kg per day, ip, for five days resulted
    in an increase in the rate of sulfate conjugation of carbaryl,
    following a high dose of carbaryl (16.4 mg/kg), but not a low dose
    (1.64 mg/kg) (Knight  et al., 1987).

    6.3.3  Metabolic transformation in plants

         The formation of carbaryl metabolites in plants is primarily
    dependent on the hydrolytic, oxidative, and conjugative potential of
    the plant tissues, which are similar to the tissues of insects and
    mammals. The metabolism in plants is of a shorter duration than that
    in insects and mammals, and the tendency to accumulate metabolites
    is more pronounced. The carbamate ester bond appears to be quite
    stable in plants, which explains the small amount of recovery of
    1-naphthol from treated plants. The extent of oxidation is generally
    higher in plants and insects than in mammals. Several
    hydroxymetabolites are formed by oxidation of the  N-methyl group
    and naphthalene ring. They are conjugated as glycosides.

    Non-enzymatic factors, such as light, heat, and humidity may
    contribute to the degradation of carbaryl in plants as well (Kuhr,
    1971).

         The metabolism of carbaryl has been defined in a wide variety
    of plant species (Table 31). Metabolites were isolated in microgram
    quantities for mass and ultraviolet spectroscopic analyses (Mumma
     et al., 1971).

    6.3.4  In vitro studies with human tissues

         The metabolism of carbaryl in selected human tissues was
    studied  in vitro by Chin  et al. (1974). On the basis of the
    total anionic characteristics of the metabolites derived from each
    organ, metabolic activity occurred in the following organs in
    descending order: liver, lung, kidney, placenta, vaginal mucosa,
    uterus.

         The metabolic profiles of carbaryl in human postembryonic fetal
    autopsy tissue were determined using 1-naphthyl-14C or
     N-methyl-14C-carbaryl. The anionics from fetal liver amounted to
    20% of those found with the adult liver. Naphthyl glucuronide and
    naphthyl sulfate were produced in the kidney, whereas the lung
    produced naphthyl sulfate from carbaryl (Chin  et al., 1979a).

         Carbaryl was metabolized oxidatively by primary human embryonic
    cells in culture (Lin  et al., 1975). Complete degradation occurred
    after 72 h of incubation. Unconjugated metabolites were identified
    as 1-naphthol, 5-hydroxycarbaryl, 4-hydroxycarbaryl, and
    5,6-dihydro-5,6-dihydroxycarbaryl. The water-soluble components were
    identified as 4-hydroxycarbaryl, 1,4-naphthalenediol, and
    5,6-dihydro-5,6-dihydroxycarbaryl. The primary human embryonic lung
    cells did not convert carbaryl to carbon dioxide. They may not
    possess the enzyme system that is necessary to break down the
    naphthalene ring of carbaryl to form carbon dioxide.

         Sakai & Matsumura (1971) studied the degradation of carbaryl by
    brain esterases. Carbaryl was degraded by band E4 and E6,
    whereas, in the mouse brain preparation, the compound was degraded
    by band E8, E9, and E6.

         Cell culture techniques were used to examine the products of
    carbaryl degradation by cultures of an L-132 cell line derived from
    normal human embryonic lung. The data indicated that detoxification
    was similar to that observed in animals and in  in vitro enzyme
    systems (Baron & Locke, 1970).


    
    Table 31.  The composition of water-soluble metabolites of carbaryl in plants.
               (% distribution of released aglycones 21 days after treatment (for apples, 53 days))

                                                                                                                                              

    Metabolite                          Beana      Beana     Wheatb       Potatoc       Cornd          Riced       Tomatoc    Applese
                                       (mature    (shell   (seedlings)    (mature    (seedlings)    (seedlings)    (mature
                                       foliage)    only)                  foliage)                                 foliage)
                                                                                                                                              

    5,6-Dihydrodihydroxycarbaryl         2.5       12.7        2.1          NDd          1.3            2.9            ND        2.1

    Methylol carbaryle                  29.9       47.9       10.5         16.2         13.3            7.8          25.4        2.8

    7-Hydroxycarbaryl                   24.2      trace         ND           ND           ND             ND            ND        0.8

    4-Hydroxycarbaryl                   15.0        4.1       23.6          4.1          8.9            3.7          13.8       13.7

    5-Hydroxycarbaryl                    7.3        9.4       21.3          4.1         12.9            5.6           3.4        9.2

    1-Naphthol                          13.8       21.0        1.1          5.8          3.2            3.5           8.1       11.3

    5,6-Dihydrodihydroxynaphthol          ND         ND         ND           ND          0.5            1.0            ND

    Carbaryl                             0.3        0.8       20.8         27.0         24.1           42.8          16.8       33.3

    Unknown(s)                            ND         ND        3.2           ND          2.9            2.2           5.2        3.0

    Unhydrolysed conjugate               7.1        4.1       17.4         42.8         33.0           30.4          27.3       12.6
                                                                                                                                             

    References: aWiggins & Weiden (1969); bAndrawes & Chancey (1970); cChancey & Andrawes (1971b); dChancey & Andrawes (1971a);
                eChancey (1974).
                fND = not detected.


    
         Studies on the  in vitro metabolism of carbaryl by a human
    liver fraction indicated that there was a difference in the
    metabolic pattern compared with that in the rat liver. The human
    liver produces at least two more metabolites (Strother, 1970).

    6.3.5  In vivo studies on humans

         The metabolism of carbaryl in humans appears to be
    qualitatively similar to that previously reported in other mammals.
    Metabolic reactions include: hydroxylation, hydrolysis, and
    conjugation. Metabolites of carbaryl were identified in the urine of
    human volunteers after ingestion of a 2 mg/kg dose (Andrawes &
    Myers, 1976). Only traces of the unchanged carbaryl could be
    detected in the urine indicating rapid metabolism. From the spectrum
    of the metabolites identified, a metabolic pathway of carbaryl in
    humans is proposed and shown in Fig. 6.

         The only detectable metabolites in urine samples taken from
    workers exposed to carbaryl dust were 1-naphthylglucoronide and
    sulfate (Knaak  et al., 1965). Later 1-naphthyl and
    4-hydroxycarbaryl, as conjugates of glucuronic and sulfuric acid,
    were found in a study on volunteers.

         Human exposure to carbaryl during aerial application for Gypsy
    moth control was assessed by Schulze  et al. (1979). The results of
    this study indicated a strong positive correlation between carbaryl
    exposure and the excretion of urinary 1-naphthol within 24 h of
    known exposure and a total lack of 1-naphthol in pre-exposure
    samples.

         The presence of these metabolites has been confirmed in six
    urine samples of workers with high exposures to carbaryl (Andrawes &
    Myers, 1976).

         One major and three minor interfering chemicals were detected
    in no-exposure samples as well as the maximum exposure samples.
    These interfering materials developed a colour similar to that of
    carbaryl metabolites upon spraying the chromatograms with
     p-nitrobenzene diazonium fluoborate. It is estimated that the
    major interfering pigment accounted for as much as one-third of the
    total colour observed on thin-layer chromatograms. These interfering
    chemicals may also be the cause of high blank values often
    encountered during the routine analysis of urine samples (Andrawes &
    Bailey, 1979).

    FIGURE 6

    6.4  Elimination and excretion in expired air, faeces, urine,
         milk, and eggs

         The elimination of metabolized carbaryl is rapid, and
    accumulation in animals seems unlikely, under normal exposure
    conditions. Carbaryl is generally excreted entirely within 24-96 h
    of intake. Elimination takes place mainly through the urine, faeces,
    and respiration, and, to a lesser extent, through the milk of dairy
    animals and the eggs of poultry.

         Carbaryl is mainly excreted as its product of hydrolysis,
    1-naphthol, which is detoxified to water-soluble glucuronide
    (Carpenter  et al., 1961), and sulfate (Whitehurst  et al., 1963),
    and only in trace amounts as 1-naphthol or unchanged.

         The average percentage of metabolites recovered after orally
    administered doses of 1-naphthyl 14C, methyl 14C, and carbonyl
    14C carbaryl to rats was 94% over a 7-day period (Knaak  et al.,
    1965). Only residues from carbaryl methyl 14C were detected after
    that, since the methyl moiety is incorporated in tissue (2-3%).
    Liberated naphthol is conjugated and excreted, while the liberated
    carbonyl groups are disposed of as respiratory14CO2 (Knaak
     et al., 1965). Forty-seven to 57% of the metabolites excreted
    retain the intact C-O-C(O)N-C structure, indicating a nonhydrolytic
    pathway for carbaryl. Monkeys and pigs (2 young females) excreted
    carbaryl as a conjugate of intact carbaryl and 4-hydroxycarbaryl,
    mainly glucuronides. Sheep also excreted 1-naphthyl glucuronide and
    sulfate and 4 (methylcarbamoyloxy)1-naphthylsulfate (Knaak  et al.,
    1968).

         Myers (1977) studied the correlation between the amount of
    carbaryl ingested and urinary metabolites levels. Metabolites were
    measured as three groups:

         I.   naphthyl sulfate; 

         II.  free and sulfated 5,6-dihydrodihydroxycarbaryl
              and dihydrodihydroxynaphthol;

         III. other conjugated (glucuronides) of naphthol,
              5,6-dihydrodihydroxycarbaryl, and
              5,6 dihydrodihydroxynaphthol.

    The amounts in groups I and II were 25.5-36.5% of the dose. When all
    three groups of metabolites were analysed, the amounts of
    metabolites for the same period represented 41.5-52.7% of the dose.
    Naphthol was the major metabolite found in Group III (mean 75% of
    all metabolites of the group). A good correlation was found between
    the amount ingested and urinary metabolites.

         Rats treated orally with naphthyl14C carbaryl (2.3 µci)
    excreted 90% of the administered radioactivity in the urine within 3
    days. During the 72-h sampling period, the faeces contained only
    2-5% of the radioactivity (Lucier  et al., 1972).

         Eighty per cent of 5 mg of 14C naphthyl carbaryl, given
    intraperitoneally to rats, (see section 6.3.2) was eliminated in the
    24-h urine and 10% in the faeces (Bend  et al., 1971). Enzymatic
    hydrolysis and reverse isotope dilution showed that 10% of the dose
    was excreted as 1-naphthyl-glucoronide, 5%, as 1-naphthylsulfate,
    3%, as conjugates of 4-hydroxycarbaryl, 5%, as 1-naphthylsulfate,
    3%, as conjugates of 4-hydroxycarbaryl, and 5% of 5-hydroxycarbaryl.
    About 2% of the carbaryl appeared unchanged in urine. Other
    radioactive metabolites were not identified.

         Following a single, ip injection in albino rats of both sexes,
    of methyl 14C and carbonyl 14C carbaryl at 30 mg/kg, 75-80% was
    recovered after 48 h in the expired air and urine. Liberated by
    hydrolysis,  N-methyl carbamic acid was spontaneously decomposed to
    methylamine and carbon dioxide (43.5%). The methylamine moiety was
    later demethylated to 14CO2, which was eliminated in the expired
    air and 14C formate (9.2%), which was excreted in the urine
    (Hassan  et al., 1966).

         In the study of Nye & Dorough (1976), 2.5% of the
    endotracheally administered carbaryl dose was exhaled as
    14C-carbon dioxide. More than 90% of the dose was eliminated in
    the urine during 3 days. The faeces contained 2-5%.

         A comparative study on the excretion of carbaryl after a
    7.5 µmol/kg, ip dose in rats was reported by Krishna & Casida (1966)
    who used three types of labelled carbaryl (Table 32).

    Table 32.  Fate of 14carbon in male Sprague-Dawley rats
               after ip administration of carbaryla
                                                                 

    Labelled position       Administered 14carbon recovered (%)
                                                                
                            Expired 14CO2       Urine      Faeces
                                                           
                                          0-24 h    24-48 h
                                                                 

    Carbonyl 14C                24.5       62.1       2.4    2.1

    Methyl 14C                  12.3       54.6       3.4    3.9

    Naphthyl 14C                 0.2       74.2       2.3    8.9

    Hydrolysis product         < 0.1       86.4       3.3    1.4
     naphthol 14C
                                                                 

    aFrom:  Krishna & Casida (1966).

         Biliary excretion of carbaryl was studied in bile-duct
    cannulated rats. Naphthyl 14C and methyl 14C carbaryl (50 µg)
    were administered intravenously to rats (see section 6.3.2). During
    the first 2 h of collection, 90% of the total biliary radioactivity
    was eliminated (Bend  et al., 1971). After oral application of
    0.01 mg/kg naphthyl-14C carbaryl to rats, 37.5% was excreted via
    the bile in the first 3 h and 45.4% (cumulative percentage) of the
    dose was eliminated within 48 h. Faecal elimination was 1.4% and
    urine elimination was 42.3% (Marshall  et al., 1979). The results
    of Struble  et al. (1983a), who used higher doses of carbaryl (1.5,
    31, and 300 mg/kg) on male Sprague-Dawley rats were similar. Twelve
    hours after administration, 15-46% of the 14C was excreted in the
    bile, 10-40% in the urine, and less than 1% was eliminated in
    faeces. Three metabolites were identified from the bile, the major
    one being 5-6-dihydro-5-6-dihydroxycarbaryl glucoronide (12-18% of
    the biliary 14C).

         On the basis of a study on 50, male, Sprague-Dawley rats,
    Borzelleca & Skalsky (1980) reported that carbaryl metabolites in
    the blood were also present in the saliva, at similar
    concentrations.

         Leeling & Casida (1966) studied carbaryl metabolites in the
    urine of one male and one female New Zealand White rabbit. The
    ether-extractable metabolites found in the urine were:
     N-hydroxymethyl carbaryl, 4-hydroxycarbaryl, 5-hydroxycarbaryl,
    5,6-dihydro-5,6-dihydroxycarbaryl, 5,6-dihydro-5,6-trihydroxy-1-
    naphthol, and 1-naphthol.

         Thirty-five, adult, female American cockroaches ( Periplaneta
     americana) were injected through the central abdominal wall with
    5 µg of carbaryl-carbonyl 14C, carbaryl methyl 14C, or 2 µg
    carbaryl naphthyl 14C. Metabolites similar to those appearing in
    rat liver microsomes were formed. About 19% of the radioactivity of
    carbaryl carbonyl 14C was eliminated as 14C-carbon dioxide in
    24 h (Dorough & Casida, 1964).

         Excretion of carbaryl in milk was studied by Baron (1968).
    Application of a total dose of 2 g carbonyl carbaryl 14C to a
    lactating cow resulted in approximately 1% of radioactive residues
    in the milk. In skim milk, 87% of these residues were water-soluble
    and 13% chloroform-soluble. About 90-95% of the14C radioactivity
    in the soluble component was removed after crystallization of
    lactose.

         The metabolism of carbaryl naphthyl 14C was studied in one
    lactating Jersey cow (Dorough, 1967). Two consecutive single
    treatments at 6-day intervals with 0.25 mg/kg body weight (total
    125 mg) and one single dose of 3.05 mg carbaryl naphthyl 14C/kg
    body weight added to the feed, resulted in radiolabelled residues in
    the milk for as long as 60 h after treatment. The first sample of
    milk, taken after 6 h, showed maximum concentrations of chloroform
    extractables, water-soluble, and unextractable, residues in whole
    milk in the range of 0.063-0.95 mg/litre. Residues of only a
    slightly lower magnitude were detected in the 12-h milk samples and
    rapidly declined in 24-h samples. Thirty per cent of the residues in
    the 6-h sample was a chloroform-extractable metabolite, tentatively
    identified as 5,6-dihydro-5,6-dihydroxy-1-naphthyl-
     N-methylcarbamate. About 0.35% of the total dose was detected in
    the milk in both treatments, 70% in the urine, and 11% in the faeces
    in 0.25 mg/kg treatment, and 58% in the urine and 15% in the faeces
    in the 3.05 mg/kg treatment. The highest levels in the tissues of
    the cow, killed on an unspecified day after treatment, were found in
    the liver, kidney, and ovaries.

         A single lactating cow was treated orally with a daily total
    dose of 518 mg 14C-carbaryl (0.77 mg/kg body weight), given in two
    doses, 12 h apart. Results are shown in Table 33 (Dorough, (1969).
    Fifty-nine per cent of the radioactivity from a14C-labelled oral
    dose of carbaryl administered to a cow was recovered from the urine
    within the first 24 h (Saini & Dorough, 1978).

         The passage of14C into the milk and its presence in the
    suckling neonates has been studied by whole-body autoradiography in
    rats fed 14C-methyl carbaryl. The highest concentrations in
    newborn offspring, after 48 h, were found in the stomach contents,
    the liver, the hair, and the bone marrow (Benard  et al., 1979).

    Table 33.  Distribution and excretion of total-14C equivalents in
               milk, urine, faeces, and tissues, 24 h after one-day oral
               application of carbaryl in a lactating cow
                                                                

    Sample                   mg/kg               Dose recovered
                                                       (%)
                                                                

    Milk                     0.04                      0.09

    Urine                   22.4                      58.64

    Faeces                   0.47                      1.65

    Tissues:

    - liver                  0.098                     0.21

    - kidney                 0.382                     0.17

    - leg muscle             0.027                      nil

    - fat                    0.014                      nil
                                                                

         A Saanen goat was treated orally with 1.34 mg carbaryl carbonyl
    14C/kg. The excretion of radioactivity in the urine was 7.4% at
    2 h, 24% at 4 h, and 45% at 24 h. In total, 47% of the radioactivity
    was excreted the urine. In the milk, the peak was 0.9 mg/litre at
    8 h, dropping to 0.008 mg/litre 60 h after the administration of
    carbaryl (Dorough & Casida, 1964).

         The excretion of carbaryl was studied in hens. Carbaryl-
    carbonyl14C (10 mg/kg body weight) was given orally to Leghorn
    hens. Fifty per cent of the 14C was expired within 48 h. When
    carbarylnaphthyl 14C was applied at the same dose, no
    radioactivity was detected in the expired gases. The urine was the
    primary route of excretion. 14Carbon remaining in the carcass,
    48 h after dosing, accounted for 1.4 and 7.1% of the dose given as
    the ring-labelled and carbonyl-labelled compound, respectively
    (Paulson & Feil, 1969). The main metabolites found in the urine of
    hens were: 1-naphthol, 1-naphthyl glucoronide, and sulfate esters of
    1-naphthol, 4-hydroxycarbaryl, and 5-hydroxycarbaryl. Conjugates
    with other metabolites were also found in small quantities (Paulson
     et al., 1970). Mature hens were given a single oral dose of
    carbaryl naphthyl 14C at 10 mg/kg body weight. Eggs collected for
    12 days contained a total dose of 0.33% of the 14C administered
    (Paulson & Feil, 1969).

         The fate of naphthyl-1-14C carbaryl in laying chickens was
    studied by Andrawes  et al. (1972). Chickens (3 White Leghorn in
    each group) were fed 7, 12, or 70 mg/kg carbaryl in the feed twice
    daily for 14 days. They had been pretreated for 17 days with the
    same doses of nonlabelled carbaryl in feed. Residues reached maximum
    levels within 1 day in excrement, 2 days in egg white, and 6-8 days
    in egg yolk. After the end of dosing, the half-life of 14C
    residues was <1 day in the excrement and egg white, 2-3 days in the
    egg yolk, and 5 days in the carcass. Metabolites and carbaryl found
    in the eggs of hens, fed 70 mg carbaryl/kg averaged in total 19.7 µg
    of 14C carbaryl equivalent per egg (16.3 µg in yolk and 3.4 µg in
    white), collected between the 9th and the 14th day of dosing.
    Naphthyl-l-sulfate was the largest single component of egg residues
    accounting for the higher concentration of residues in the egg yolk.

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Microorganisms

    7.1.1  Soil microorganisms

         Studies of the effects of insecticides on soil microorganisms
    are complex and subject to many sources of variation. It is
    therefore difficult to assess the practical significance of the
    results of such studies.

         Varsheny & Gaur (1972) studied the impact of carbaryl (as
    Sevin) on soil fungi. They determined the size of the fungal
    population and the species composition of the fungal community after
    plating out extracts of soil samples on various media. The authors
    suggested that, at very high rates of addition to the soil (up to
    5000 mg/kg), there was evidence of a change in species composition
    and an increase in the total fungal population.

         In laboratory cultures of saltmarsh protozoans (dominated by
     Euplotes sp.), Weber  et al. (1982) found that both carbaryl and
    1-naphthol caused dose-related mortality. For both compounds,
    mortality at 1 mg/litre was about 50%. There was almost 100%
    mortality at 10 mg/litre.

         Carbaryl inhibited the growth of cultures of  Bacillus subtilis
    (DeGiovanni & Donnelly, 1968).

    7.1.2  Aquatic microorganisms

         Edmiston  et al. (1985) conducted a detailed study of the
    effects of carbaryl on  Paramecium multimicronucleatum. The 24-h
    LC50 was 28 µg/litre in a static plate test. Effects on the oxygen
    uptake of cultures and effects on the cell surface were also

    reported, but these results were mostly obtained using
    concentrations in excess of the 24-h LC50, and must be of limited
    value.

         Murray & Guthrie (1980) studied the responses of bacterial
    cultures originating from Lake Houston. The respiratory rate of
    bacterial cultures was increased at water temperatures of between
    23-33 °C. Plate counts of bacterial colonies suggested that carbaryl
    treated cultures contained more bacteria than control cultures on
    most days in a 26-day study.

    7.2  Aquatic organisms

         Aquatic toxicity studies have been conducted in the laboratory
    and field to define the biological effects associated with acute and
    long-term exposure to carbaryl and the degradation product,
    1-naphthol, of aquatic vertebrates and invertebrates. More data are
    available for freshwater organisms than for saltwater organisms. In
    addition, actual and simulated field studies have been conducted to
    assess the impact of carbaryl exposure on freshwater invertebrates.

    7.2.1  Aquatic invertebrates

         Studies on the toxicity of carbaryl for non-target aquatic
    invertebrates have included investigations on molluscs, crustaceans,
    and insects, concentrating on organisms of commercial importance,
    organisms most likely to be exposed during a typical application of
    carbaryl, or on standardized test species typically used in aquatic
    toxicity tests. The acute and long-term laboratory studies under
    various environmental conditions (pH, temperature, water hardness,
    etc.) are briefly reviewed in Table 34.

         Most of the studies on the toxicity of carbaryl for aquatic
    invertebrates have been conducted under laboratory conditions and,
    consequently, the results only yield data on the relative toxicity
    of the substance. They do not reflect realistic exposure in the
    environment. Most of the laboratory studies evaluate constant,
    short-term (less than 1 week) exposure to carbaryl under static or
    flow-through conditions. There are few long-term studies on the
    effects of carbaryl on aquatic invertebrates. Exposures in the
    environment are typically localized, at much lower concentrations
    than in aquatic toxicity tests and are not constant.

         The toxicity of carbaryl on the early development of the sea
    urchin was studied by Hernandez  et al. (1990). Developmental
    stages with active cleavage and cellular mobilization (blastula and
    gastrula) turned out to be more sensitive. The next two stages
    (prism and pluteus) were less sensitive and EC50 values were 8-26
    times higher. This effect may be connected with increased
    detoxication processes by the cytochrome oxidase system.


    
    Table 34.  Acute toxicity of carbaryl for invertebrates
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Crustacea
    (Freshwater)

    Water flea

    Daphnia magna      unknown               stat         16           42         7.4   48-h LC50          5.6        Sanders et al. (1983)

    Daphnia magna      technical                                                        96-h LC50         3280        Lejczak (1977a)

    Daphnia magna      unknown                                                          48-h EC50         0.26        Rawash et al. (1975)

    Daphnia magna      technical                                                        21-day MATC      1.5-3.3      Surprenant (1985c)
                                                                                        21-day NOEC        6.0
                                                                                        (survival)

    Daphnia pulex      technical             stat         16           44         7.1   48-h LC50          6.4        Mayer & Ellersieck (1986)

    Simocephalus       unknown               stat         10           44         7.1   48-h LC50          11         Johnson & Finley (1980)
    serrulatus                               stat         16           44         7.1   48-h LC50          7.6
                                             stat         21           44         7.1   48-h LC50          8.1

    Ostracod

    Cypridopsis
    vidua              unknown    adult      stat         21           272        7.4   48-h LC50          115        Mayer & Ellersieck (1986)

    Sow bug

    Asellus
    brevicaudus        technical  adult      stat         18           44         7.1   96-h LC50          280        Johnson & Finley (1980)
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Crustacea
    (Freshwater)

    Amphipod

    Gammarus
    fasciatus          unknown    adult      stat         21           44         7.1   96-h LC50          26         Johnson & Finley (1980)

    Gammarus
    lacustris          unknown    adult      stat         21           44         7.1   96-h LC50          22         Johnson & Finley (1980)

    Gammarus           unknown    adult      stat         12           40         6.5   48-h LC50         8.13        Mayer & Ellersieck (1986)
    pseudolimnaeus                adult      stat         12           40         7.5   48-h LC50         11.5
                                  adult      stat         12           40         8.5   48-h LC50          7.8

    Gammarus pulex     technical                                                        48-h LC50          29         Bluzat & Seuge (1979)

    Gammarus           technical                                                        96-h LC50          16         Sanders et al. (1983)
    pseudolimnaeus

    Gammarus           technical                                                        96-h LC50          13         Woodward & Mauck (1980)
    pseudolimnaeus

    Glass shrimp

    Palaemonetes       unknown    adult      stat         21           272        7.4   96-h LC50          5.6        Johnson & Finley (1980)
    kadiakensis                   25-31 mm   stat                                       96-h LC50          120        Chaiyarach et al. (1975)
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Crayfish

    Procambarus sp.    technical  immature   stat         12           42         7.5   96-h LC50         1900        Mayer & Ellersieck (1986

    Procambarus        unknown    60-70 mm   stat                                       96-hLC50          2430        Chaiyarach et al. (1975)
    simulans

    Procambarus        technical                                                        96-h LC50          500        Cheah et al. (1978)
    acutus

    Crustacea
    (Freshwater)

    Prawn

    Macrobrachium      technical                                                        96-h LC50          19         Omkar & Shukla (1985)
    lamarrei

    Upogebia           wettable powderd                                                 48-h EC50          90         Stewart et al. (1967)
    pugettensis        1-naphthol                                                       48-h EC50         4400

    Callianassa        wettable powderd                                                 48-h EC50          80
    californiensis     1-naphthol                                                       48-h EC50         3500

    Hemigrapsus        wettable powderd                                                 24-h EC50          710
    oregonensis        1-naphthol                                                       24-h EC50        74 200
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Crustacea
    (estuarine &
    marine)

    Blue crab

    Callinectes        unknown    juvenile   flow         29           27s              48-h LC50          320        Mayer (1987)
    sapidus

    Brown shrimp

    Penaeus aztecus    unknown    juvenile   flow         30           28s              48-h LC50          1.5

    Pink shrimp

    Penaeus
    duorarum           unknown    juvenile   flow         23           29s              48-h LC50          32

    Grass shrimp

    Palaemonetes       unknown    juvenile   flow         23           29s              48-h LC50          28
    pugio                         3-4 days   stat         24         28-30s             96-h LC50          22         Thursby & Champhon (1991)

    Crustacea
    (estuarine &
    marine)
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Mysid shrimp

    Mysidopsis bahia   unknown               flow                                       96-h LC50         > 7.7       Nimmo et al. (1981)

    Mysidopsis bahia   technical                                                        96-h LC50          6.7        Surprenant (1985b)
                                                                                        NOEC               5.1

    Mysidopsis bahia              24 h       flow         25           31s              96-h LC50         8.46        Thursby & Champhon (1991)
                                  24 h       stat         24           30s              96-h LC50          19
                                  24 h       flow         26         31-32s             28-day LC50        9.9

    Ostracod

    Cypretta kawatai   technical                                                        72-h LC50         1800        Hansen & Kawatski (1976)

    Insects

    Stonefly

    Isogenus sp.       unknown    larva      stat          7           35          7    96-h LC50          2.8        Mayer & Ellersieck (1986)

    Pteronarcys        technical                                                        96-h LC50          4.8        Johnson & Finley (1980)
    californica

    Mosquito

    Culex pipiens      technical                                                        24-h LC50          75         Rawash et al.  (1975)
                                                                                                                                              
    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Insects

    Midge

    Chironomus         technical                                                        24-h LC50           7         Karnak & Collins (1974)
    tentans

    Chironomus         technical                                                        72-h LC50         5900        Hansen & Kawatski (1976)
    tentans

    Chironomus         technical                                                        48-h EC50          10         Sanders et al. (1983)
    plumosus

    Chironomus         unknown    larva      stat         20                       4    24-h LC50          106        Fisher & Lohner (1986)
    riparius                      larva      stat         20                       6    24-h LC50          133
                                  larva      stat         20                       8    24-h LC50          127

    Back swimmer

    Notonecta          technical                                                        96-h LC50          200        Federle & Collins (1976)
    undulata

    Water stick

    Ranatra elongata   wettable                                                         96-h LC50          624        Shukla et al. (1982)
                       powder
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Diptera

    Chaoborus          technical                                                        48-h LC50          296        Bluzat & Seuge (1979)

    Ephemeroptera
    (Mayfly)

    Cloeon             technical                                                        48-h LC50          480

    Crawling water
    beetle

    Peltodytes sp.     technical                                                        96-h LC50         3300        Federle & Collins (1976)

    Insects

    Stone fly

    Pteronarcella      unknown    larva      stat         16           44         7.1   96-h LC50          1.7        Johnson & Finley (1980)
    badia                         larva      stat         12           38         6.5   96-h LC50          11         Woodward & Mauck (1980)
                                  larva      stat         12           38         7.5   96-h LC50          13         Mayer & Ellersieck (1986)
                                  larva      stat         12           38         8.5   96-h LC50          29

    Claasenia          unknown    larva      stat         16           44         7.1   96-h LC50          5.6        Johnson & Finley (1980)
    sabulosa
                                                                                                                                              
    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              
    Molluscs

    Common mussel

    Mytilus edulis     unknown                                                          48-h EC50       > 30 000      Roberts (1975)
                                                                                        for byssal
                                                                                        attachment

    Mytilus edulis     wettable   larva                                                 48-h EC50         2300        Stewart et al. (1967)
                       powder                                                           48-h EC50         1300
                       1-naphthol

    Giant oyster

    Crassostrea gigas  wettable   larva                                                 48-h EC50         2200
                       powder                                                           48-h EC50          800
                       1-naphthol

    Clinocardium       wettable   adults                                                24-h EC50         7300
    nuttallii          powder                                                           24-h EC50         6400
                       1-naphthol

    Molluscs

    Eastern Oyster

    Crassostrea                   juvenile   flow         29           27s              96-h EC50        > 2000       Mayer (1987)
    virginica
                                                                                                                                              

    Table 34 (continued)
                                                                                                                                              

    Organism           Test       Size/age   Stat/    Temperature   Hardness      pH    Parameterc    Concentration   Reference
                       material              Flowa       (°C)      (mg/litre)b                         (µg/litre)
                                                                                                                                              

    Crassostrea        technical                                                        48-h EC50         2700        Surprenant (1985a);
    virginica                                                                                                         Dionne et al. (1985)

    Mactrid clam

    Rangia cuneata                35-50 mm   stat                      5s               96-h LC50        125 000      Chaiyarach et al. (1975)

    Lymnaea            technical                                                        48-h LC50        21 000       Bluzat & Seuge (1979)
    stagnalis
                                                                                                                                              

    aStat = static conditions (water unchanged for the duration of the test).
     Flow = flow-through conditions (carbaryl concentration in water continuously maintained).
    bHardness = expressed as mg CaCO3/litre.
     s = salinity (%).
    cEC50s for oyster based on shell deposition.
    d50-80% wettable powder.


    
         Carbaryl is slightly toxic for freshwater and marine molluscs
    (clams, mussels, oysters). Acute toxicity typically occurs in adult
    molluscs at concentrations ranging from 1 mg carbaryl/litre to over
    100 mg/litre. The major hydrolytic product of carbaryl, 1-naphthol,
    is slightly more acutely toxic for molluscs (mussel, pacific oyster)
    than the parent compound (Stewart  et al., 1967). In addition,
    larvae and young juveniles are more sensitive to carbaryl exposure
    than older juveniles and adults.

         There have been few studies on the effects of carbaryl on the
    growth of molluscs. Davis (1961) and Butler (1962) found that
    carbaryl (80% WP) concentrations of 1.0-2 mg/litre reduced the
    larval development and growth of oysters ( Crassostrea virginica)
    and clams ( Venus mercenaria).

         The effects of a 1-h exposure to carbaryl (80% WP) and its
    hydrolytic product, 1-naphthol, were studied on six developmental
    stages of the mussel ( Mytilus edulis) (Armstrong & Millemann,
    1974c). The six stages included unfertilized eggs to the early
    veliger stage, 32 h after fertilization. Unfertilized eggs and the
    first polar body stage were exposed to carbaryl and 1-naphthol
    (separately). The acute toxicity values of carbaryl and 1-naphthol
    were similar for the first two stages, ranging from approximately 5
    to 25 mg/litre. The stage of development most sensitive to carbaryl
    was the first polar body stage. Thereafter, susceptibility decreased
    as age of the larvae increased.

         LC50 values for crustacea varied from 5 to 9 µg/litre (water
    fleas, mysid shrimps), 8 to 25 µg/litre (scud), and 500 to
    2500 µg/litre for crayfish. The hydrolytic metabolite 1-naphthol was
    less toxic for daphnids and shrimps.

         The effects of carbaryl (80% WP) on the life stages of
    crustacea have been studied in the Dungeness crab ( Cancer magister)
    (Buchanan  et al., 1970). Early larvae were more sensitive to
    carbaryl than juveniles and adults. Carbaryl (1.0 mg/litre) did not
    affect hatching of eggs but prevented moulting of all prezoeae to
    zoeae. The concentration that killed 50% of the first zoeae during a
    96-h exposure was estimated to be 1 mg/litre.

         Young juvenile crabs were more sensitive than older juveniles
    or adults. The 24-h EC50s (death or irreversible paralysis) were
    estimated to be 0.076 and 0.35-0.62 mg/litre for second and ninth
    stage juveniles, respectively. At 0.032 mg/litre, juvenile crabs

    were not affected when held in uncontaminated water after exposure.
    In adult crabs, the 24-h and 96-h EC50s (death or paralysis) were
    0.49 and 0.26 mg/litre, respectively. Post-larval Dungeness crabs
    had about the same sensitivity to carbaryl as other crabs. The 24-h
    EC50 (death or paralysis) of small stone crabs was 1.0 mg/litre
    (Butler, 1962), that of juvenile blue crabs, 0.55 mg/litre (Butler,
    1963), and that of adult crabs, 0.06-1.05 mg/litre (Stewart  et al.,
    1967).

         As part of fresh water biota, daphnids have been used as assay
    organisms to determine toxic concentrations of a variety of
    pesticides. Laboratory bioassays were conducted with carbaryl to
    determine its toxicity and immobilization values for two species of
    daphnids,  Daphnia pulex and  Simocephalus serrulatus. The EC50s
    for overt effects were 0.0064 mg/litre for Daphnia pulex and
    0.0076 mg/litre for  Simocephalus serrulatus (Sanders & Cope,
    1966).

         In a long-term study,  Daphnia magna was exposed to technical
    carbaryl for 21 days; reproductive performance was the most
    sensitive indicator; the MATC was 1.5-3.3 µg/litre (Surprenant,
    1985c).

         Aquatic insects in the orders Plecoptera (stoneflies) and
    Ephemeroptera (mayflies) are generally highly sensitive to low
    levels of carbaryl.

         The effects of 0.6-50.0 mg carbaryl/litre were studied on
    selected aquatic organisms, including:  Scanedesmus quadricauda,
     Lemna minor, Lebistes reticulatus and  Daphnia magna (Bogacka &
    Groba, 1980). Carbaryl depressed reproduction, biomass, and
    chlorophyll content in  Lemna minor (vascular plant) after 24 h
    exposure at a concentration >6.6 mg/litre. An almost 100% decrease
    occurred at a concentration of 50 mg/litre. Inhibition of
    photosynthesis intensity in the alga  Scenedesmus quadricauda was
    about 50% at a concentration of carbaryl in the water of
    32 mg/litre, and 65% at a concentration of 56 mg/litre, after 24 h
    exposure. Less than 10% inhibition occurred at a concentration of
    1.8 mg/litre. A decrease in the production of chlorophyll was
    demonstrated at 4.4 mg/litre.

         Carbaryl applications of 5.7 or 11.4 kg/ha were effective in
    controlling ghost shrimp ( Callianassa californiensis) as an oyster
    pest. The numbers of various clams in the mud were reduced by 22 and

    38%, respectively. Clam species differed in susceptibility. For
    example, gaper clams (Tresus capax) were reduced by 58 and 69%.
    Polychaetes and nemertean worms were not affected during 30 days of
    observation (Armstrong & Millemann, 1974a,b).

    7.2.2  Fish

    7.2.2.1  Acute toxicity

         Acute toxicity studies have been conducted with technical
    carbaryl, several formulations, and 1-naphthol to determine LC50
    values for several freshwater and marine fish (Table 35). The
    results indicated that short-term exposure (< 4 days) to carbaryl
    and its formulations showed some toxicity for fish (96-h LC50s =
    1-30 mg/litre). There were no differences in the toxicity of two
    formulations (4-oil-sevin and XLR) for rainbow trout and bluegill.
    The LC50s for sheepshead minnow (exposed to technical material)
    and rainbow trout (exposed to 4-oil and XLR) were similar and both
    were generally more sensitive than bluegill. The toxicity of
    1-naphthol for rainbow trout, bluegill, and sheepshead minnow was
    determined by Springborn (1988a); 96-h LC50 values for these
    species were 0.76, 1.4, and 1.2 mg/litre, respectively. The
    corresponding NOECs were < 0.43, 0.55, and 0.47 mg/litre. The
    metabolite, 1-naphthol, was more acutely toxic than the formulations
    for bluegill. However, the toxicities of 1-naphthol and the
    formulations were similar for rainbow trout and sheepshead minnows.

         Few studies report acute toxicity values for fish that are
    lower than 1 mg/litre. Cold water fish (Salmonidae), such as Coho
    Salmon and trout, seem to be susceptible to carbaryl, while the
    catfish (Ictaluridae) is tolerant (Macek & McAllister, 1970; Post &
    Schroeder, 1971). Irritability, sluggishness, and loss of
    equilibrium were classical signs of acute intoxication. Rainbow
    trout (Oncorhynchus mykiss), exposed to 1 mg carbaryl/litre for
    96 h, exhibited decreased swimming capacity and swimming activity;
    the capacity to capture and consume prey was also diminished (Little
     et al., 1990).

         Other end-point concentrations have been established for
    carbaryl for various species. Reference should be made to the
    original documentation to obtain a fuller understanding of these
    measures of toxicity. The lowest no-observed-effect concentration
    (NOEC) was found for rainbow trout at 0.065 mg/litre. Other NOECs
    were at least an order of magnitude greater. Maximum acceptable
    toxic concentrations (MATCS) have also been calculated. Bansal
     et al. (1980) estimated 30-day MATCs for 4 species of carp exposed
    to carbaryl (Sevin as a 50% wettable powder). For all species, the
    MATC was between 0.052 and 0.078 mg/litre. Verma  et al. (1984)
    reported a 60-day MATC of between 0.09 and 0.11 mg/litre for another
    carp species, exposed to the same type of formulation of Sevin.


    
    Table 35.  Acute toxicity of carbaryl for fish
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Freshwater

    Coho salmon           1 g    stat        13            44        7.1                96-h LC50        4.3        Mayer & Ellersieck (1986)
    (Oncorhynchus                stat        13            42        7.1                96-h LC50        2.4
    kisutch)            4.6 g    stat        13            42        7.1                96-h LC50        1.8
                        5.1 g    stat        13            42        7.1                96-h LC50        2.7
                       10.6 g    stat        13            42        7.1                96-h LC50        1.2
                       19.1 g                                                 CT        96-h LC50        0.8        Macek & McAllister (1970)
                                                                              CT        96-h LC50        1.3        Post & Schroeder (1971)

    Chinook salmon   fingerling  flow        13           314        7.5                96-h LC50        2.4        Mayer & Ellersieck (1986)
    (Oncorhynchus
    tshawytscha)

    Cutthroat trout     0.5 g    stat        12            40        7.5                96-h LC50        7.1
    (Salmo clarkii)     0.5 g    stat        12           330        7.8                96-h LC50        4.0
                        0.6 g    stat         7            42        7.5                96-h LC50        6.0
                        0.7 g    stat        12            40        6.5                96-h LC50        5.0
                        0.6 g    stat        12            40        8.5                96-h LC50        1.0
                                                                              CT        96-h LC50        6.0        Woodward & Mauck
                                                                              C49       96-h LC50        6.7        (1980)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Rainbow trout       1.5 g    stat        12            42        7.1                96-h LC50        2.0        Mayer & Ellersieck (1986)
    (Oncorynchus        1.5 g    stat        12           272        7.4                96-h LC50        1.2
    mykiss)             1.2 g    stat        12            40        7.4                96-h LC50        3.5
                        1.2 g    stat        12           320        7.4                96-h LC50        3.0
                          1 g    stat        12            40        7.4                96-h LC50        1.6
                          1 g    stat        17            40        7.4                96-h LC50        1.1
                          1 g    stat        12            40        6.5                96-h LC50        1.2
                          1 g    stat        12            40        7.5                96-h LC50        0.8
                          1 g    stat        12            40        8.5                96-h LC50        1.5
                        0.5 g    flow        17           314        7.5                96-h LC50        1.3

                                                                              CT        96-h LC50        4.3        Macek & McAllister (1970)
                                                                              XLR       96-h LC50        1.4        Springborn (1985)
                                                                              S4        96-h LC50        1.3
                                                                              CT        96-h LC50        2.2        Sanders et al. (1983)
                                                                              CT        96-h LC50        1.5        Post & Schroeder (1971)

    Atlantic salmon     0.2 g    stat         7            42        7.5                96-h LC50        0.3        Mayer & Ellersieck (1986)
    (Salmo salar)       0.2 g    stat        12            42        7.5                96-h LC50        0.9
                        0.2 g    stat        17            42        7.5                96-h LC50        1.0
                        0.4 g    stat        12            42        6.5                96-h LC50        1.3
                        0.4 g    stat        12            42        8.5                96-h LC50        0.9

    Brown trout         0.6 g    stat        12            42        7.5                96-h LC50        6.3
    (Salmo trutta)   fingerling  flow        12           314        7.5                96-h LC50        2.0
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Brook trout         0.8 g    stat        12            42        7.5                96-h LC50        2.1        Mayer & Ellersieck (1986)
    (Salvelinus         0.8 g    stat         7            42        7.5                96-h LC50        3.0
    fontinalis)           1 g    stat        17            42        7.5                96-h LC50        0.7
                        0.7 g    stat        12            42        6.5                96-h LC50        4.6
                        0.7 g    stat        12            42        8.5                96-h LC50        2.1
                        0.7 g    stat        12            42        9                  96-h LC50        1.1
                        0.8 g    stat        12            42        7.5                96-h LC50        1.2
                        0.8 g    stat        12           300        7.5                96-h LC50        1.3

    Lake trout          1.7 g    stat        12            40        7.5                96-h LC50        0.7
    (Salvelinus         1.7 g    stat        12            40        6                  96-h LC50        0.7
    namaycush)          1.7 g    stat        12            40        9                  96-h LC50        0.9
                        0.5 g    stat        12           162        7.4                96-h LC50        0.9
                        2.6 g    flow        12           162        7.4                96-h LC50        2.3

    Gold fish           0.9 g    stat        18            40        7.1                96-h LC50       13.2
    (Carassius          0.9 g    stat        18           272        7.4                96-h LC50       12.8
    auratus)

    Common carp         0.6 g    stat        18            40        7.1                96-h LC50        5.3
    (Cyprinus
    carpio)

                         fry                                                  CT        96-h LC50        1.7        Chin & Sudderuddin (1979)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Carp                                                                    C50 WP      72-h LC50       10.4        Toor & Kaur (1974)
    (Cyprinus
    carpio
    communis)

    (Catla catla)                                                              S        96-h LC50        6.4        Tilak et al. (1981)

    (Cirrhina                                                               S50 WP      96-h LC50        2.0        Verma et al. (1984)
    mrigala)

    Fathead             0.5 g    stat        12            42        7.5                96-h LC50       14.0        Mayer & Ellersieck (1986)
    minnow              0.8 g    stat        18            40        7.1                96-h LC50       14.6
    (Pimephales         0.8 g    stat        18           272        7.4                96-h LC50        7.7
    promelas)

    Sheepshead                                                                CT        96-h LC50        2.2        Springborn (1985)
    minnow
    (Cyprindon
    variegatus)

    Black bullhead      1.2 g    stat        18            40        7.1                96-h LC50       20.0        Mayer & Ellersieck (1986)
    (Ictalurus
    malas)

    Channel catfish     1.5 g    stat        18            40        7.1                96-h LC50       15.8
    (Ictalurus          1.5 g    stat        18           272        7.4                96-h LC50        7.8
    punctatus)       fingerling  flow        12           314        7.5                96-h LC50       17.31
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Freshwater          1.1 g    stat        28                             S50 WP      72-h LC50       17.5        Arunachalam et al. (1980)
    catfish
    (Mystus
    vittatus)

                                                                               S        96-h LC50        2.4        Tilak et al. (1981)

    (Mystus                                                                    S        96-h LC50        4.6
    cavasius)

    Freshwater                                                                CT        96-h LC50       46.9        Tripathi & Shukla (1988)
    catfish
    (Clarias
    batrachus)

                                                                              CT        96-h LC50      107.7

    Catfish                                                                   CT        96-h LC50        9.7        Lejczak (1977a)
    (Lebistes
    reticulatus)

    Green sunfish       1.1 g    stat        18            40        7.1                96-h LC50       11.2        Mayer & Ellersieck (1986)
    (Lepomis            1.1 g    stat        18           272        7.4                96-h LC50        9.5
    cyanellus)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Bluegill            1.2 g    stat        18            40        7.1                96-h LC50        6.8
    (Lepomis            1.2 g    stat        18           272        7.4                96-h LC50        5.2
    macrochirus)        0.4 g    stat        12            44        7.4                96-h LC50        7.4
                        0.4 g    stat        22            44        7.4                96-h LC50        5.2
                        0.8 g    stat        12            40        7.4                96-h LC50       16.0
                        0.8 g    stat        17            40        7.4                96-h LC50        7.0
                        0.8 g    stat        22            40        7.4                96-h LC50        8.2
                        0.4 g    stat        17           320        7.4                96-h LC50        6.2
                        0.7 g    stat        17            40        6.5                96-h LC50        5.4
                        0.7 g    stat        17            40        7.5                96-h LC50        5.2
                        0.7 g    stat        17            40        8.5                96-h LC50        1.8
                        0.7 g    stat        17            40        9.5                96-h LC50        2.6
                        0.6 g    flow        12           314        7.5                96-h LC50        5.1
                                                                              XLR       96-h LC50        9.8        Springborn (1985)
                                                                              S4        96-h LC50       10

    Mosquito fish     30-40 mm   stat                                                   96-h LC50       31.8        Chaiyarach et al. (1975)
    (Gambusia
    affinis)

    Largemouth          0.9 g    stat        18            40        7.1                96-h LC50        6.4        Mayer & Ellersieck (1986)
    bass
    (Micropterus
    salmoides)

    Black crapple         1 g    stat        18            40        7.1                96-h LC50        2.6
    (Pomoxis
    nigromaculatus)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Yellow perch        1.4 g    stat        18            40        7.1                96-h LC50        0.7        Mayer & Ellersieck (1986)
    (Perca              0.6 g    stat        12            42        7.5                96-h LC50        5.1
    flavescens)           1 g    stat         7            42        7.5                96-h LC50       13.9
                          1 g    stat        12            42        7.5                96-h LC50        5.4
                          1 g    stat        17            42        7.5                96-h LC50        3.4
                          1 g    stat        22            42        7.5                96-h LC50        1.2
                        0.9 g    stat        12            42        6.5                96-h LC50        4.0
                        0.9 g    stat        12            42        7.5                96-h LC50        4.2
                        0.9 g    stat        12            42        8.5                96-h LC50        0.5
                        0.9 g    stat        12            42        9                  96-h LC50        0.4
                          1 g    stat        12            42        8                  96-h LC50        3.8
                          1 g    stat        12           170        8                  96-h LC50        5.0
                          1 g    stat        12           300        8                  96-h LC50        3.8
                     fingerling  flow        12           314        7.5                96-h LC50        1.4

    Snakehead fish                                                            CT        48-h LC50        8.7        Rao et al. (1985a)
    (Channa
    punctatus)

                                                                            C50 WP      96-h LC50       19.5        Singh et al. (1984)

                                                                            C50 WP      48-h LC50        8.1        Rao et al. (1985b)

    (Anabas                                                                    S        96-h LC50        5.5        Tilak et al. (1981)
    testulus)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Tilapid fish                                                            S50 WP      72-h LC50        8.0        Koudinya & Ramamurthi
    (Sarotherodon                                                                                                   (1980)
    mosambica)

    (Tilapia sp.)                                                              C        48-h LC50        5.5        Basha et al. (1983)

    Estuarine                                                                  C        96-h LC50        2.2        Lingaraja & Venugopalan
    teleost                                                                                                         (1978)
    (Therapon
    jarbus)

    (Hetero-pneustes                                                        C50 WP      96-h LC50       20.1        Singh et al. (1984)
    fossilis)

    (Macropodus)                                                              CT        96-h LC50        3.5        Arunachalam &
                                                                                                                    Palanichamy (1982)

    (Cypanus)                                                                 CT        96-h LC50        4.0

    Estuarine &
    marine

    Longnose          juvenile   stat        28           19s                           48-h LC50        1.6        Mayer (1987)
    killifish
    (Fundulus
    similis)
                                                                                                                                              

    Table 35 (continued)
                                                                                                                                              

    Organism         Size/age    Stat/   Temperature    Hardness     pH  Formulationc   Parameter   Concentration   Reference
                                 flowa      (°C)       (mg/litre)b                                   (mg/litre)
                                                                                                                                              

    Striped mullet    juvenile   stat        24           17s                           48-h LC50        2.4
    (Mugil
    cephalus)
                                                                                                                                              

    aStat = static conditions (water unchanged for the duration of the test); Flow = flow-through conditions (carbaryl concentration
     in water continuously maintained).
    bHardness = expressed as mg CaCO3/litre; s = salinity (%).
    cFormulation: C = carbaryl; CT = Carbaryl technical (> 95%); C50 WP = Carbaryl 50% wettable powder; S = Sevin; S4 = Sevin-4-oil;
     S50 WP = Sevin 50% wettable powder; XLR = Sevin (44% carbaryl); C49 = Carbaryl (49%).  Where information on formulation is not given
     the carbaryl formulation used was mostly carbaryl technical.


    
         Exposure of  C. punctatus to carbaryl at a concentration of
    3 mg/litre for 48 h resulted in an increase in free fatty acids,
    cholesterol, and lipase activity in the liver (Rao  et al., 1985b).
    However, the total lipid content was reduced.

         The literature indicates that water temperature, hardness, and
    pH may influence the toxicity of carbaryl, as well as the size of
    the fish (Table 35).

         In a study by Post & Schroeder (1971), water was supplied from
    a well, classified as very hard and highly alkaline at temperatures
    of 13.6-14.6 °C. Carbaryl was more toxic for cutthroat trout
    weighing 0.37 g than for those weighing 1-2 g (96-h LC50 1.5 and
    2.2 mg/litre, respectively) and more toxic for brook trout weighing
    1.15 g than for those weighing 2.04 g (96-h LC50 1.2 and
    2.1 mg/litre, respectively).

         A comparative toxicity study on carbaryl and 1-naphthol, under
    laboratory conditions showed that 1-naphthol was approximately 5
    times more toxic than carbaryl for goldfish ( Carassius auratus)
    and 2 times more toxic for killifish ( Fundulus heteroclitus) (Shea
    & Berry, 1983).

         Synergism of the effects of carbaryl and phenthoate on  Channa
     punctatus was found (Rao  et al., 1985a,b). Carbaryl produced
    potentiation of the effects of 2,4-D,  n-butyl ester, dieldrin,
    rotenone, pentachlorophenol, and arecoline on trout (Statham & Lech,
    1975).

         Application of carbaryl to a forest resulted in a significant
    (15-34%) decrease in brain acetylcholinesterase activity in brook
    trout from a nearby stream (Haines, 1981). No other effects were
    observed.

    7.2.2.2  Short-term and long-term toxicity

         There is a limited data base on the effects of long-term
    carbaryl exposure on fish. In one study, juvenile spot  Leiostomus
     xanthurus were exposed for five months to carbaryl (technical,
    98%) at a level of 0.1 mg/litre in a flow-through system (Lowe,
    1967). No carbaryl-related mortality was observed and there was no
    effect on growth.

         Carlson (1972) conducted the only full life-cycle study on fish
    with carbaryl (80%), in which fathead minnows ( Pimephales promelas)
    were exposed to five concentrations (0.008-0.68 mg/litre) for 9
    months, beginning with the larvae. Survival of fatheads after 6
    months at 0.68 mg/litre was lower than that in the controls. After 9
    months at 0.68 mg/litre, the mean number of eggs produced per female
    was reduced, the mean number eggs per spawning was also affected and
    no hatching occurred. No other demonstrable effects were noted at

    0.017, 0.062, and 0.21 mg/litre concentrations; thus, the maximum
    acceptable toxicant concentration (MATC) for fathead minnows,
    exposed to carbaryl in water, was between 0.21 and 0.68 mg/litre.
    The lethal threshold concentration for 2-month-old minnows was
    9 mg/litre.

         Kaur & Toor (1977) exposed different stages of the embryo of
    carp ( Cyprinus carpio) to carbaryl through the hatching stage.
    There was 100% mortality of carp eggs and embryos at 2.5 mg/litre.
    There appeared to be no effect of carbaryl on hatching at
    0.01-0.75 mg/litre. However, there was decreased hatching at
    1.0 mg/litre and deformed larvae (3.3%) with enlargement of the
    pericardial sac and coiling of the posterior region of the embryo.

         Thirty days exposure of  Channa striatus to 10 or 20 mg
    carbaryl/litre retarded oocyte production, with an increase in the
    number of immature oocytes and a decrease in the number of mature
    oocytes (Kulshrestha & Arora, 1984).

         Statistically significant reductions in gonadotropic hormone in
    the pituitary gland and plasma in  Channa punctatus were observed
    following exposure to carbaryl at a concentration of 1.66 mg/litre
    (Ghosh  et al., 1990). Gonadotropic hormone levels continued to
    decrease with continued exposure, with a 30% decrease in the
    pituitary gland and a 50% decrease in serum after 30 days of
    exposure.

         Exposure of the freshwater fish  Puntius conchonius to carbaryl
    at a concentration of 0.194 mg/litre for 15 days resulted in an
    increase in the incidence of lesions in the gill and liver (Gill
     et al., 1988). A higher level of exposure also resulted in lesions
    in the kidney.

         A 27-day exposure to 12.5 mg/litre led to a decrease in the
    feeding and growth rate of the catfish ( Mystus rittatus)
    (Arunachalam  et al., 1980). Long-term toxicity of carbaryl for
    fish in most natural surface waters will not occur, since exposure
    would not be high enough or constant, because of the substance's
    degradation.

    7.2.3  Amphibians

         The LC50s for bullfrog ( Rana tigrina) 0.1 g tadpoles with
    24, 48, 72, or 96 h of exposure were determined to be 12.8, 8.2,
    6.7, and 6.3 mg/litre, respectively (Marian  et al., 1983). Growth
    and feeding were decreased in a dose-dependent manner by doses
    ranging from 0.5 to 5 mg/litre.

    7.3  Terrestrial organisms

    7.3.1  Worms

         Carbaryl was classified as extremely toxic for earthworms
    (LC50 = 9.1 µg/m2) by Roberts & Dorough (1984). The LC50 value
    for the worm  Eisenia fetida-Savigny was 14 µg/cm2 (Neuhauser
     et al., 1985). The number of earthworms was reduced by 60% when
    carbaryl was applied at 0.5 kg (1.12 lb) a.i. per hectare (Thompson,
    1971).

         Exposure of earthworms to carbaryl (1-8 mg/kg) significantly
    increased the burrowing time, which was directly proportional to the
    dose and time of exposure, because of the AChE inhibition in the
    neural tissue (Gupta & Sundararaman, 1991).

    7.3.2  Insects

         Administration of carbaryl in sublethal doses produced death in
    the early embryonal stage of the silkworm (Kuribayashi, 1981).

         The alfalfa leaf-cutting bee ( Megachile pacifica), which is
    very important in the pollination of alfalfa, has been reported to
    be particularly tolerant to carbaryl (Lee & Brindley, 1974). Waller
    (1969) also classified carbaryl as relatively non-toxic for the
    alfalfa leaf-cutting bee. The carbaryl tolerance was related to sex
    and age. The LD50 was similar for 1-day-old males and 1-and
    4-day-old females (240, 245, and 262 µg/g, respectively). However,
    four-day-old males were much more susceptible to carbaryl, and had
    an LD50 of 51 µg/g. Guirgius & Brindley (1975, 1976) showed that
    carbaryl toxicity in alfalfa leaf-cutting bees was controlled by the
    activity of mixed function oxidase or microsomal enzymes. This
    detoxification system varies with the age and sex of the bees and
    results in significantly different carbaryl persistence which, in
    turn, leads to differences in carbaryl toxicity. In the more
    tolerant groups, carbaryl metabolites were rapidly conjugated and
    moved to an aqueous fraction of the bee. Less tolerant insects
    (4-day-old males) accumulated these metabolites with time,
    indicating that the conjugation mechanisms had deteriorated with
    age.

         Carbaryl is known to be highly toxic for honey-bees. When
    ingested, the LD50 was 0.18 µg/bee (Alvarez  et al., 1970). The
    contact LD50 (approximately 10-15 mg/kg) for adult bees is
    approximately 1.3 µg (Stevenson  et al., 1977; Stevenson, 1978).

         The carbaryl residue content of bee bread was correlated with
    the amount of residue found in the bees and occurred at higher
    levels than in honey throughout the 56-day period (Winterlin &
    Walker, 1973).

    7.3.3  Birds

         The toxicity of carbaryl for birds appears to be low
    (Table 36). LD50s for six species of waterfowl and game birds were
    all greater than 1000 mg/kg (Bart, 1979). There were some
    exceptions; thus the red-winged blackbird has an LD50 of 56 mg/kg
    (Schafer, 1972). In this study, 180 compounds were found to be toxic
    for the red-winged blackbirds and the LD50s ranged between 0.24
    and 100 mg/kg.

         Food intake, body weight, and locomotor activity were monitored
    in adult male bobwhites ( Colinus virginianus), given diets that
    contained levels of carbaryl typical of normal exposure under
    agricultural conditions in Kansas. No changes were observed in diets
    containing 127 or 1235 mg carbaryl/kg (Robel  et al., 1982).

         Technical carbaryl fed to young Mallard ducks at dietary levels
    of 10, 100, 1000, or 3000 mg/kg, revealed dose-correlated signs of
    toxicity (reduced intake and/or body weight depression) at the 100,
    1000, and 3000 mg/kg level (Fletcher & Leonard, 1986).

         There was some tentative evidence that low dosages of carbaryl
    may increase the susceptibility of bobwhites ( Colinus virginianus)
    to the protozoan parasite  Histomonas meleagridis, to which they are
    usually resistant (Zeakes  et al., 1981).

         A study of the effects of carbaryl on forest birds was
    conducted in southern New York; plots had been treated 3-4 weeks
    previously with carbaryl at the normal rate of 1.1 kg/ha, and at 6
    times the normal rate (6.6 kg/ha). In this study, carbaryl had
    little, if any, effect on birds. Young birds gained weight normally,
    adults continued nesting in the area, no changes were detected in
    song frequency, and there was no evidence of birds leaving the area
    to forage. This lack of detectable effects, despite the heavy dose
    (6.6 kg/ha), indicates that carbaryl applied at the normal rate
    (1.1 kg/ha) would have little if any adverse effect on birds (Bart,
    1979).

         The LC50 of carbaryl for mallard embryos, following field
    applications, was determined by Hoffman & Albers (1984) to be
    greater than 26.4 kg/ha or 118 µg/g egg. Carbaryl was estimated to
    be relatively nontoxic compared with other pesticides.

         Inhibition of the brain ChE activity of birds from forests
    sprayed with carbaryl 1.13 (kg/ha) was found in 3 out of 12 species
    studied (Zinkl  et al., 1977) up to 5 days after application.


        Table 36.  Acute toxicity of carbaryl for birds
                                                                                                 
    Species                       Age        Parametera     Concentration     Reference
                                                               (mg/kg)
                                                                                                 
    Japanese quail               7 days       LD50                2290     Hudson et al.
    Coturnix coturnix                                                      (1984)
    japonica                     2 months     5 day-LC50      > 10 000     Hill & Camardese
                                                                           (1986)

    Bobwhite quail               23 days      5 day-LC50        > 5000     Hill  et al. (1975)
    Colinus virginianus

    California quail             10 months    LD50              > 2000     Hudson et al. 
    Callipepla californica                                                 (1984)

    Chukar Alectoris chukar      4 months     LD50                1888

    Sharp-tailed grouse                       LD50              < 1000
    Tympanuchus
    phasianellus

    Pheasant                     3-4 months   LD50          707-> 2000
    Phasianus colchicus          23 days      LD50              > 5000     Hill  et al. (1975)

    Mallard                      3 months     LD50              > 2564     Hudson  et al. (1984)
    Anas platyrhynchos           24 days      5 day-LC50        > 5000     Hill  et al. (1975)

    Rock dove                                 LD50           1000-3000     Hudson  et al. (1984)
    Columbia livia

    Canada goose                              LD50                1790
    Branta canadensis

    Red-winged blackbird                      LD50                  56     Schafer (1972)
    Agelaius phoeniceus
                                                                                                 
    a LD50 = single oral dose expressed as mg/kg body weight.
      5 day-LC50 = 5-day dietary exposure (expressed as mg/kg feed) followed by
      3 days on a "clean" diet.
    
    7.3.4  Mammals

         The effect of carbaryl on wild mice ( Clethrionomys glareolus
    and  Apodemus sylvaticus) in their natural environment was studied
    by Krylov (1970). Carbaryl-containing bait, each consisting of 2 kg
    grain treated with 50 g carbaryl in oil suspension, were distributed
    twice (in March and June) over 10 ha of woods, at a rate of 1
    bait/ha. An adjacent territory of 10 ha was used as a control.
    Effects on mice, assessed 1´ months after the last application,
    were: reduction of the population by 31.5% compared with the
    control; changes in the reproduction system (e.g., decreased number
    of embryos  in utero, and of corpora lutea, reduced weight of
    testicles), and increased weight of adrenal glands.

    7.4  Effects on the population and ecosystem

         The effects of carbaryl on terrestrial ecosystems have been
    studied by Stegeman (1964), Barrett (1968), and Spain (1974).

         A large-scale study was performed by Barrett in 1968. It was
    designed to determine the effects of carbaryl on an intact ecosystem
    in a field that was planted with millet ( Panicum ramosum). The
    area was sprayed with a single application of 2.24 kg carbaryl/ha.
    There was a highly significant decrease in litter decomposition in
    the treated area, 3 weeks after spraying, which was probably because
    of a reduction in microarthropods and other decomposers. After 5
    weeks, there was a more than 95% reduction in the number of
    arthropods and in the total biomass. Phytophagous insects were
    severely affected, and predatory insects and spiders were less
    affected. The number of species was also reduced, but all species
    returned to control levels within 1-2 weeks, except Hemiptera and
    Hymenoptera. Reproduction of cotton rats was delayed by 4 weeks.
    However, the total mammal population was not affected, because of a
    compensating increase in the population of house mice. Old field
    mice did not seem to be affected.

         The effects of carbaryl on forest soil mites and Collembola,
    the two most numerous soil arthropods, were studied by Stegeman
    (1964). Mites and Collembola are an important link in the
    decomposition process of dead plants and animal matter. They also
    are a natural means of decomposing the accumulating litter, and they
    provide nutrients for already existing or future crops and fungi.
    Application of carbaryl to a test plot in a red-pine plantation, at
    doses of 11.2 and 56 kg/ha, reduced the arthropod population
    proportional to the severity of the treatment. Neither mites nor
    Collembola were totally exterminated by any treatment. The rate of
    population increase of the mites, 4-5 months after treatment, was
    directly proportional to the dose applied. Collembola were more
    vulnerable to treatment than mites and did not recover as rapidly.

         The effect of carbaryl at two application rates (0.11 and
    1.13 g a.i. per m2) on mixed species population of the litter
    fauna of a Corsican pine forest was studied by Spain (1974). He took
    a quantitative sampling of the fauna at intervals of 11, 106, 209,
    and 315 days after application to record the pattern and the time of
    the recovery process (Table 37). The effect of carbaryl varied in
    different populations. For Collembola, there was a marked reduction
    at the two treatment levels. For Coccoidea and Symphyla, there was a
    slight effect at the lower level, and a marked decrease at the
    higher level. For Coleoptera, Diptera, Cryptostigmata, Mesostigmata,
    and Prostigmata, the effect was small or insignificant. The recovery
    process during the period of 315 days was not sufficient to reach
    the status of the untreated population.

         Tagatz  et al. (1979) studied the effects of carbaryl on
    animal communities that develop from planktonic larvae in aquaria
    containing sand and estuary water. Samples collected after 10 weeks
    of exposure were analysed. The numbers of animals and species were
    significantly less at 11.1 and 103 µg carbaryl/litre (Table 38)
    being decreased to nearly half (from 21 to 12). A carbaryl
    concentration of 1.1 µg/litre did not produce significant effects,
    except a decrease in the particularly sensitive amphiopod,
     Coraphium acerusicum. Carbaryl might have caused changes in
    biological interactions that affect the relative abundance of
    species. The annelid  Polydora ligni increased at a concentration
    of 103 µg/litre, and there was a marked decrease in the number of
    other annelids and nemerteas.

         There have been a number of field studies evaluating the impact
    of carbaryl applications on macroinvertebrate populations. In one
    study in New York State, carbaryl was applied aerially at a rate of
    1.3 kg/ha, in fuel oil with a paraffin oil sticker, and its effects
    upon the aquatic fauna of two streams were studied (Burdick  et al.,
    1960). The data indicated that carbaryl (in oil suspension) was
    toxic for mayflies (Ephemeroptera), stoneflies (Plecoptera) and
    caddisflies (Trichoptera). Other groups of insects were less
    affected and the application did not affect fish. Square-foot
    samples, collected before, and shortly after, spraying, showed
    reductions of from 50 to 97.2% in the weight of invertebrate
    (standing crop) fish food. A progressive effect from upstream to
    lower sections was correlated with increased 44-151 exposure time.
    No exposure concentrations in water were documented. Owen (1965)
    also reported a reduction of 54.2 to 62.8% in the standing crop of
    aquatic insects following aerial spraying with carbaryl (80 WP)
    (1.3 kg/ha). A control stream showed a 5.9% increase in the same
    period.


    
    Table 37.  Geometric means for assessed taxa (individuals/m2), post-application sampling of carbaryl-treated plotsa
                                                                                                                                              

    Sampling day (after treatment)         Taxon                            Control plot           High carbaryl           Low carbaryl

                                                                                                                                              

                                           Coccoidea                             272.9                   90.8                   129.4
                                           Coleoptera (imagines)                 425.6                  137.7                   153.1
                                           Coleoptera (immature)                  54.0                   47.3                    41.4
                                           Collembola                         42 771.5                 5033.4                  9819.7
                                           Diptera                               350.9                  244.2                   243.7
    11                                     Cryptostigmata                       5707.3                 3933.2                  5863.5
                                           Mesostigmata                         7239.5                 3688.9                  5038.2
                                           Prostigmata                          1335.6                  305.3                   564.8
                                           Aranese                               238.7                  222.7                   155.0
                                           Chilopoda                              71.1                  102.4                    37.4
                                           Symphyla                              872.1                  359.0                   388.9

                                           Coccoidea                             847.8                  157.0                   162.9
                                           Coleoptera (imagines)                  41.9                  379.1                   170.7
                                           Coleoptera (immature)                  41.9                   31.7b                    0.0b
                                           Collembola                         18 185.1                 1621.3                  5205.9
                                           Diptera                               264.0                  173.8                   160.5
    106                                    Cryptostigmata                       5855.3                 6237.9                  6623.7
                                           Mesostigmata                         8610.3                  846.4                   595.2
                                           Prostigmata                           631.5                  846.4                   595.2
                                           Aranese                               360.6                  224.9                   253.2
                                           Chilopoda                             114.0                  157.8                    94.3
                                           Symphyla                              317.5                   47.0b                  223.4
                                                                                                                                              

    Table 37 (continued)
                                                                                                                                              

    Sampling day (after treatment)         Taxon                            Control plot           High carbaryl           Low carbaryl

                                                                                                                                              

                                           Coccoidea                             358.3                  181.0                   141.0
                                           Coleoptera (imagines)                 520.0                   86.6                   232.6
                                           Coleoptera (immature)                 289.6                  125.9                    74.1
                                           Collembola                         41 198.7                 3469.4                19 238.9
                                           Diptera                               449.9                   28.2b                  209.5
    209                                    Cryptostigmata                     16 298.4               11 184.8                12 014.8
                                           Mesostigmata                       16 150.0                 7293.9                11 709.0
                                           Prostigmata                          2721.6                 2407.2                  3152.4
                                           Aranese                               264.7                  108.3                   220.2
                                           Chilopoda                             241.9                   28.2b                  150.5
                                           Symphyla                              357.3                   78.3                   174.4
                                           Coccoidea                             142.0                  207.5                    51.5
                                           Coleoptera (imagines)                 261.6                   64.4                   132.5
                                           Coleoptera (immature)                  37.0                   88.8                    23.1b
                                           Collembola                         40 139.5                 4121.3                10 294.6
                                           Diptera                               533.9                  291.2                   173.1
    315                                    Cryptostigmata                     10 889.3               12 743.6                10 506.6
                                           Mesostigmata                       11 290.3                 7762.7                14 912.0
                                           Prostigmata                          2995.0                 1844.7                  4765.7
                                           Aranese                               217.4                  157.4                   117.8
                                           Chilopoda                             159.5                   83.4                    88.8
                                           Symphyla                              349.6                   85.4                   158.8
                                                                                                                                              

    aSource:Spain (1974).
    b95% confidence limits for the parametric mean include zero.

    Table 38.  Animals and species, by phylum, collected from control aquaria and aquaria exposed to carbaryla
                                                                                                                                              

                                   Control                                                     Carbaryl
                                                                                                                                              
                                                               1.1 µg/litre                 11.1 µg/litre                  103 µg/litre
                                                                                                                                              

    Phylum                  Number         Species        Number         Species        Number         Species        Number         Species

    Mollusca                 1691             3            1563             3            1340             3            1321             5

    Arthropoda                380             7             339             8             336             2             269             2

    Annelida                  102             8              94             7              79             4             200             5

    Nemerica                   16             1              25             1              20             1               0             0

    Coelenterata                3             1               5             1               0             0               0             0

    Platyhelmintes              0             0               2             1               0             0               0             0

    Echinodermata               0             0               0             0               1             1               0             0

      All phyla              2192            20            2086            21            1776            11            1790            12
                                                                                                                                              

    aFrom:Tagatz et al. (1979).


    
         The effects on stream invertebrates of carbaryl, applied at a
    rate of 840 g a.i./ha for spruce budworm suppression, was studied.
    Benthos samples showed significant declines among Plecoptera,
    Ephemeroptera, and Trichoptera. Plecoptera had not repopulated any
    treated stream, 60 days after treatment (Courtemanch & Gibbs, 1980).

         Gibbs  et al. (1984) conducted a 42-month (1980-83) study on
    the occurrence/persistence of carbaryl residues in pond water and
    sediment as a result of an application of Sevin-4-oil (840 g
    a.i./ha). The immediate and long-term effects on pond
    macroinvertebrates and emerging aquatic insects were also evaluated.
    A preliminary study by these investigators in 1977 and others
    (Coutant, 1964) had shown that there were large increases in the
    number of drift organisms, several days after aerial spraying with
    carbaryl. Most drift was accompanied by dead Amphipoda,
    Ephemeroptera, Plecoptera, and Trichoptera, and carbaryl residues
    persisted longer than 30 days in pond sediment. The increase in the
    number of dead organisms was accompanied by a reduction in the
    standing crop of benthic macroinvertebrates. The most severe and
    persistent impact was on Amphipoda with  Hyallela azteca and
     Crangonyx richmondensis reduced to almost 0/m2;  C. richmondensis
    failed to recolonize in one of the two treatment ponds, 42 months
    after treatment. The numbers of immature Ephemeroptera and
    Trichoptera were reduced immediately following spray application,
    but this effect did not persist throughout the season or into the
    following year. Immediate reduction in numbers of adult
    Ephemeroptera and Trichoptera emerging from the ponds was also
    found, but recovery of populations was observed. Numbers of immature
    Odonata were also reduced following treatment and remained low the
    following year. The Chironomidae populations did not appear to be
    affected, either as immatures or emerging adults.

         The effects of two consecutive years of spraying with
    Sevin-4-oil on other aquatic systems appear similar to those
    observed in areas treated once (Courtemanch & Gibbs, 1978; Trial,
    1978,1979).

         In simulated aquatic field studies, 1 mg carbaryl (WP)/litre
    was applied to one outdoor concrete pond (4 x 5 x 1 m deep)
    (Hanazato & Yasuno, 1987). All zooplankton (Cladocera included) and
    Chaoborus larvae were killed. The zooplankton community recovered
    rapidly and Cladocera reappeared only two days after application.
    Since Chaoborus populations are predators of crustacean zooplankton,
    their suppression may also have added to the recovery of increased
    populations of Cladocerans. Carbaryl exposure also changed the
    community from a rotifer-predominating zooplankton community to that
    of Cladocera-predominating. Rotifers in this study were also highly
    sensitive to carbaryl. The same phenomenon was observed again after
    the second application of carbaryl. Subsequent to this study,
    Hanazato & Yasuno (1989) applied carbaryl to simulated ponds in the

    same way as in the previous study, but in the spring when the water
    temperature was approximately 10 °C lower. Cladocerans never
    recovered to the density level of the pre-treatment period. The
    rapid recovery of Chaoborus seemed to interfere with the recovery of
    Cladoceran populations after treatment. The authors suggested that
    the different recovery patterns of the zooplankton community
    resulted from different temperatures in the ponds. In another study,
    Hanazato & Yasuno (1990a) examined Chaoborus density in relation to
    the effects of carbaryl (0.1 and 0.5 mg/litre) on zooplankton
    communities in ponds, where the abundance of Chaoborus larvae was
    controlled. They concluded that Chaoborus density and/or temperature
    may influence the recovery of the zooplankton community following
    the effects of carbaryl. The recovery of a zooplankton community may
    differ in different aquatic ecosystems (with different community
    structures) and under different temperatures, even when the same
    treatment is applied.

         Hanazato & Yasuno (1990b) also studied the effect of the time
    of application of carbaryl (0.5 mg/litre) on recovery patterns of
    zooplankton communities in simulated ponds. The loss of carbaryl
    from pond water was rapid. The concentration decreased to less than
    1% of its initial value, three days after the first or second
    application, and six days after the third application. This study
    also showed that applications of carbaryl at different times induced
    different zooplankton structures (and different recovery patterns),
    and, various factors other than toxicity of carbaryl, such as
    temperature, competitive interactions between zooplankters, and
    trends of zooplankton populations may play important roles in
    determining zooplankton community structure after chemical
    application. Furthermore, the significance of predators in the
    recovery process after chemical treatment was re-emphasized.

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         Reviews of toxicological aspects of carbaryl were prepared by
    NIOSH (1976); US EPA (1977, 1980, 1982, 1984); USDHHS/USDL (1978);
    US EPA (1980b); Mount & Oehme (1981a); Weston (1982); and Cranmer
    (1986). Studies from the Soviet Union were reviewed by IRPTC (1982,
    1989).

    8.1  Single exposures

    8.1.1  Oral toxicity

         The oral LD50s for the rat are given in Table 39 and for
    other mammals in Table 40. The values varied by about a factor of 4
    depending on formulation, route of production, vehicle, and strain
    of rat. Interspecies differences were found. Cats are the most
    sensitive, with guinea-pigs, rats, mice, and rabbits showing more
    resistance in that order. Pigs and monkeys seem to be less sensitive
    (Carpenter  et al., 1961; Gladenko & Malinin, 1970; Smalley, 1970).

         Cattle are more sensitive than pigs. After a single oral
    application of carbaryl in cattle, symptoms appeared at a dose level
    of 25 mg/kg; 100 mg/kg was the minimum effective dose in pigs
    (Gladenko & Malinin, 1970).

         Mount & Oehme (1981b) observed that the lethality of carbaryl,
    administered to sheep at doses ranging from 300 to 1000 mg/kg, was
    highly correlated with concentrations in the brain (>1 mg/kg) and
    liver (>3 mg/kg), and with inhibition of acetylcholinesterase
    (greater than 50% inhibition).

    8.1.2  Acute inhalation toxicity

         Acute toxic effects following inhalation at different
    concentrations are presented in Table 41.

    8.1.3  Dermal toxicity

         A dose of 2500 mg/kg, applied as a 40% aqueous suspension of
    50% wettable powder, killed 1 out of 4 rabbits (Carpenter  et al.,
    1961). When 99% technical carbaryl was applied to male and female
    rabbits, the LD50 was >2000 mg/kg (Bushy Run, 1983b). In rats,
    the LD50 is thought to be >4000 mg/kg (Yakim, 1965; Gaines,
    1969).


    
    Table 39.  Acute oral LD50s for the rat
                                                                                                                                              

    Strain (sex)        Weight     Formulation of          Vehicle                 LD50(mg/kg            Symptoms            References
                          (g)         carbaryl                                    body weight)
                                                                                                                                              

    CF-N                            technical        0.25% agar
    (male)             90-120                                                    510 (360-650)               -               Carpenter et al.
    (female)           90-120                                                    610 (490-750)               -               (1961)

    Sherman                                                                      850 (600 LD min)                            Gaines (1969)
    (male)
    (female)                                                                     500 (100 LD min)

    Inbred                                                                       721 (653-789)                               Yakim (1965)

    Inbred             120-200                       sunflower oil               515                                         Rybakova (1966)

    Sprague Dawley     203-246      technical        carboxymethyl-cellulose     300                                         Hamada (1990)
    (male, female)                                   in water

    Sprague Dawley     112-173      technical        0.25% methyl-cellulose      685 (612-767)         death, 4-24 h         Field (1980b)
    (male, female)

    Sprague Dawley     100-160      95% technical    0.25% methyl-cellulose      225 (202-321)         death, 2-24 h         Field (1980a)
    (male, female)
                                                                                                                                              

    Table 39 (continued)
                                                                                                                                              

    Strain (sex)        Weight     Formulation of          Vehicle                 LD50(mg/kg            Symptoms            References
                          (g)         carbaryl                                    body weight)
                                                                                                                                              

    Sprague Dawley     200-264      40.38%           water                                            tremor, prostration,   Hazleton Lab.
    (male)                                                                       750 (467-1202)       laboured respiration,  American Inc. 
                                                                                                           salivation        10 February 1982
    (female)                                                                     527 (257-977)         death, 4-3 days

    Harlem                          Sevin XLR        not diluted                                       death, 0.5 h-3 days   Kuhn (1991a)
    Sprague Dawley                  plus 44%
    (male)             229-286                                                   867 (562-1336)
    (female)           182-219                                                   575 (459-721)

    Harlem                          Sevin-4-oil      not diluted                 658 (456-979)         3 h-3 days            Kuhn (1991b)
    Sprague Dawley                  47% (w/w)
    (male)             229-286                                                   963 (802-1160)
    (female)           182-219                                                   473 (364-620)

    Hilltop Wistar     200-250      98% technical    0.25% methyl-cellulose                                                  Bushy Run
    (male)                                                                       283                   death, 1.5-24 h       (1983b)
    (female)                                                                     246

    Hilltop Wistar     204-237      80% sprayable    water
    (male)                                                                       406                                         Bushy Run
    (female)                                                                     203                   death, 1 min-24 h     (1983c)
                                                                                                                                              

    Table 40.  Acute oral toxicity for mammals other than rats
                                                                                                                                              

    Species                 Number of animals                        Toxicitya                         Reference
                                                                (mg/kg body weight)
                                                                                                                                              

    Mouse                      6 per dose                          363 (294-431)                       Yakim (1965)

    Mouse (female)              80 white                             437 ± 70                          Rybakova (1966)

    Mouse                      1310 white                          206 (175-480)                       Bukin (1965)

    Guinea-pig                 5 per dose                               280                            Carpenter et al. (1961)

    Rabbit                     4 per dose                               710

    Rabbit                         56                               700 (LD100)                        Bukin (1965)

    Cat (female)                    3                               250 (LD100)                        Carpenter et al. (1961)

    Cat                          no data                                150                            Yakim (1965)

    Swine                      3 per dose                            800-1000                          Gladenko & Malinin
                                                                                                       (1970)

    Swine                      1 per dose                            1500-2000                         Smalley (1970)

    Monkey                       no data                              > 1000                           FAO/WHO (1970)

    Duckling                       106                              500 (LD15)                         Bukin & Filatov (1965)

                                                                  6000 (LD100)
                                                                                                                                              

    Table 40 (continued)
                                                                                                                                              

    Species                 Number of animals                        Toxicitya                         Reference
                                                                (mg/kg body weight)
                                                                                                                                              

    Chick                          48                               250 (LD33)

                                                                  1000 (LD100)

    Hen                            12                            > 1000 (no death)

    Hen                            12                                 > 3000                           Bukin (1965)
                                                                                                                                              

    aLD50, unless otherwise stated.

    Table 41.  Inhalation toxicity single exposure
                                                                                                                                              

    Species                    Concentration                           Effects observed                               References
                                                                                                                                              

    Guinea-pig 6         390 mg 50% wettable powder/m3         nasal and ocular irritation  after 14 days -         Carpenter et al.
                         (average particle size 15 µm) 4 h     haemorrhage areas in the lungs                       (1961)

    Guinea-pig 6         230 mg carbaryl 85S/m3                slight weight decrease; recovered by day 14
                         (average particle size 5 µm) 4 h

    Dog                  75 mg carbaryl 85S/m3 5 h             typical symptoms for ChE inhibition

    Cat 3 groups         82 mg/m3 dust 6 h                     tremor salivation, muscle fibrillation decreased     Yakim (1967, 1968)
    of 4 animals                                               ChEA by 39-55% serum; 53-71% red blood
                                                               cells; normalization after 72 h

                         37 mg/m3 dust 6 h                     decreased ChEA by 23% in serum and 41% in
                                                               red blood cells; recovery after 48 h

                         20 mg/m3 dust 6 h                     decreased ChEA by 11-27% in serum and
                                                               15.28% in red blood cells; recovery after 24 h

    Rat                  20-23 mg/m3 dust                      no effect                                            Weil & Carpenter
                         98% particles                                                                              (1974)
                         less than 1.0 µm diameter

    Rat                  1800 mg/m3 water aerosols             lacrimation, tremor with 1.5 h of exposure           Myers et al. (1975)

    Rat Wistar Albino    Aerosols Sevin XLR 44% 792 mg         1/5 females died, tremor, ataxia, increased          Faït (1984)
    male 5               a.i./m3 per 4 h (the highest          respiratory rate; recovery period 6 days
    female 5             attainable concentration) 
                         particle size 3.6 ± 2.64 µm
                                                                                                                                              


    
    8.1.4  Other routes of exposure

         Other routes of exposure are presented in Table 42.

        Table 42.  Toxicity following parenteral application
                                                                                      

    Species    Weight      Vehicle       Route of            LD50      References
                 (g)                     administration   mg/kg body
                                                            weight)
                                                                                      

    Rat        10-107      propylene     intravenous      18           Mellon Institute
    female                 glycol                                      (1958)

    Rat        92-126      polyethylene  intravenous      24 
                           glycol 400    intravenous      (17-33)

    Rat        90-120      95% ethyl     intravenous      33
                           alcohol                        (26-41)

    Rabbit     1686-3544   0.25% agar    intraperitoneal  223
                                                          (122-407)

    Rat        90-120      in lard       subcutaneous     1410

    Leghorn    10-11 days                in alantoic      3.44 mg      Tós-Luty et al.
    chick      old                       cavity           per embryo   (1973)
    embryos
    (250)
                                                                                      
    
    8.2  Skin and eye irritation, sensitization

    8.2.1  Skin and eye irritation

         The results of several studies on skin irritation from carbaryl
    were negative (Carpenter  et al., 1961; Yakim, 1965). Transient
    erythema was noted after an application of 0.5 ml 43.4% carbaryl on
    occluded rabbit skin (Bushy Run, 1983a).

         Carbaryl is a weak eye irritant (Table 43).

        Table 43.  Eye irritation
                                                                                     

    Species    Number   Formulation        Effects observed          Reference
                                                                                     

    Rabbit        5     technical grade    mild injury in one        Carpenter et al.
                        10% suspension     of five eyes              (1961)
                        in propylene
                        glycol

                        25% aqueous        no injury
                        suspension

                        50 mg dust         spots of
                                           corneal-necrosis

    Rabbit        6     0.1 ml (90 mg)     conjunctival irritation   Bushy Run (1983b)
    New                 99% technical      after 2 days recovery
    Zealand             product
    White

                        0.1 ml             transient iritis in       Bushy Run
                        43.4% carbaryl     2 of 6, conjunctival      (1983a)
                                           irritation in 6 of 6.
                                           Recovery in 3 days
                                                                                     
    
    8.2.2  Sensitization

         The sensitization response following topical application of
    carbaryl was studied by Myers & Christopher (1987). The induction
    which consisted of an application of carbaryl to covered skin, once
    a week during 3 weeks, was followed by a 2-week incubation period. A
    single challenge dose of 50% (w/v) technical carbaryl in 0.25%
    aqueous methyl cellulose solution (0.1-0.3 ml) was administered.
    Carbaryl did not produce a positive response in any of the
    guinea-pigs tested.

         Four out of 16, male, albino guinea-pigs were treated with 8
    intravenous injections (3 per week) of 0.1 ml of a 0.1% dispersion
    of carbaryl in 3.3% propylene glycol. After a 3-week incubation
    period, a challenge dose was given, but did not cause sensitization

    (Carpenter  et al., 1961). In a more recent study, a similar
    procedure, but with 9 doses and a 2-week incubation period, was
    used. Although there was some skin irritation, it was considered
    that carbaryl had little or no sensitizing potential (Bushy Run,
    1983a).

    8.3  Short- and long-term oral exposure

         Several short- and long-term feeding studies with carbaryl have
    been reported (Carpenter  et al., 1961; Rybakova, 1967; Orlova &
    Zhalbe, 1968; Gladenko & Malinin, 1970; Dikshith  et al., 1976;
    Hamada, 1991a). Results are shown in Table 44. Doses that do not
    show any effects are 200 mg/kg diet equal to 7.9 mg/kg body weight
    in rats, and 100 mg/kg diet for mice, and 1.8 mg/kg body weight for
    dogs (approximately 100 mg/kg diet).

         The cumulation coefficient (LD50 for 3-month exposure/LD50
    single application) was 18 (Kassin, 1968), demonstrating a very low
    cumulative potential for carbaryl.

    8.4  Short- and long-term inhalation toxicity

         Short-term and long-term inhalation toxicity data are given in
    Table 45.

    8.5  Reproduction and developmental toxicity

         The reproduction and developmental toxicity of carbaryl has
    been studied in many vertebrate species using a wide variety of
    study designs.

         The data have shown that carbaryl can affect reproduction
    (Table 46) and embryo/fetal development (Table 47 and 48) in a
    number of species. The relevance of these studies for risk
    assessment is influenced by several factors related to experimental
    design, dose levels, and the types of effects noted. Shortcomings of
    the studies included small sample size; inappropriate dose
    selection; the variable degree of maternal toxicity (ranging from no
    effect to lethality); and a lack of historical data for some
    species. The following sections have been arranged according to
    end-point (reproduction and developmental toxicity) and species of
    animals studied (mammalian, non-mammalian). Studies that are of
    dubious value for risk assessment are listed at the end of the table
    sections, and are not discussed in the text. The reasons for such an
    evaluation are given below the references to the individual papers.


    
    Table 44.  Short- and long-term feeding and oral studies
                                                                                                                                              

    Species   Sex       Number      Dosage (mg/kg diet      Period of       Effects observed                                    References
                          of        or mg/kg body weight)   exposure
                        animals
                                                                                                                                              

    Mouse     male      48          100, 400 mg/kg diet     80 weeks        no changes in survival rate, pathology, and tumour  FAO/WHO (1965)
              and                                                           incidence
              female

    Mouse     male      10/sex      100, 1000, 7000 mg/kg   53 weeks        at 7000 mg/kg diet: decreased survival, body        Hamada (1991b)
              and       per group   diet                                    weight gain and erythrocyte count; increased liver
              female                                                        weight and decreased ovary weight; increased
                                                                            frequency and severity of chronic nephropathy in
                                                                            females; cholinesterase (plasma, RBC, and brain)
                                                                            depressed at 100 and 7000 mg/kg; NOEL
                                                                            100 mg/kg diet

    Rat       male      2x10        1500 (58.5 mg/kg        96 days         no changes                                          Carpenter et al.
                                    body weight)                                                                                (1961)

              female    2x10        1500 (58.5 mg/kg        96 days         kidney weights significantly increased
                                    body weight)

              male      2x10        2250 (87.5 mg/kg        96 days         increase in liver weight as a % of body weight,
                                    body weight)                            diffuse cloudy swelling in the kidney tubules in
                                                                            4 animals (male and female)

              female    2x10        2250 (87.5 mg/kg        96 days         decrease of body weight, increase in kidney weight
                                    body weight)
                                                                                                                                              

    Table 44 (continued)
                                                                                                                                              

    Species   Sex       Number      Dosage (mg/kg diet      Period of   Effects observed                                     References
                          of        or mg/kg body weight)   exposure
                        animals
                                                                                                                                              

    Rat       male      4x40        50, 100, 200 (2, 4,     2 years     no changes                                           Carpenter et al.
    CF-N      and                   7.9 mg/kg body weight)                                                                   (1961)
              female

    Rat       male      2x40        400 (15.6 mg/kg         2 years     weight depression in male, cloudy swelling of the    Carpenter et al.
              CF-N      and         body weight)                        hepatic cords, principally located around the        (1961)
              female                                                    central veins in both sexes; transitory diffuse
                                                                        cloudy swelling of the epithelial lining of the
                                                                        primarily convoluted proximal, and loop tubules

    Rat                             75, 150, 300 mg/kg      3 months    cytoplasmatic vacuolization in the proximal tubules  FAO/WHO (1970)
                                    body weight

    Rat       male      4x48        7, 14, 70 mg/kg                     weight depression at all dose levels; at 70 mg/kg,   Rybakova (1967)
              and                   body weight                         slight morphological liver changes; cloudy swelling
              female                                                    in convoluted tubules; decreased motility of
                                                                        spermatocytes at all dose levels, more pronounced
                                                                        at 70 mg/kg; oedema in the interstitial tissue;
                                                                        desquamation of spermatogenic epithelium;
                                                                        destruction of parenchyma; decreased production of
                                                                        spermatocytes was found at 14 and 70 mg/kg dose
                                                                        levels; increased estral cycle; increased hypophysis
                                                                        gonadotropic function; decreased ascorbic acid
                                                                        contents; cell proliferation, hypertrophy, increased
                                                                        lipid content in suprarenal glands; decreased thyroid
                                                                        function; augmentation of follicles, colloid retention,
                                                                        thickness of follicular epithelium
                                                                                                                                              

    Table 44 (continued)
                                                                                                                                              

    Species   Sex       Number      Dosage (mg/kg diet      Period of   Effects observed                                     References
                          of        or mg/kg body weight)   exposure
                        animals
                                                                                                                                              

    Rat       male      80-90/      250, 1500, 7500 mg/kg   52 weeks    body weight and food consumption lower at middle     Hamada (1991c)
    Sprague   female    group       diet                                dose; significantly increased total cholesterol;
    Dawley                                                              increase in liver and kidney weight; NOEL
                                                                        250 mg/kg diet

    Rat       male      876         2, 5, 15 mg/kg          1 year      changes in sex glands function at 15 and 5 mg/kg     Orlova & Zhalbe
              and                   body weight                         dose levels; enzymatic activity, spermatozoids and   (1968)
              female                                                    the estral cycle; reduced fecundity; no effect at
                                                                        2 mg/kg dose level

    Rat       male      total       200 mg/kg               90 days     decreased AChE in blood with 33.8%; no               Dikshith et al.
    local               28          body weight,                        histological changes                                 (1976)
    strain                          3 x per week 
                                    in peanut oil

    Dog       male      total       0.45, 1.8,              1 year      diffuse cloudy swelling of proximal convoluted and   Carpenter et al.
    Basenji-  and       14          7.2 mg/kg body                      loop tubules of kidney; local sudanophilic granules  (1961)
    cocker    female                weight in capsules,                 in the glomeruli at 400 mg/kg level; the same in
    hybrids                         5 days/week, to                     control dogs to a lesser extent; transient hind leg
                                    approximate levels                  weakness in 1 female after 189th dose at
                                    of 24, 95, 414 mg/kg                0.45 mg/kg body weight
                                    dry diet

    Beagle    male      24+         125, 400, 1250 mg/kg    1 year      at 400 and 1250 mg/kg diet, decreased AChE in        Hamada (1987)
    dogs      and       24          diet                                plasma, red blood cells, and in brain; increase in
              female                                                    leucocyte count and segmented nitrophil count;
                                                                        increase in liver weight in male; no effect level
                                                                        125 mg/kg diet
                                                                                                                                              

    Table 44 (continued)
                                                                                                                                              

    Species   Sex       Number      Dosage (mg/kg diet      Period of   Effects observed                                     References
                          of        or mg/kg body weight)   exposure
                        animals
                                                                                                                                              

    Beagle    male      24          0, 20, 45, 125 mg/kg    5 weeks     significant inhibition of cholinesterase activity    Hamada (1991a)
    dogs      female    24          diet                                in plasma at week 2 for males dosed 20 and
                                                                        125 mg/kg

    Monkey                          150, 300, 600 mg/kg     38 weeks    kidney alterations similar to those found in rats    FAO/WHO (1970)
                                    body weight

    Swine     male      3           150 mg/kg body weight   72-83       progressive myasthenia, incoordination ataxia,       Smalley et al.
              female    3           in diet                 days        intentional tremor, chronic muscular contraction,    (1969)
                                                            until       terminal paraplegia and prostration;
                                                            death       myodegeneration

    Swine                           5 and 10 mg/kg          147-176     no changes                                           Gladenko & Malinin
                                    body weight             days                                                             (1970)

    Cattle                          1 and 4 mg/kg           148 days    decreased Hb with 20%, and erythrocytes with
    (young)                         body weight                         30% occasionally
                                                                                                                                              

    Table 45.  Short- and long-term inhalation toxicity
                                                                                                                                              

      Species      Number of      Concentration of carbaryl      Days of        Effects                                  References
                    animals                                     exposure
                                                                                                                                              

        Cat            4          0.06 mg/litre                    30           typical cholinergic symptoms,            Yakim (1968)
                                                                                inhibition of ChE plasma 31-40%,
                                                                                erythrocytes 40-59%

        Cat            4          0.03-0.04 mg/litre               30           reaction time increased

        Cat            4          0.016 mg/litre                   120          no symptoms, fluctuation in
                                                                                plasma ChE inhibition around 18%

        Rat         no data       10 mg/m3 dust (85%               90           no mortality no gross visible injury     Carpenter et al.
                                  suspension) 7 h/day          inhalation                                                (1961)
                                  5 days per week                periods
                                                                                                                                              

    Table 46.  Reproduction studies
                                                                                                                                              

    Species                         Treatment                               End-point(s)                            Reference
    (number)
                                                                                                                                              

    Mouse

    Swiss Webster males 30-40 g     0, 8.5, 17, 34 mg/kg body weight        weight and uptake of testosterone:      Thomas et al. (1974)
    (10 + animals/group)            orally (5 days)                         testes and accessory glands

    Swiss Webster males 30-40 g     0, 34, 68 mg/kg body weight             biotransformation of                    Dieringer & Thomas
    (5 + animals/group)             orally (5 days)                         testosterone-1,2-3H                     (1974)

    C57Bl/6 x C3H 6-8 weeks of      0, 12, 25, 50...800 mg/kg body          sperm morphology, testes weight         Osterloh et al. (1983)
    age (4 animals/group)           weight per day 5 days i.p.              on day 35                               [route of
                                                                                                                    administration]

    Rat

    Osborne-Mendel                  0, 2000, 5000, 10 000 mg/kg diet        fertility, litter size, and viability   Collins et al. (1971)
    (20 females and 1 male per      (3 generations)
    group)

    Wistar                          0, 7, 25, 100, 200 mg/kg body           fertility, litter size, and viability   Weil et al. (1973)
    (13-21 animals/group)           weight per day in the diet

                                    0, 3, 7, 25, 100 mg/kg body
                                    weight per day orally
                                    (3 generations)

    Male and female                 0, 1, 5, 10, 20, 40, 50 mg/kg           general toxicity, serum protein,        Vashakidze (1975)
                                    body weight per day orally              numbers of male reproductive
                                    (1 month)                               cells, sperm viability, testicular
                                                                            histology, litter viability
                                                                                                                                              

    Table 46 (continued)
                                                                                                                                              

    Species                       Treatment                           End-point(s)                                  Reference
    (number)
                                                                                                                                              

    Wistar males                  0, 12.5, 25.0, 250.0 mg/kg body     sperm morphology                              Luca & Balan (1987)
    (36 animals per group)        weight per day

    Rats

    Male and female               0, 50, 100, 300 mg/kg body          fertility indices                             Vashakidze (1966)
                                  weight per day orally 2 weeks to                                                  [insufficient data]
                                  3 months

    Male and female               0, 2, 5, 15 mg/kg body weight per   fertility indices                             Orlova & Zhalbe
    (total of 876 animals)        day orally 12 months for F°                                                       (1968); Zhalbe et  al.
                                  and 6 months for the F1                                                           (1968) [insufficient
                                                                                                                    data]

    Male and female               0, 2, 5 mg/kg body weight per day   fertility indices                             Shtenberg & Ozhovan
                                  for 6 months (follow-up to Orlova                                                 (1971) [insufficient
                                  & Zhable) 2 through 5 generations                                                 data]

    Male and female               0, 2, 5, 15 mg/kg body weight per   fertility indices                             Shtenberg et al.
                                  day for 12 months                                                                 (1973) [insufficient
                                                                                                                    data]

    Gerbil

    (32-80 animals per group)     0, 2000, 4000, 6000, and            fertility, litter size, and viability         Collins et al. (1971)
                                  10 000 mg/kg body weight diet
                                  (3 generations)
                                                                                                                                              

    Table 47.  Developmental toxicity studies, mammalian
                                                                                                                                              

    Species                       Treatment                                  End-point(s)                   Reference
    (number)
                                                                                                                                              

    Mouse

    CF-1                          0, 100, 150 mg/kg body weight              fetal examination              Murray et al. (1979)
    (23-44 in a group)            per day orally or 5660 mg/kg diet.
                                  Gestation day 6-15

    Swiss albino                  0, 100, 150, or 200 mg/kg body             fetal examination              Mathur & Bhatnagar
    (10 per group)                weight per day orally. Gestation                                          (1991)
                                  days 8, 12, or 6-15

    Charles River                 0, 10, 20 mg/kg body weight.               fetal examination              Benson et al. (1967)
    (8 per group)                 Gestation day 6-parturition                                               [doses too low]

    CD-1                          100 mg/kg body weight per day              postnatal viability            Chernoff & Kavlock
    (23 animals)                  orally. Gestation day 8-12                                                (1982) [teratology
                                                                                                            screen test]

    CD-1                          200 mg/kg body weight per day              postnatal viability            Kavlock et al. (1987)
    (30 animals)                  orally. Gestation day 8-12                                                [teratology screen
                                                                                                            test]

    Rat

    Harlan Wistar                 0, 20, 100, 500 mg/kg diet.                fetal examination              Weil & Carpenter
    (6 per group)                 Gestation days 1-7, 5-15, 1-21                                            (1965); Weil et al.
                                                                                                            (1972)

    Wistar                        0, 200, 350 mg/kg body weight orally       fetal examination              Golbs et al. (1974)
    (10 per group)                40 mg/kg ip. Variety of gestation days.
                                                                                                                                              

    Table 47 (continued)
                                                                                                                                              

    Species                       Treatment                                  End-point(s)                   Reference
    (number)
                                                                                                                                              

    Sprague-Dawley                0, 1, 10, 100 mg/kg body weight            fetal examination              Lechner &
    (6 or 7 per group)            orally. 3 months before and during                                        Abdel-Rahman
                                  gestation                                                                 (1984)

    Sprague-Dawley                0, 20, 37.5 mg/kg body weight              fetal examination              Hart (1972)
    (22 or 23 per group)          per day. Gestation day 6-15                                               [doses too low]

    Rats                          unknown dose (1/50 LD50).                  fetal examination              Dinerman et al.
                                  Gestation days 9, 11, or 13                                               (1970) [insufficient
                                                                                                            data]

    Rats                          0, 10.6, 106 mg/kg body weight             fetal examination              Shtenberg et al.
                                  per day. Gestation day 1-20                                               (1973) [insufficient
                                                                                                            data]

    Guinea-pigs

    HRA/HART                      0, 50, 100, 200 mg/kg body                 fetal examination              Weil et al. (1973)
    (9-4 per group)               weight per day orally. 0, 100,
                                  200, 300 mg/kg body weight per
                                  day in the diet

    Coulston strain               300 mg/kg body weight per day.             fetal examination              Robens (1969)
    (26 gestation day treatment   Gestation day 11-20 and a variety                                         [insufficient data]
    11-20; other treatments       of other treatment periods within
    unknown)                      this time
                                                                                                                                              

    Table 47 (continued)
                                                                                                                                              

    Species                       Treatment                                  End-point(s)                   Reference
    (number)
                                                                                                                                              

    Rabbit

    New Zealand White             0, 150, 200 mg/kg body weight              fetal examination              Murray et al. (1979)
    (15-20 per group)             per day orally. Gestation day 6-18

    New Zealand White             0, 10, 30 mg/kg body weight per            fetal examination              Shaffer & Levy
    (9-12 per group)              day. Gestation day 9-16                                                   (1968) [doses too
                                                                                                            low]

    New Zealand White             0, 50, 100, 200 mg/kg body                 fetal examination              Robens (1969) [small
    (4-9 per group)               weight per day orally. Gestation                                          number of animals]
                                  day 5-15

    Dog

    Beagle                        0, 3.125, 6.25, 12.5, 25,                  examination of pups            Smalley et al. (1968)
    (6-13 per group)              50 mg/kg per day in the diet
                                  throughout gestation

    Beagle                        0, 2.0, 5.0, 12.5 mg/kg per day in         examination of pups            Imming et al. (1969)
    (7-9 per group)               the diet throughout gestation

    Pig

    Hormel-Hanford                0, 4, 8, 16 mg/kg in the diet 20           examination of fetuses (I)     Earl et al. (1973)
    (5-16 per group)              days before/7 days after breeding          or piglets after birth (II)
                                  throughout gestation
                                                                                                                                              

    Table 47 (continued)
                                                                                                                                              

    Species                       Treatment                                  End-point(s)                   Reference
    (number)
                                                                                                                                              

    Pig (30)                      up to 30 mg/kg body weight per                       ?                    Smalley (1968)
                                  day                                                                       [insufficient data]

    Monkey

    Rhesus                        0, 2, 20 mg/kg body weight per             examination of gestational     Dougherty et al.
    (4-6 per group)               day orally throughout gestation            course and new born            (1971)

    Rhesus                        0, 20, 32 mg/kg body weight per            examination of gestational     Coulston et al. (1974)
    (15-16 group)                 day orally. Gestation day 20-38            course and new born

    Sheep

    (25 and 26 per group)         159, 297.5 mg/kg diet                      examination of lambs           Panciera (1967)
                                                                             after birth                    [significance of
                                                                                                            defects impossible to
                                                                                                            assess]

    Hamster

    Golden Syrian                 125 mg/kg body weight per day              fetal examination              Robens (1969)
    (6 or 8 per group)            on gestation day 6-8; 250 mg/kg                                           [number tested too
                                  body weight per day on gestation                                          small]
                                  day 7 or 8
                                                                                                                                              

    Table 48.  Non-mammalian studies
                                                                                                                                              

    Species                       Dosage                                     End-points                     Reference
                                                                                                                                              

    Fish

    Medaka                        0.5, 1.0, 2.5, 5.0, 10.0, and              embryonic development          Solomon & Weis (1979)
    (Oryzias latipes)             20.0 mg/litre, 4-cell through
    10 eggs per group             blastula

    Amphibian

    Xenopus laevis                0.1, 1.0, 10.0 mg/litre; embryos to        embryonic development,         Elliott-Feeley & Armstrong
    10-12 per group               hatching or tadpoles for 24 h              posthatching activity          (1982)

    Birds

    Chicken                       0, 0.01, 0.1, 1.0, 10.0 mg/kg              embryonic development          Olefir & Vinogradova (1968)
    4-6 per group                 body weight

    White Leghorn chicken         0, 250, 500 mg/kg diet to pullets          egg production, embryonic      Lillie (1972)
    20 per group                  for 36 weeks and hatchlings for            development, hatchability,
                                  4 weeks                                    posthatching development

    White Leghorn chicken         0, 1.0, 2.5, 5.0, and 10.0 mg/egg          embryonic development          Swartz (1981)
    38-40 per group               embryonic development injected
                                  into yolk sac after fertilization,
                                  prior to incubation for 5 or 12 days

    White Leghorn chicken         10 mg/egg after fertilization prior        primordial germ cell           Swartz (1985)
    8 per group                   to incubation                              migration

    White Leghorn chicken         1.0, 0.3 mg/egg and lower                  examination of embryos         Eto et al. (1980)
                                                                                                            [insufficient data]
                                                                                                                                              

    Table 48 (continued)
                                                                                                                                              

    Species                       Dosage                                     End-points                     Reference
                                                                                                                                              

    720 eggs                      0, 1, 2, and 4 mg/egg                      examination of hatchlings      Ghadiri & Greenwood (1966)
                                                                                                            [insufficient data]

    Duck and chicken              10-1000 µg/egg 0, 4, 7, 10, and            examination of embryos or      Khera (1966)
                                  13 day eggs                                hatchlings                     [insufficient data]

    Chicken                       -                                          examination of embryos         Dinerman et al. (1970)
                                                                                                            [insufficient data]

    Quail

    Coturnix coturnix             0, 50, 150, 300, 600, 900,                 growth, reproduction,          Bursian & Edens (1977)
    japonica                      1200 mg/kg diet from hatching              post-hatching viability
    10 per group                  through 14 weeks

    Colinus virginianus           0, 300, 1000, 3000 mg/kg diet for          reproduction, post-hatching    Fletcher & Leonard (1986a)
    36 per group                  22 weeks                                   viability, gross pathology

    Duck

    Anas platyrhyncos             0, 300, 1000, 3000 mg/kg diet for          reproduction, post-hatching    Fletcher & Leonard(1986b)
    36 per group                  22 weeks                                   viability, gross pathology

                                  10-1000 µg/egg 0, 4, 7, 10, and            examination of embryos or      Khera (1966)
                                  13 days eggs                               hatchlings                     [insufficient data]
                                                                                                                                              


    
    8.5.1  Mammalian reproductive toxicity studies

    8.5.1.1  Mouse

         Studies on the effects of carbaryl (8.5-34 mg/kg per day),
    given orally for 5 days, to mature male Swiss Webster mice,
    indicated no effects on the weights of testes and accessory sex
    glands or uptake of C14-labelled testosterone by the prostate
    gland, as measured on the day after treatment (Thomas  et al.,
    1974). These workers also examined the biotransformation of
    testosterone-1,2-3H in animals given 34 or 68 mg/kg per day,
    orally, for 5 days. They found a significant decrease in
    androstenedione synthesis in the high-dose group, indicating
    increased hepatic androgen hydroxylase activity (Dieringer & Thomas,
    1974).

    8.5.1.2  Rat

         Collins  et al. (1971) studied the effects of carbaryl given
    in the diet (0, 2000, 5000, and 10 000 mg/kg) to Osborn-Mendel rats
    over 3 generations. The doses actually administered could only be
    estimated since there were no measurements of food intake. On the
    basis of a 15 g/day food intake and a 235 g rat, it can be estimated
    that animals received of the order of 125, 250, or 500 mg/kg per
    day. It should be noted, however, that the food intake of lactating
    rats greatly increases, so these figures may considerably
    under-estimate carbaryl exposure during this critical time period.
    The author used the number of animals mated rather than the number
    giving birth as the number for litter size and viability, therefore
    their calculations are overestimates. Nevertheless, the data do show
    impaired fertility in the high-dose group (which also exhibited
    growth rate reduction) as well as reduced postnatal survival. The
    number of live-born offspring and growth rate were reduced in the
    5000 and 10 000 mg/kg diet groups.

         A three-generation study on Wistar rats was carried out by Weil
     et al. (1973) in which animals were given 0, 7, 25, 100, or
    200 mg/kg per day in the diet or 0, 3, 7, 25, or 100 mg/kg per day
    orally. Maternal toxicity was seen in the dietary study at 200 mg/kg
    per day (decreased weight) and in the gavage study at 100 mg/kg per
    day (decreased weight and mortality). Postnatal toxicity was noted
    in the 100 mg gavage group (reduced litter size and viability), but
    not in lower dose groups. The dietary study indicated fewer effects
    in the maternal animals with only an initial loss in weight. No
    perinatal effects were noted.

         Vashakidze (1975) exposed male and female rats (number and
    strain unspecified) to 0, 1, 5, 10, 20, 40, and 50 mg carbaryl/kg,
    orally, for 1 month. Dose-related changes were noted in serum
    albumin (decrease), globulins (increase), ChE and AChE (decrease),
    aspartate transaminase (increase), and alanine transaminase

    (decrease). Reductions in stem cells as well as spermatozoa were
    noted at doses of 5 mg/kg or more. Adverse litter effects were seen
    in treated females. These effects included increased embryo/fetal
    death, decreased implantations, and prolonged estrus cycle.

         Luca & Balan (1987) administered carbaryl-beta-naphthol to
    Wistar rats in the diet for up to 18 months. The treated groups
    showed an increase in sperm shape abnormalities, though there were
    no clear dose- or time-relationships with effects.

    8.5.1.3  Gerbil

         Collins  et al. (1971) published the results of a 3-generation
    reproduction study in which animals were exposed to 0, 2000, 4000,
    6000, or 10 000 mg/kg diet. Since all postnatal calculations used
    the number of animals mated rather than the number giving birth, the
    authors' data must be recalculated. When this is done, the magnitude
    of the effects reported is reduced. Adverse effects on various
    reproductive parameters are nevertheless seen, though the effects
    are not clearly related to dose levels in the 2000-6000 mg/kg diet
    groups. These data are difficult to interpret given the lack of
    information on maternal effects at doses other than the highest,
    where mortality was observed.

    8.5.2  Mammalian developmental toxicity studies

    8.5.2.1  Mouse

         Murray  et al. (1979) administered 100 or 150 mg carbaryl/kg
    per day, by gavage, or 5660 mg/kg diet (calculated to be 1166 mg/kg
    per day) to CF-1 mice on gestation days (g.d.) 6-15. Maternal
    toxicity was noted in the 150-mg group (ataxia, lethality). Litter
    effects were noted in the 150 mg/kg per day group, where an increase
    in entirely resorbed litters was seen, and in the dietary group
    where there was decreased fetal weight.

         Pregnant mice were given 0, 100, 150, or 200 mg carbaryl/kg per
    day, orally, on gestation days 8, 12, or 6-15, and fetuses were
    examined at term (Mathur & Bhatnagar, 1991). Maternal death was
    noted at the high dose in the group receiving carbaryl on gestation
    days 6-15. Fetal weight reductions were seen at the high-dose levels
    in all groups, as was reduced ossification, open eyelids, and
    enlarged renal pelvis. These effects may be indicative of fetal
    growth retardation.

    8.5.2.2  Rat

         Carbaryl was administered to Harlan Wistar rats at 0, 20, 100,
    or 500 mg/kg per day, orally, on gestation days 1-7, 5-15, or 1-21
    (Weil & Carpenter, 1965; Weil  et al., 1972). Maternal toxicity was
    evident as was reduced weight gain in the high-dose groups receiving

    the chemical on gestation days 5-15 or 1-2. No adverse fetal effects
    were seen.

         Golbs et al.(1975) treated Wistar rats with 0, 200, or 350 mg
    carbaryl/kg, orally, or 40 mg/kg ip on a variety of single or
    multiple gestation days. Reductions in fetal weight were seen in
    some groups. No other effects were noted.

         Sprague-Dawley rats were treated orally with 0, 1, 10, or
    100 mg carbaryl/kg per day, three months before and during
    gestation, and litters were examined at term (Lechner &
    Abdel-Rahman, 1984). Maternal weight gain was significantly less in
    the 100 mg/kg group than in controls. No compound-related effects on
    fetuses were noted.

    8.5.2.3  Guinea-pig

         Weil  et al. (1973) administered carbaryl to guinea-pigs at
    dose levels of 0, 100, 200, or 300 mg/kg per day in the diet, or 0,
    50, 100, or 200 mg/kg per day, orally. These dose levels were
    determined to be maximum non-maternally toxic doses in preliminary
    studies by the authors, though the 200 mg/kg dose did reduce
    maternal weight gain. No significant adverse embryo/fetal effects
    were seen in any treatment groups.

    8.5.2.4  Rabbit

         Murray  et al. (1979) tested the effects of carbaryl on New
    Zealand White rabbits during gestation. Dams had diarrhoea at the
    high dose of 200 mg/kg per day and animals at this dose level as
    well as at the lower dose level (150 mg/kg per day) gained less
    weight during gestation than controls. A significant increase in
    umbilical hernia was noted in fetuses at the 200 mg/kg per day
    group.

    8.5.2.5  Dog

         Smalley  et al. (1968) administered 3.125, 6.25, 12.5, 25, or
    50 mg carbaryl/kg in the diet, throughout gestation, to beagle dogs.
    Maternal toxicity was noted at all dose levels. This toxicity was
    described by the authors as dystocia and symptoms included delayed
    delivery, anorexia, and restlessness. A variety of birth defects
    were found at doses of 6.25 mg/kg or more. The defects included
    ectopic intestines, brachygnathia, acaudia, polydactyly, and
    intestinal agenesis.

         Another study was carried out by Imming  et al. (1969) on the
    beagle dog. These workers used 0, 2.0, 5.0 or 12.5 mg/kg per day,
    orally, throughout gestation. As in the Smalley (1968) study,
    treated females exhibited toxicity during labour and single deaths
    were recorded at this time in all treated groups. Birth defects

    including umbilical hernia and gastrointestinal defects were seen at
    the 5.0 and 12.5 mg dose levels only.

    8.5.2.6  Pig

         Two studies on pigs were carried out by Earl  et al. (1973).
    In the first study, fetal pigs were examined from dams given 0, 4,
    8, or 16 mg carbaryl/kg per day in the diet; in the second, dams
    were allowed to farrow after receiving 0, 16, or 32 mg/kg per day in
    the diet. Animals were exposed throughout most or all of gestation.
    Effects noted were not consistent across the studies and increased
    prenatal lethality seen in the first was not noted in the second,
    even at a higher dose level. A small number of malformations were
    noted, but no characteristic dose-related pattern was evident.

    8.5.2.7  Monkey

         Dougherty  et al. (1971) exposed a small number of female
    Rhesus monkeys to 0, 2, or 20 mg carbaryl/kg, throughout gestation.
    Of the 8 pregnant, treated females, 5 were reported as having
    aborted as opposed only 1 out of 5 in the controls. The Coulston
     et al. (1974) study included a larger number of animals per dose,
    an additional lower dose level (0.2 mg/kg per day), and a shorter
    dosage period (days 20-38 of gestation). No adverse effects were
    noted in the second study. These studies are not comparable for the
    evaluation of the abortifacient potential of carbaryl, since the
    dosing began later in gestation in the second study. The authors
    noted that the determination of abortion in the Rhesus monkeys may
    not have been reliable.

    8.5.3  Reproductive and developmental toxicity studies in
           non-mammalian species

    8.5.3.1  Fish

         Medaka ( Oryzias latipes) embryos were exposed to nominal
    carbaryl concentrations of 0.5, 1.0, 2.5, 5.0, 10.0, 20.0, or
    30.0 mg/litre in the water from the 4-cell through to the blastula
    stages (Solomon & Weis, 1979). Exposure of the eggs resulted in
    increased cardiovascular anomalies (heart defects, circulatory
    defects, and edema) at dose levels of 5 mg/litre or more.

    8.5.3.2  Amphibian

         Elliott-Feeley & Armstrong (1982) treated both embryos and
    tadpoles of  Xenopus laevis with nominal carbaryl concentrations in
    the water of 0.1, 1.0, or 10.0 mg/litre. Defects were seen in
    embryos exposed to 10 mg/litre, which also resulted in significant
    lethality. Embryo growth was reduced at all dose levels.
    Carbaryl-exposed tadpoles exhibited decreased activity at all dose
    levels.

    8.5.3.3  Birds

         Chicken eggs have been used by a number of workers to test the
    potential of carbaryl to affect avian development. Olefir &
    Vinogradova (1968) injected eggs with carbaryl at 0.01, 0.1, 1.0, or
    10.0 mg/kg and examined embryos at different times after injection.
    Death and anomalies were recorded at 5, 10, 15, and 20 days of
    incubation at all doses above 0.01 mg/kg. Lillie (1973) administered
    0, 250, or 500 mg/kg diet to pullets for 36 weeks beginning at 32
    weeks of age. The adult birds showed reduced weights at both levels
    of carbaryl in the adults and at 500 mg in the progeny. No
    embryotoxicity or other effects were noted. Swartz (1981) examined
    the effects of carbaryl on chicken embryo development. They examined
    chick embryos at different days after injection, for 5 or 12 days
    post-fertilization. They found vehicle-related increased mortality
    (carbaryl was more toxic when administered in sesame oil than in
    acetone) for both periods of exposure. Scattered anomalies were
    recorded in surviving embryos. In another study (Swartz, 1985)
    primordial germ cell migration was followed after injection of 10 mg
    carbaryl per egg prior to incubation. Results did not indicate any
    significant adverse effects on the primordial germ cells or
    reproductive organs.

         Bursian & Edens (1977) studied the effects of carbaryl on the
    fertility and post hatching viability of Japanese quail ( Coturnix
     coturnix japonica). Birds were exposed from hatching to 14 weeks
    of age (breeding maturity). Fertility and the hatchability of eggs
    were measured. The animals received 0, 50, 150, 300, 600, 900, or
    1200 mg carbaryl/kg diet. Growth of the adult birds was reduced at
    the 900 and 1200 mg/kg dose levels. There were no significant
    effects on any reproductive parameter.

         Fletcher & Leonard (1986a) investigated the effects of carbaryl
    on reproduction in bobwhite quail ( Colinus virginianus) exposed to
    0, 300, 1000, or 3000 mg/kg diet for 22 weeks. No adverse effects
    were described in any factors related to hatchability, posthatching
    viability, or gross pathology of newly hatched birds. These workers
    used a similar protocol to study the effects of carbaryl on mallard
    ducks ( Anas platyrhyncos) (Fletcher & Leonard, 1986b). The 3000
    mg/kg diet level was toxic with some lethality, decreased numbers of
    eggs, and thinner egg shells. No effects were seen at the 300 or
    1000 mg/kg diet levels.

    8.5.4  Appraisal

         In summary, mammalian studies on the reproductive or

    developmental toxicity of carbaryl clearly show that this compound
    is capable of inducing adverse effects  in utero and during the
    reproductive process. These effects are always seen only at dose
    levels at which there is concurrent maternal toxicity, with the

    possible exception of a few studies on the rat which have not been
    replicated by other workers. For a number of species, the dams
    appear to be more sensitive than their litters. In general, the
    adverse effects noted in developmental toxicology studies cannot be
    simply attributed to maternal toxicity (Chernoff  et al., 1990).
    However, the pattern of maternal and fetal toxicity occurring at the
    same dose levels indicates that the developing mammalian
    embryo/fetus is not especially susceptible to carbaryl.

         Carbaryl has been shown to be embryotoxic for fish, amphibians,
    and birds, at some exposure concentrations.

    8.6  Mutagenicity of carbaryl and  N-nitrosocarbaryl

         In this section on mutagenicity, and in the section on
    carcinogenicity (8.7.1), the two compounds, carbaryl and
    nitrosocarbaryl, are discussed (separately), since the formation of
     N-nitrosocarbaryl was reported to occur in the stomach of rats and
    guinea-pigs, in the presence of sodium nitrite and carbaryl, under
    acid conditions (Elespuru & Lijinsky, 1973; Beraud  et al., 1979;
    Rickard & Dorough, 1984). See also section 8.9.3.

    8.6.1  Genotoxicity assays in vitro

    8.6.1.1  Primary DNA damage

          (a) Carbaryl

         Carbaryl did not cause DNA damage in different wild type
    strains and DNA recombination lacking strains of  Bacillus subtilis
    (Table 49). Carbaryl was reported to be non-genotoxic for
     B. subtilis Marburg 17A Rec+ and Marburg M45T Rec- strains,
    highly sensitive to frameshift mutagens, even at the highest tested
    concentration of 10 mg/plate (Uchiyama  et al., 1975).

         Carbaryl (10-4 mmol/litre) did not affect the sedimentation
    profiles of DNA from human skin cells in culture (both normal and
    xeroderma pigmentosum), either immediately or 20 h after treatment
    (Regan  et al., 1976).

         There are two controversial reports on the genotoxicity of
    carbaryl, evaluated by the induction of mitotic gene conversion in
    the diploid strain of  Saccharomyces cerevisiae, heteroallelic at
    the two different loci ade2 and trp5. Siebert & Eisenbrand (1974)
    used an assay system with a 16-h incubation time and a concentration
    of carbaryl of 4.97 mmol/litre and did not observe any changes in
    the control frequency of mitotic gene conversion. However, Jaszczuk
    & Syrowatka (1979), reported a weak positive response with a lower
    concentration of carbaryl (2.5 mmol/litre) and shorter (5 h)
    incubation time. No converting activity of  N-hydroxy carbaryl (2.5
    mmol/litre) was found under the same assay conditions.


    
    Table 49.  Bacterial assays of genetic toxicity of carbaryl
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

    DNA          B. subtilis        700 mg/litre          Rec assay            -          negative       DeGiovanni-Donnelly et al. (1968)
    damage

                 B. subtilis        20                    Rec assay            -          negative       Shirasu et al. (1976)

                 B. subtilis        0.4, 4, 40, 400       Rec assay            -          negative       Eto et al. (1982)

    Gene         B. subtilis        up to 10 000          Rec assay            -          negative       Uchiyama et al. (1975)
    mutation

                 E. Coli WP2        1000                    Try-               -          negative       Ashwood-Smith et al. (1972)

                 E. Coli WP2        1000-3000               Try-               -          negative       Nagy et al. (1975)

                 E. Coli WP2        10 000                  Try-               -          negative       Uchiyama et al. (1975)

                 H. influenzae      10 µmol/litre        Novobiocim            -          negative       Elespuru et al. (1974)

                  S. typhimurium

                 TA 98              up to 2000              His-               -          negative       McCann et al. (1975)

                 TA 98              up to 2000              His-              Rat         negative

                 TA 98              50 nmol/litre           His-               -          negative       Blevins et al. (1977)

                 TA 98              10-1500                 His-               -          negative       DeLorenzo et al. (1978)
                                                                                                                                              

    Table 49 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 98              10-1500                 His-              Rat         negative

                 TA 98              0.25, 2, 5, 50, 1000    His-               -          negative       Jaszczuk et al. (1979)

                 TA 98              up to 5000              His-               -          negative       Moriya et al. (1983)

                 TA 98              up to 5000              His-              Rat         negative

                 TA 98              0.2, 2, 20              His-               -          negative       Eto et al. (1982)

                 TA 98              0.2, 2, 20              His-              Rat         negative

                 TA 98              5-2000                  His-               -          negative       Lawlor (1989)

                 TA 98              5-2000                  His-              Rat         negative

                 TA 100             up to 2000              His-               -          negative       McCann et al. (1975)

                 TA 100             up to 2000              His-              Rat         negative

                 TA 100             50 nmol/litre           His-               -          negative       Blevins et al. (1977)

                 TA 100             10-1500                 His-               -          negative       DeLorenzo et al. (1978)

                 TA 100             10-1500                 His-              Rat         negative

                 TA 100             0.25, 2, 5, 50, 1000    His-               -          negative       Jaszczuk et al. (1979)

                 TA 100             0.2, 2, 20              His-               -          negative       Eto et al. (1982)
                                                                                                                                              

    Table 49 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 100             0.2, 2, 20              His-              Rat         negative

                 TA 100             5-2000                  His-               -          negative       Lawlor (1989)

                 TA 100             5-2000                  His-              Rat         negative

                 TA 1535            up to 2000              His-               -          negative       McCann et al. (1975)

                 TA 1535            up to 2000              His-              Rat         negative

                 TA 1535            2500                    His-               -          positive       Marshall et al. (1976)

                 TA 1535            1000                    His-              Rat         negative

                 TA 1535            50 nmol/litre           His-               -          negative       Blevins et al. (1977)

                 TA 1535            10-1500                 His-               -          negative       DeLorenzo et al. (1978)

                 TA 1535            10-1500                 His-              Rat         negative

                 TA 1535            up to 5000              His-               -          negative       Moriya et al. (1983)

                 TA 1535            up to 5000              His-              Rat         negative

                 TA 1535            5-2000                  His-               -          negative       Lawlor (1989)

                 TA 1535            5-2000                  His-              Rat         negative
                                                                                                                                              

    Table 49 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 1536            2500                    His-               -          negative       Marshall et al. (1976)

                 TA 1536            1000                    His-              Rat         negative

                 TA 1537            up to 2000              His-               -          negative       McCann et al. (1975)

                 TA 1537            up to 2000              His-              Rat         negative

                 TA 1537            50 nmol/litre           His-               -          negative       Blevins et al. (1977)

                 TA 1537            2500                    His-               -          negative       Marshall et al. (1976)

                 TA 1537            1000                    His-              Rat         negative

                 TA 1537            10-1500                 His-               -          negative       DeLorenzo et al. (1978)

                 TA 1537            10-1500                 His-              Rat         negative

                 TA 1537            0.25, 2, 5, 50, 1000    His-               -          negative       Jaszczuk et al. (1979)

                 TA 1537            up to 5000              His-               -          negative       Moriya et al. (1983)

                 TA 1537            up to 5000              His-              Rat         negative

                 TA 1537            5-2000                  His-               -          negative       Lawlor (1989)

                 TA 1537            5-2000                  His-              Rat         negative

                 TA 1538            100                     His-               -          positive       Egert & Greim (1976)
                                                                                                                                              

    Table 49 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 1538            100                     His-             Mouse        positive

                 TA 1538            50 nmol/litre           His-               -          negative       Blevins et al. (1977)

                 TA 1538            2500                    His-               -          negative       Marshall et al. (1976)

                 TA 1538            1000                    His-              Rat         negative

                 TA 1538            10-1500                 His-               -          negative       DeLorenzo et al. (1978)

                 TA 1538            10-1500                 His-              Rat         negative

                 TA 1538            up to 5000              His-               -          negative       Moriya et al. (1983)

                 TA 1538            up to 5000              His-              Rat         negative

                 TA 1538            5-2000                  His-               -          negative       Lawlor (1989)

                 TA 1538            5-2000                  His-              Rat         negative
                                                                                                                                              


    
         Carbaryl was inactive in the rat primary hepatocytes
    unscheduled DNA synthesis assay (Cifone, 1989). It did not induce
    significant changes in the nuclear labelling of rat primary
    hepatocytes in two independent trials with applied concentrations
    ranging from 5 to 25 µg/ml.

         No DNA-damaging properties of carbaryl, assessed by its
    capacity for inducing unscheduled DNA synthesis (UDS) in cultured
    human lymphocytes, were reported by Rocchi  et al. (1980). However,
    the authors did not use a standardized test protocol meeting
    established criteria for the UDS assay performance. They tested only
    one concentration of carbaryl (50 µg/ml), did not use any metabolic
    activation system, did not run negative and adequate positive
    controls concomitantly (other than the ultraviolet irradiation), and
    did not apply relevant criteria to assess data.

         The lack of DNA-damaging properties of carbaryl, as measured by
    the induction of UDS, was confirmed by Probst  et al. (1981). They
    used a standardized protocol and autoradiographic techniques in
    metabolically competent, cultured rat hepatocytes with test
    concentrations ranging from 0.5 to 1000 nmol/ml. In contrast, Ahmed
     et al. (1977a) reported that carbaryl induced the UDS of the
    ultraviolet type (long patch repair) in a cultured human fibroblast
    VA-4 cell line with, and without, metabolic activation in
    concentration ranges of 1, 10, 100, and 1000 µmol/litre. However,
    this study had several experimental shortcomings. The protocol, the
    control value, and the results of compounds tested were not in
    accordance with comparable assays by other authors.

     (b) N-nitrosocarbaryl

         The DNA-damaging properties of  N-nitrosocarbaryl in
     B. subtilis have been reported (Table 50).

         In one study (Uchiyama  et al., 1975), more pronounced
    genotoxicity of  N-nitrosocarbaryl to  B. subtilis was registered
    compared with that of  N-methyl- N'-nitro- N-nitrosoguanadine.
    However, the genotoxicity of  N-nitrosocarbaryl was the lowest when
    compared with other concomitantly tested nitrocarbamates.

         In contrast to carbaryl,  N-nitrosocarbaryl showed pronounced
    genotoxicity toward  S. cerevisiae D4 (Siebert & Eisenbrand, 1974).

          N-nitrosocarbaryl, but not carbaryl, reacted with human DNA
    in cell culture to form alkaline-sensitive bonds (Regan  et al.,
    1976). The DNA of nitrosocarbaryl-treated (10-4 mmol/litre) cells
    showed a substantial reduction in sedimentation rate immediately,
    and up to 20 h, after treatment. Presumably, the effect observed was
    related to the induction of numerous single-strand breaks in the DNA
    and the formation of DNA adducts. On the basis of selective
    labelling, the authors suggested that the methyl-containing moiety

    of nitroso-carbaryl was separated from the naphthalene ring in a
    human fibro-blast culture and bound irreversibly to DNA (Regan
     et al., 1976).

    8.6.1.2  Gene mutation assay

     (a) Carbaryl

         As summarized in Table 49, carbaryl did not exert a mutagenic
    effect in studies with  E. coli, H. influenzae, or  Salmonella.
    Among the many reports on  Salmonella, only two indicated a
    positive effect. Thus, Marshall  et al. (1976) observed increased
    mutagenicity at 1000 µg/plate with S9 mix for TA1535. An evaluation
    of this data is difficult because no negative and positive control
    data were presented. Egert & Greim (1976) reported a positive
    response for TA1538 by 100 µg/plate. The mutagenicity of carbaryl in
    this study greatly increased when a non-standard metabolic
    activation system (mouse liver microsome) was used.

         Ahmed  et al. (1977b) reported a positive mutagenic response
    to carbaryl in Chinese hamster V79 cells at a dose level of
    0.01 mmol/litre, with no metabolic activation. There was a
    concentration-related effect of carbaryl on cell survival; less than
    50% of the cells survived at concentrations >0.01 mmol/litre.
    Mutation studies carried out with a concentration of 0.01 mmol/litre
    showed an approximately 8-fold increase in ouabain resistance
    forward mutation in V79 cells as compared with the spontaneous
    mutation rate.

         However, Wojciechowski  et al. (1982) found no
    ouabain-resistance with carbaryl in a cell-mediated mutagenesis
    assay when they used an exogenous activating system in which
    irradiated fetal cells of Syrian hamsters were co-cultivated with
    cells of Chinese hamsters V79. No mutagenic response was observed
    for carbaryl at concentrations of 0.01, 0.05, 0.1 mmol/litre with,
    or without metabolic activation. The toxicity of carbaryl at these
    concentrations ranged from 7% at the lowest concentration to 23% at
    the highest.

         Carbaryl produced a negative result for inducing forward
    mutations at the HPRT locus in Chinese hamster ovary cells both
    with, and without, metabolic activation (Young, 1990).


    
    Table 50.  Bacterial assays of the genetic toxicity of nitrosocarbaryl
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

    DNA          B. subtilis        0.4, 4, 40            Rec assay            -          positive       Eto et al. (1982)
    damage

                 B. subtilis        up to 100             Rec assay            -          positive       Uchiyama et al. (1975)

    Gene
    mutation     E. Coli 30 R       0.1 mmol/litre          Try-               -          positive       Elespuru et al. (1974)

                 E. Coli WP2        5, 10, 50, 100          Try-               -          positive       Uchiyama et al. (1975)

                 E. Coli K12        100                     Try-               -          positive       Egert & Greim (1976)

                 E. Coli K12        100                     Try-             Mouse        positive

                 H. influenzae      10 µmol/litre        Novobiocin            -          positive       Elespuru et al. (1974)

                  S. typhimurium

                 TA 98              0.001-11                His-               -          positive/      Blevins et al. (1977)
                                                                                          negative

                 TA 9               10-1500                 His-               -          negative       DeLorenzo et al. (1978)

                 TA 98              10-1500                 His-              Rat         negative

                 TA 98              0.25-1000               His-               -          positive       Jaszczuk et al. (1979)
                                                                                                                                              

    Table 50 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 98              0.02, 0.2, 2            His-               -          negative       Eto et al. (1982)

                 TA 98              0.02, 0.2, 2            His-              Rat         negative

                 TA 98              0.01-100                His-               -          negative       Rickard et al. (1982)

                 TA 98              0.1-100                 His-              Rat         negative

                 TA 100             0.001-11                His-               -          positive       Blevins et al. (1977)

                 TA 100             0.02, 0.2, 2            His-               -          positive       Eto et al. (1982)

                 TA 100             0.02, 0.2, 2            His-              Rat         negative

                 TA 100             0.1-100                 His-               -          positive       Rickard et al. (1982)

                 TA 100             0.1-100                 His-              Rat         positive

                 TA 1535            0.5-100                 His-               -          positive       Marshall et al. (1976)

                 TA 1535            50-1000                 His-              Rat         positive

                 TA 1535            0.001-11                His-               -          positive       Blevins et al. (1977)

                 TA 1535            0.25-1000               His-               -          positive       Jaszczuk et al. (1979)

                 TA 1535            0.1-100                 His-               -          positive       Rickard et al. (1982)

                 TA 1535            0.1-100                 His-              Rat         positive
                                                                                                                                              

    Table 50 (continued)
                                                                                                                                              

    Test         Test organism      Concentration          Genetic         Metabolic      Result         Reference
                                      (µg/plate)          end-point       activation
                                                                                                                                              

                 TA 1536            0.5-100                 His-               -          negative       Marshall et al. (1976)

                 TA 1536            50-1000                 His-              Rat         negative

                 TA 1537            0.001-11                His-               -          negative       Blevins et al. (1977)

                 TA 1537            0.5-100                 His-               -          positive       Marshall et al. (1976)

                 TA 1537            50-1000                 His-              Rat         positive

                 TA 1537            0.25-1000               His-               -          positive       Jaszczuk et al. (1979)

                 TA 1538            100                     His-               -          positive       Egert & Greim (1976)

                 TA 1538            100                     His-              Rat         positive

                 TA 1538            0.001-11                His-               -          negative       Blevins et al. (1977)

                 TA 1538            0.5-100                 His-               -          positive       Marshall et al. (1976)

                 TA 1538            50-1000                 His-              Rat         negative

                 TA 1538            0.25-1000               His-               -          negative       Jaszczuk et al. (1979)
                                                                                                                                              


    
     (b) N-nitrosocarbaryl

          N-nitrosocarbaryl has shown a positive response in a number
    of bacterial assays (Table 50). In  Salmonella, N-nitrosocarbaryl
    was mutagenic to strains responding to both base substitution
    (TA1535, TA100) and frame shift (TA1536, TA1537, TA1538, TA98). The
    mutagenic potential of  N-nitrosocarbaryl toward  Salmonella TA1535
    was greatly diminished by the added exogenous activation system
    (Marshall  et al., 1976). A decrease in mutagenic activity by the
    addition of S9 mix on frame shift mutagenesis has also been reported
    (Marshall  et al., 1976; Jaszczuk  et al., 1979).

    8.6.1.3  Chromosomal aberration assays and sister chromatid exchange

     (a) Carbaryl

     Animals

         Carbaryl induced a clastogenic response in the three  in vitro
    bioassays (Ishidate & Odashima, 1977; Kazarnovskaya & Vasilos, 1977;
    Önfelt & Klasterska, 1983). All the positive responses were observed
    at toxic dose levels (30-80 µg/ml; 50, 100 µmol/litre); exogenous
    metabolic activation was not required for activity. Thus, Ishidate &
    Odashima (1977) observed a strong positive response for carbaryl
    (30 µg/ml) in a chromosomal aberration assay using a Chinese hamster
    fibroblast cell line. Carbaryl produced predominantly chromatid type
    gaps, breaks, translocations, rings, and fragmentation, 48 h after
    treatment.

         Carbaryl was negative for inducing chromosomal aberrations in
    CHO cells without metabolic activation but was positive under
    metabolic activation conditions (Murli, 1989).

         Kazarnovskaya & Vasilos (1977) reported a positive response for
    carbaryl in cultures of human embryonic fibroblast: levels of 40 and
    80 µg/ml caused a 4-fold and 10-fold increase, respectively, in the
    frequency of chromosomal aberrations, at 24 h exposure time,
    compared with a control rate of 2% (without S9-mix). Again, the
    aberrations produced were mainly of a chromatid type; the type most
    frequently observed was single fragments. An increased number of
    paired fragments was found only at 80 µg carbaryl/ml. Carbaryl
    (80 µg/ml) increased the percentage of cells with chromosomal
    coiling (9.8% in the control group; 17.9% in the test group) and
    aneuploidy (3% in the control group; 29.2% in the test group).
    Previously, Kazarnovskaya & Vasilos (1977) had shown that carbaryl
    suppressed mitosis, changed the rate of the mitotic phase, and
    significantly increased the number of pathological forms of mitosis
    in a human embryonic fibroblast culture, with a dose-time response.
    Onfelt & Klasterska (1983) observed induction of viable
    aneuploid/polyploid cells and multiple chromatid exchanges after

    treatment of V79 Chinese hamster cells with carbaryl. The compound
    exerted a pronounced chromosome-breaking effect, at a concentration
    of 100 µmol/litre, 26 and 50 h after treatment. There was an
    increased frequency of multiple chromatid exchanges and fragments,
    as well as pulverisation and more diffuse signs of chromosome
    damage. The effects of carbaryl on chromosome structure and
    distribution were almost abolished by the simultaneous addition of
    Aroclor-induced 2 or 10% rat S9-mix and glutathion.

         In two  in vitro assays for chromosome damage using Chinese
    hamster lung fibroblasts, carbaryl was found to be positive
    (Ishidate  et al., 1981; Onfelt & Klasterska, 1984). In the latter
    study, the effect of carbaryl on the incidence of sister chromatid
    exchange was decreased by the addition of rat liver microsomes.
    Söderpalm & Önfelt (1988) related the mitotic aberrations in V79
    Chinese hamster cells, in part, to a reduction in the intracellular
    levels of glutathione, and increased lipid peroxidation. They also
    hypothesized that the anticholinergic effects of carbaryl may play a
    role in the cleavage process.

     Plants

         A negative clastogenic response for carbaryl in a concentration
    range of 50-200 mg/litre was reported by Ma  et al. (1984) who used
    the  Tradescantia micronucleus test. At present, this test is
    considered the most established and standardized plant assay system
    for the purposes of in situ monitoring of environmental mutagen
    pollution (Ma  et al., 1984).

         Carbaryl induced chromosomal effects in different plant assays
    (Wuu & Grant, 1966; Amer & Farah, 1968; Brankovan, 1972). Carbaryl
    increased by approximately 10-fold the number of aberrant cells in
    the root tips of barley seedings ( Hordeum vulgare) in C1 and C2
    generations after the seeds were treated with concentrations of 500,
    1000, or 1500 mg carbaryl/litre for 6 and 12 h. The cytogenetic
    effects induced included mostly metaphase and anaphase fragments and
    anaphase bridges and were time-dependent (Wuu & Grant, 1966).

         The mitotic, cytogenetic effects of carbaryl were seen in
     Vicia faba (Amer & Farah, 1968) and sugar corn (Brankovan, 1972).
    Carbaryl caused chromosomal abnormalities (chromosome lagging;
    stickiness, mainly in diakinesis, polyploidy, fragments, anaphase
    bridges) in different meiotic states in the pollen mother cells of
     Vicia faba after spraying flower buds of different ages (2 weeks,
    1 month) with saturated aqueous solutions of a commercial carbaryl
    preparation. The percentage of the chromosomal aberrations increased
    with increase in the frequency of spraying (every week) or 2 weeks
    for l month; daily for 8 days) and then decreased when the recovery
    time was increased (Amer & Farah, 1968).

    8.6.2  Genotoxicity in vivo

    8.6.2.1  Host-mediated assay

     (a) Carbaryl

         Usha Rani  et al. (1980) reported that carbaryl did not have a
    gene-mutation potential  in vivo, when given orally in a toxic dose
    of 438 mg/kg, 3 times daily for 3 days, to 6 Swiss male mice, which
    were subsequently injected with  Salmonella strain G46. These data
    are consistent with those that showed that carbaryl was not
    mutagenic for  Salmonella in vitro.

    8.6.2.2  Drosophila melanogaster and other insects

     (a) Carbaryl

         There are several reports of bioassays for carbaryl
    genotoxicity in which  Drosophila melanogaster was used (Brzeskii,
    1972; Brzeskii & Vaskov, 1972; Hoque, 1972; Woodruff  et al., 1983;
    Omer  et al., 1986).

         In studies by Hoque (1972), carbaryl at 1.5 and 10 mg/litre was
    given to female  Drosophila. It was reported that the treatment
    caused a changed sex ratio, changes in eye colour, and various
    chromosomal aberrations in the offspring. The small amounts of
    material used and the lack of any detailed presentation of the
    findings preclude any evaluation or conclusion.

         At high doses (0.3 ml from a 1% suspension of 85% commercial
    product in glucose), carbaryl caused a slight increase in mutation
    frequency in the F1 generation males of a  Drosophila line, which
    were studied at different stages of spermatogenesis. There were no
    deletions or disturbed fertility (Brzeskii, 1972; Brzeskii & Vaskov,
    1972).

         Woodruff  et al. (1983), who used a sensitive experimental
    protocol that incorporated the mating scheme with repair-deficient
    females, reported that carbaryl was not mutagenic for  Drosophila.
    F1 male progeny of males that had ring X chromosomes and double
    marked Y chromosomes, were treated with carbaryl at 200 mg/litre and
    mated with mus-302, repair-deficient females of  Drosophila. The
    male progeny did not show any induced complete (ring chromosome) or
    partial (Y chromosome markers) chromosome loss.

         The mutagenic activity of carbaryl in  Drosophila melanogaster
    was studied by Omer  et al. (1986). The results indicated that
    carbaryl does not increase the rate of dominant and sex-linked
    recessive lethal mutations.

         Carbaryl did not cause chromosome abnormalities in the meiotic
    cells of male grasshoppers, when they were given a single toxic dose
    (not precisely indicated) of 0.25 ml of the supernatant of an
    aqueous suspension/solution of carbaryl by ip injection; however,
    there were morphological disturbances in the spermatocytes (Venkat
    Reddy  et al., 1974).

     (b) N-nitrosocarbaryl

         Results obtained by Omer  et al. (1986) from the
    nitrosocarbaryl-treated populations of  Drosophila melanogaster
    suggested that nitrosocarbaryl increased significantly the
    percentage of dominant lethal mutations above the spontaneous
    mutation frequency. The results obtained from the 0.05, 0.10, and
    0.15% nitrosocarbaryl-treated populations also showed a significant
    increase in the percentages of sex-linked recessive mutations.

    8.6.2.3  Chromosomal aberrations and sister chromatid exchange

     (a) Carbaryl

         There are several negative chromosomal studies on carbaryl and
     N-nitrosocarbaryl in somatic and germ cells  in vivo in mammals
    (Venkat Reddy  et al., 1974; Degraeve  et al., 1976; Seiler, 1977,
    Usha Rani  et al., 1980; Dzwonkowska & Hübner, 1986). In all these
    studies, sufficiently high dose levels of carbaryl were used (up to
    the LD50) in order to define the negative cytogenetic responses.

         Using the micronucleus test and the cytogenetic analysis of
    metaphase chromosomes, Degreave  et al. (1976) found no clastogenic
    effects in the bone marrow of mice that had been given a single oral
    dose of carbaryl (0.2 ml), an intraperitoneal dose (0.5 ml) of
    carbaryl, or 7 oral doses of carbaryl solution (1x10-3 mg/litre)
    alone, or with sodium nitrite (2x10-3 mg/litre).

         A negative response for a high dose of carbaryl (146 mg/kg,
    orally, 2 times per 24 h; 30-h sampling time) was reported by Usha
    Rani  et al. (1980) with an adequate protocol for the mouse bone
    marrow micronucleous test.

         No increase in the rate of the micronucleated, polychromatic
    erythrocytes in the bone marrow of mice was found during  in vivo
    nitrosation of carbaryl after its oral administration at the maximum
    tolerated dose of 100 mg/kg, together with an excess of sodium
    nitrite (100 mg/kg) (Seiler, 1977).

         A dose of 64 mg carbaryl/kg produced a negative result in an
     in vivo assay of chromosomal aberrations in the bone marrow cells
    of the Syrian hamster (Dzwonkowska & Hubner, 1986).

         No chromosome aberrations were observed in the bone marrow of
    Syrian hamsters (6 per dose), given single intraperitoneal
    injections of doses up to the LD50 (64, 128, 320, and 640 mg/kg)
    of a commercial mixture of carbaryl/lindane (40:10) (Dzwonkowska &
    Hubner, 1986).

         Daily oral doses of technical carbaryl (10 mg/kg) suspended in
    peanut oil were given to male, albino rats for a period of 5 days.
    There were no significant chromosomal changes in the bone marrow
    cells of the exposed animals (Dikshith, 1991).

    8.6.2.4  Dominant lethal assays in rodents

     (a) Carbaryl

         Epstein  et al. (1972) studied the mutagenicity of carbaryl
    using the dominant lethal test. In this assay, male ICR/Ha Swiss
    mice were treated orally with 1000 or 50 mg carbaryl/kg daily for 5
    successive days and then caged with 3 untreated virgin females,
    which were replaced weekly for 8 consecutive weeks. The frequency of
    early fetal deaths and preimplantation losses in the test groups
    were within the limits of the control values. Therefore, dominant
    lethal mutations were not induced in mice given sufficiently high
    oral doses of carbaryl.

    8.6.3  Other end-points

    8.6.3.1  Cell transformation

     (a) Carbaryl

         Transformation of the fibroblast clone A31 of the BALB/3T3
    mouse was not induced by carbaryl when given in non-toxic (1.5 and
    10 µg/ml) or moderately cytotoxic (20 and 40 µg/ml) doses, over 24 h
    (Quarles & Tennant, 1975).

     (b) N-nitrosocarbaryl

          N-nitrosocarbaryl showed transforming activity, at
    concentrations of 10-20 µg/ml, which was cytotoxic for the BALB/3T3,
    A31 cells. That 3-10 cell passages are necessary for detecting the
    transforming event suggests that the transformation frequency for
     N-nitrosocarbaryl in this test system is low. Transformed cells
    showed morphological alterations, loss of contact inhibition, and
    growth in soft agar, as well as carcinogenic activity in normal
    newborn, irradiated, suckling, or athymic BALB/C mice. The tumour
    incidence (anaplastic sarcomas) was relatively low; in several
    instances, tumours regressed in normal mice, but not in athymic
    mice, after 2-3 weeks of growth.  N-nitrosocarbaryl did not
    activate detectable amounts of the endogenous murine leukaemia
    viruses carried by the BALB/3T3 cells or viral protein. However,

    viral antigen production in the transformed cells was induced by
    iododeoxyuridin, which indicated the presence of the viral genome.
    On the basis of this  N-nitrosocarbaryl transforming activity in
    mammalian cells in culture, Quarles & Tennant (1975) suggested that
    the compound may be an active, though weak, carcinogen  in vivo.

    8.6.3.2  Aneuploidy induction

     (a) Carbaryl

         Tests of the chemical induction of spindle fibre inactivation
    and c-mitosis (colchicine-mitosis) in  Allium revealed the
    existence of an unspecific physico/chemical mechanism, based on the
    partitioning of compounds into hydrophobic compartments of the cell.
    This means that chemical compounds, in general, cause c-mitosis
    according to their lipophilic characteristics, as indicated by the
    octanol/water partition coefficient. Thus, a close correlation
    exists between the lipophilicity of compounds and the dose at which
    spindle disturbance occurs. However, besides this unspecific effect
    on the spindle fibres mechanism, there are some compounds that
    exhibit specific effects causing inactivation of the spindle fibre
    mechanism at lower doses than indicated by their lipophilicity. This
    can occur via different mechanisms, such as specific binding to
    actin (colchicine) or binding to sulfhydryl groups (organic
    mercury). Onfelt (1987) analysed the c-mitotic effects of 22
    compounds in V79 hamster cells. Five of these compounds fell outside
    the regression line for lipophilicity/c-mitosis, among them
    colchicine, methyl mercury, and carbaryl. Further analyses revealed
    that carbaryl owes its pronounced c-mitotic action to its reactivity
    with sulfhydryl groups. It is therefore not surprising that several
    authors have reported mitotic disturbances caused by carbaryl in
    various experimental systems. Onfelt & Klasterska (1983) reported
    that a significant increase in the aneuploidy/polyploidy cells was
    obtained with both 50 and 100 µmol carbaryl/litre, 26, 59, and 74 h
    after treatment. Carbaryl caused mitotic disturbances in  Allium
     cepa, Vicia faba, Gossypium barbadense, Nigella damascena (Amer,
    1965; Amer  et al., 1971; Degraeve  et al., 1976). Amer (1965)
    reported c-mitotic effects of carbaryl in the roots of  Allium cepa
    that had been treated for 4 or 24 h with different concentrations of
    pure (0.5, 0.25%) and commercial products (85% sprayable powder).
    The increased rate of abnormal meta-telophases and ana-telophases
    depended on the concentration and temperature of the test solutions.
    The types of induced abnormal metaphases included star-metaphases
    and a few prophase-metaphases. Two types of anaphases, the c-type
    and the multipolar type, as well as multinuclear interphase cells,
    were observed. Continuous treatment with carbaryl for 24 h nearly
    arrested mitosis. There was a full recovery of mitosis in 48 h and
    induced signs of polyploidy appeared.

         Consistent with these findings are the c-mitotic effects of
    carbaryl in  Vicia faba and  Gossypium barbadense (Amer  et al.,

    1971). The mitotic index of  Vicia faba, after root treatment,
    decreased with increased concentrations of carbaryl (25, 50, or
    100 mg/litre for 4 h. There was no effect from carbaryl after
    seed-soaking for different lengths of time. Mitotic anomalies
    (mostly disturbed meta- and anaphases) in the roots of  Vicia faba
    and  Gossypium barbadense showed a concentration-time response.

         Carbaryl caused mitotic disturbances (c-mitotic effect,
    multipolar anaphases) or cytotoxicity (pycnotic nuclei, tissue
    degeneration) after root treatment of  Nigella damascena with
    concentrations of 2.5x10-4 and 1x10-3 mg/litre. When NaNO2 (2x10-3)
    was added to carbaryl solutions of 1x10-2 and 1x10-3 mg/litre, the
    effects increased, possibly because of the formation of
    nitrosocarbaryl (Degreave  et al., 1976). No effect was observed
    after grain treatment.

         Soaking sugar corn seeds for 48 h with a 0.12 or 0.25% aqueous
    solution of 50% commercially prepared carbaryl, resulted in a
    dose-response induction of aberrations of anaphase chromosomes of
    types not seen in the controls (bridges with, or without, fragments,
    dicentrics). Repeated treatment of young plants with a 0.25%
    solution of carbaryl for 6 h during meiosis caused typical c-mitotic
    effects in metaphase and anaphase through the arrest of cell
    division and spindle inactivation. Some of the induced aberrations
    persisted until the generative stage. They were fixed and
    incorporated through the embryonal and generative development stages
    and thus increased pollen sterility (Brankovan, 1972).

         Carbaryl was reported to increase the number of aberrant forms
    of mitosis (mostly c-mitotic effect) in the small intestine, cornea,
    and spleen of rats given oral doses of 400 mg/kg. The authors also
    reported that at lower doses of carbaryl (40 or 80 mg/kg), there was
    an increased incidence of bridge and chromosome lagging in anaphase
    and telophase, in addition to a high percentage of c-mitosis. The
    authors reported that there were no effects at 20 mg/kg. Only the
    result following the 400 mg/kg dose was fully reported (Vasilos
     et al., 1975).

    8.6.4  Appraisal

         Carbaryl has been evaluated for its potential mutagenicity in a
    number of tests  in vitro as well as in vivo, in bacterial, yeast,
    plant, insect, and mammalian systems, testing a variety of
    end-points.

         The available evidence indicates that carbaryl has no
    DNA-damaging properties. No confirmed induction of mitotic
    recombination, gene conversion, and UDS in prokaryotes
    ( H. influenzae, B. subtilis) and eukaryotes ( S. cerevisiae, A.
     nidulans, cultured human lymphocytes, and rat hepatocytes)
     in vitro has been reported.

         Negative results were obtained in tests for gene mutations in a
    number of bacterial assays, with the exception of two cases. In
    several studies of gene mutations in mammalian cells  in vitro,
    carbaryl only produced one equivocal positive result in a cell
    culture study. However, the study had several shortcomings and the
    result has not been confirmed in any other comparable studies.

         Chromosomal damage with high dosages of carbaryl, has been
    reported  in vitro in human, rat, and hamster cells and in plants.
    No such effects have been observed in mammalian tests  in vivo, even
    at doses as high as 1000 mg/kg.

         Carbaryl has been shown to induce disturbances in the spindle
    fibre mechanism in plant and mammalian cells  in vitro. The
    relevance of plant assays for extrapolation to humans is unclear.

         It can be concluded that the available data-base does not
    support the presumption that carbaryl poses a risk of inducing
    genetic changes in either the somatic or the germinal tissue of
    humans.

         The nitrosated product of carbaryl,  N-nitrosocarbaryl, is
    capable of inducing mitotic recombination and gene conversion in
    prokaryotes  (H. influenzae, B. subtilis) and eukaryotes  (S.
     cerevisiae) in vitro and gave positive results in  E. coli spot
    tests.

         Furthermore, experimental results indicate that
     N-nitrosocarbaryl binds to DNA, causing alkali-sensitive bonds and
    single-strand breakage.

         Nitrosocarbaryl has not been established as a clastogen
     in vivo (bone marrow and germ cells), even at high toxic doses.

    8.7  Carcinogenicity

    8.7.1  Carcinogenicity studies of carbaryl in rodents

    8.7.1.1  Mouse

         Seven early carcinogenicity studies with carbaryl have been
    reported (Table 51) involving different strains of mice,
    subcutaneous injection, skin painting, ip and oral routes of
    administration, different dose levels and dose schedules, and
    various lengths of exposure and observation. None of these negative
    studies (one marginal response) had sufficient data or data
    reporting and it was not possible to evaluate them.


    
    Table 51.  Carcinogenicity studies on carbaryl in rodents
                                                                                                                                              

    Chemical      Species, strain        Sex        Route and       Dose       Duration        Significant      Evaluation     Reference
                     (number)                        mode of       (mg/kg)     of study       tumour/organ     of individual
                                                 administration                                                    study
                                                                                                                                              

    Carbaryl     Mouse, A/Jax, C3H     male     SC 1/week          200 mg     20 weeks      none               inconclusive  Carpenter et al.
                 30 in group                                       (total)                                                   (1961)

    Carbaryl     Mouse, NS             not      skin painting      not        24 months     none               inconclusive  Weil & Carpenter
                                       stated                      stated                                                    (1962)

    Carbaryl     Mouse, CD-1           male     oral, diet         0.01%      80 weeks      none               inconclusive  Mellon Institute
                                       female                      0.04%      2 years                                        (1963)

    Carbaryl     Mouse, A,C3,HA        not      intraperitoneal    60         2 years       none               inconclusive  Makovskaya et al.
                                       stated   1/week                                                                       (1965)

    Carbaryl     Mouse, (C57,B16x      male     oral gavage daily  4.64       18 months     none               inconclusive  Innes et al.
                 C5H/Anf)F1            female   7 days-4 weeks     14 mg/kg                                                  (1969)
                 (C57B1/6xAKR)F1 72             of age; in diet    body
                                                4 weeks-18         weight
                                                months of age

    Carbaryl     Mouse, A/He: 16       male     intraperitoneal    6 mg       20 weeks      marginal (±)       inconclusive  Shimkin et al.
                                                3/week for         (total)                                     lung tumours  (1969)
                                                4 weeks                                                        response

    Carbaryl     Mouse, A/J: 124       female   oral, diet         1000       10 weeks      none               inconclusive  Triolo et al.
                                                                                                                             (1982)

    Carbaryl     Mouse CD-1            male     diet               100,1000   53 weeks      none               no effect     Hamada (1991b)
    technical                          female                      8000
                                                                                                                                              

    Table 51 (continued)
                                                                                                                                              
    Chemical     Species, strain       Sex      Route and          Dose       Duration      Significant        Evaluation       Reference
                 (number)                       mode of            (mg/kg)    of study      tumour/organ       of individual
                                                administration                                                 study
                                                                                                                                              

    Carbaryl     Rat, CF-N 120         male     oral, diet         0.005,     2 years       none               inconclusive  Carpenter et al.
                 per level             female                      0.01, 0.02,                                               (1961)
                                                                   0.04% in
                                                                   diet

    Carbaryl     Rat, Sprague-Dawley   male     diet               250, 1500  52 weeks      none               negative      Hamada (1991b)
    technical    80 or 90 per group    and                         7500
                                       female

    ß-Carbaryl   Rat, mongrel 60       male     oral gavage twice  30         22 months     fibrosarcoma,      positive but  Andrianova &
                 48 control                     a week                                      skin; polymorphic  inconclusive  Alexeev (1970)
                                                                                            cell sarcoma,
                                                                                            stomach;
                                                                                            osteosarcoma
                                                                                            with multiple
                                                                                            mestastases

                 48                             single             20 mg      22 months     fibrosarcoma,      positive but
                 48 control                     subcutaneous                                skin               inconclusive
                                                implantation
                                                                                                                                              


    
         Most of these studies involved the lung adenoma test in strain
    A mice. This test is no longer considered to be a satisfactory
    carcinogenicity bioassay because of the high rate of background
    tumours that occur in untreated animals (Clayson, 1987).

         Carbaryl did not increase the incidence of lung tumours in two
    strains of male mice, A/Jax and C3H, which were given 20
    consecutive, weekly, subcutaneous injections of 10 mg carbaryl
    (Carpenter  et al., 1961). As only one dose of carbaryl was tested
    and the initial number of animals entered was insufficient, no
    conclusion concerning the carcinogenic potential of carbaryl can be
    drawn from this study.

         There was no tumour development in mice (unspecified strain and
    sex) after carbaryl application by skin painting for 24 months (dose
    not specified, 48% water suspension) (Weil & Carpenter, 1962). This
    study also lacked details about the experimental procedure and
    pathology used and, so, was placed in the inconclusive category.

         Carbaryl did not induce tumours in the lungs, liver, kidney,
    heart, spleen, pancreas, and the thyroid and adrenal glands in two
    strains of mice, A and C3HA, treated ip, once per week for about 2
    years, with toxic doses of 60 mg/kg (Makovskaya  et al., 1965). The
    study involved a sufficient number of animals in the carbaryl group
    (400), untreated control group (100), and urethan positive control
    group (150), killed at 1, 3, 6, 9, 12, 15, 18, and 24 months after
    the beginning of the study and studied histopathologically. However,
    no numerical data on the background lung tumours in the untreated
    control animals were presented. This lack of data, coupled with the
    absence of tumours in the lungs of the carbaryl-treated mice strain
    A, which are known for their high rate of naturally occurring lung
    adenomas, makes the negative response of little significance.

         Carbaryl yielded a marginal tumour response in the pulmonary
    tumour induction test on mice (strain A) given a total dose of 6 mg
    by ip injections, 3 times per week for 4 weeks (Shimkin  et al.,
    1969). Again, the lung adenoma test on strain A mice was not
    reliable for evaluating possible carcinogenicity and, thus, the
    results obtained from this study are not definitive.

         No carcinogenic response was obtained with carbaryl
    administered orally, by gavage, and/or in the diet to four different
    strains of mice at doses ranging from 14 to 1000 mg/kg diet (Melon
    Institute, 1963; Innes  et al., 1969; Triolo  et al., 1982).

         There was no increase in the total tumour incidence and no
    changes in tumour patterns in either sex of CD-1 mice fed diets
    containing doses of 0.01 or 0.04% (100 or 400 mg/kg) carbaryl for 80
    weeks and 2 years, respectively (Mellon Institute, 1969). The
    survival rate in both test groups was too low for a response to be
    observed; no information was given for one-third of the animals;

    histopathology was performed only on animals that were suspected of
    having tumours. Because of these deficiencies, no conclusion can be
    drawn.

         Carbaryl did not significantly increase the incidence of any
    type of spontaneously occurring tumours (hepatomas, lung adenomas,
    lymphoid sarcomas) in either sex of two hybrid strains of mice
    (C57B1/6xC3HAnf) F1 and (C57B1/6xAKR) F1, treated orally with
    4.64 mg/kg by gavage (mice from 7 days to 4 weeks of age), and in
    the diet (mice from 4 weeks to 18 months of age) with 14 mg/kg diet
    (Innes  et al., 1969).

         Another inadequate feeding study of carbaryl carcinogenicity
    was conducted by Triolo  et al. (1982), using the model of lung
    tumour induction in strain A/J female mice. In two studies, the
    feeding level of 1000 mg carbaryl/kg, incorporated in the diet of
    mice for 20 weeks, did not cause a significant increase in the
    incidence of background lung adenomas, nor did it induce tumours in
    the glandular stomach or other tissues (spleen, intestinal tract).
    However, there were a number of confounding factors in defining the
    response in this study including: large variations in the incidence
    of lung adenomas in the four separate control groups; in particular,
    one such group had no tumours, despite high historical control
    levels in strain A mice. In addition, only one dose level was
    studied (1000 mg/kg), on the basis of which it is not possible to
    establish a dose-response relationship.

         In the second study, in which the same feeding level and
    exposure period were used, carbaryl increased the lung
    benzo( a)pyrene hydroxylase activity, which was associated with a
    modest increase in the rate of lung tumours induced by the oral
    administration of 3 mg BP twice, on days 7 and 21, respectively of
    the study. However, there was great variability in the incidence of
    BP-induced lung adenomas in the 3 control groups; the first
    (7.2±0.8) was well above the values presented for the test group
    carbaryl + BP (5.7±1.4); and the second fell within the limits of
    the incidence of spontaneous tumours in the corn-oil control group,
    (1.17±1.11), which make the results inconclusive.

         A new mouse oncogenicity study is in progress, under
    proprietary sponsorship. The study design was as follows: carbaryl
    was administered in the diet to male and female CDR-1 mice at
    rates of 0, 100, 1000, or 8000 mg/kg diet, for up to 104 weeks.
    Groups consisted of 80 mice/sex per group. Ten mice/sex per group
    were sacrificed for clinical pathology evaluation after 52 weeks of
    treatment. Results of this interim sacrifice are presented in
    section 8.3. The remaining animals were designated for continued
    exposure to the end of the 104-week treatment period. The study

    design and evaluation parameters are consistent with guidelines set
    out by the US EPA and OECD, with additional study parameters, for
    studies of this nature (Rhône-Poulenc, 1992).a

    8.7.1.2  Rats

         Two reports by Carpenter  et al. (1961) and Andrianova &
    Alexeev (1970) are controversial. They studied the carcinogenicity
    of carbaryl given to rats by oral gavage, in the diet, or by
    subcutaneous implantation. Both studies had insufficiencies in the
    protocols used.

         Carpenter  et al. (1961) noted no significant increase in the
    total tumour incidence in either sex of CF-N rats fed a diet
    containing 0.005, 0.01, 0.02, or 0.04% carbaryl, for 2 years. Female
    mice had more pituitary tumours than male mice, but there was no
    significant difference in the incidence of tumours between the
    control and test groups. The small initial number of animals used,
    their relatively old age (60 days), their low survival rate, and the
    lack of detailed pathology are complicating factors in defining a
    negative response.

         However, Andrianova & Alexeev (1970) reported that carbaryl,
    administered by both oral gavage and subcutaneous implantation,
    produced positive carcinogenic responses in mongrel rats. Male rats
    given oral doses of 30 mg carbaryl/kg, twice weekly for 22 months,
    developed skin fibrosarcoma, polymorphic cell sarcoma in the
    stomach, and osteosarcoma with multiple metastases. Carbaryl caused
    high lethality (80%) during the exposure period. The authors did not
    state whether the gross pathology was examined. One fibrosarcoma was
    discovered among 46 control animals, at 11 months. No data were
    presented on the number of control animals that lived for 22 months,
    so a comparison of survival rates in control and test groups could
    not be made.

         In a parallel study, 20 mg of carbaryl in a purified paraffin
    capsule was implanted subcutaneously in 48 male rats. At the end of
    the 22-month exposure period, subcutaneous fibrosarcomas, in sites
    far from the implantation area, and on the back and neck, were
    diagnosed in 2 out of 10 surviving animals. There was no control
    group (Andrianova & Alexeev, 1970). The carbaryl used was obtained
    from a plant in the USSR and was of technical grade and 97.65%
    purity. No information about the chemical composition and impurities
    was given. Because of these deficiencies, this study is
    inconclusive.
                 

    a Information to Task Group. These studies have not yet been
        reviewed by the IPCS. The company performing these studies has
        indicated that there is a significant increase in tumors at the
        highest dose in both species.

         A new combined long-term toxicity and oncogenicity study on
    rats is in progress, under proprietary sponsorship. The study design
    is as follows: carbaryl was administered in the diet to male and
    female Sprague-Dawley rats at rates of 0, 250, 1500, or 7500 mg/kg
    diet, for up to 104 weeks. Groups consisted of 80 rats/sex per group
    for low- and middle-dose groups and 90 rats/sex per group for the
    high-dose and control groups. Ten animals/sex per group were
    sacrificed after 26 and 52 weeks exposure and evaluated for clinical
    pathology and histopathology. In addition, 10 animals/sex from the
    control and high-dose groups were used as a recovery group, kept on
    a basal control group diet before sacrifice at 56 weeks. The results
    of the interim sacrifices are presented in section 8.3. The
    remaining animals were designated for continued exposure to the end
    of the 104-week treatment period. The study design and evaluation
    criteria are consistent with guidelines set out by the US EPA and
    OECD, with additional study parameters, for studies of this nature
    (Rhône-Poulenc, 1992).a

    8.7.1.3  Overall appraisal of carbaryl carcinogenicity

         Carbaryl has been studied for its carcinogenic potential in
    numerous studies on rats and mice via various routes of
    administration. Most of these studies are old and do not meet
    contemporary standards.

         Only one paper from the existing body of publications clearly
    reports a tumorigenic action of carbaryl. Carbaryl induced malignant
    tumours in an unidentified strain of rat by the oral and
    subcutaneous routes of administration. This study does not meet
    contemporary standards, because of insufficient reporting of control
    data.

         New studies, designed to meet with contemporary standards, are
    in progress on rats and mice. Descriptions of the studies are given
    in sections 8.7.1.1 and 8.7.1.2.

    8.7.2  Carcinogenicity studies of  N-nitrosocarbaryl

         Carbaryl is a secondary amine and is, therefore, capable of
    nitrosation in the presence of nitro donor groups, such as sodium
    nitrate, to give a nitrosamide. This nitrosamide, nitrosocarbaryl,
    has been proved to be mutagenic and carcinogenic, at high doses in

                 

    a Information to Task Group. These studies have not yet been
        reviewed by the IPCS. The company performing these studies has
        indicated that there is a significant increase in tumors at the
        highest dose in both species.

    animals (see Table 52). A condition of this nitrosation is an acidic
    pH (less than 2), which is comparable to the one found in the human
    stomach. However, nitrosocarbaryl is not stable at this pH. Its
    maximum stability is between pH 3 and 5, at which pH no significant
    amount of carbaryl can be nitrosated. Carbaryl was nitrosated in
    several studies,  in vitro as well as in vivo, in the guinea-pig,
    which has a stomach acidity similar to that of humans. See also
    section 8.9.3.

    8.7.2.1  Rats

          N-nitrosocarbaryl elicited a carcinogenic response in both
    sexes of two strains of rats (Wistar and Sprague-Dawley) by two
    routes of administration (oral gavage and subcutaneous injection)
    (Eisenbrand  et al., 1975, 1976; Lijinsky & Taylor, 1976;
    Preussmann  et al., 1976; Lijinsky & Schmähl, 1978).

         A local carcinogenic effect of N-nitrosocarbaryl was reported
    by Eisenbrand  et al. (1975) in Wistar rats given a single
    subcutaneous injection of 1000 mg/kg. Fifteen out of 16 treated
    animals developed sarcomas at the injection site; there was no
    histopathological evidence of any systemic carcinogenic effects. The
    dose of  N-nitrosocarbaryl was highly toxic and 14 out of 16
    animals had died by day 450. No spontaneous tumours were observed in
    control animals. When given to rats orally in single doses of
    200-1500 mg/kg,  N-nitrosocarbaryl did not induce tumours during 21
    months of observation. No signs of toxicity were noted in any of the
    test groups.

         Further studies involving repeated oral administration of
     N-nitrosocarbaryl to Sprague-Dawley rats gave unequivocal evidence
    of local carcinogenic effects, produced by both oral and
    subcutaneous routes of administration. (Eisenbrand  et al., 1976;
    Lijinsky & Taylor, 1976, 1977; Preussmann  et al., 1976; Lijinsky &
    Schmähl, 1978). 

         The nonglandular part of the stomach (forestomach) was the
    target organ of the local carcinogenic action of  N-nitrosocarbaryl,
    when it was given orally to rats. All stages of malignant
    transformation in the forestomach, from hyperplasia to squamous cell
    carcinoma, were observed in male Sprague-Dawley rats treated with
    oral doses of 130 mg  N-nitrosocarbaryl/kg, twice weekly, until
    spontaneous death. There was a substantial lowering of the survival
    rate of treated animals because of the pronounced toxicity. By the
    time of maximum increase of the tumour incidence (after 200 days),
    most of the animals were dead. The average survival time of
    tumour-bearing animals was 167 days after the onset of the study.
    The low background tumour incidence (3 out of 29) in control animals
    included lymphosarcomas and leukaemia.


    
    Table 52.  Carcinogenicity studies on  N-nitrosocarbaryl in rodents
                                                                                                                                              
    Chemica       Species, strain        Sex       Route and        Dose       Duration       Significant       Evaluation     Reference
                     (number)                       mode of        (mg/kg)     of study       tumour/organ     of individual
                                                 administration                                                    study
                                                                                                                                              

    N-nitroso    Rat, Wistar           male     subcutaneous,      1000       450 days      polymorphic cell   positive      Eisenbrand et al. 
    carbaryl     8: male;              female   single injection                            sarcoma at                       (1975)
                 8: female                                                                  injection site;
                                                                                            spindle cell
                                                                                            sarcoma
                 37                    male,    oral gavage,       200-1500   21 months     none               inconclusive
                                       female   single

    N-nitroso    Rat, Sprague-Dawley   male     oral gavage,       130 (5000  till          squamous cell      positive      Eisenbrand et al.
    carbaryl     31                             twice per week     total)     spontaneous   sarcoma,                         (1976)
                                                                              death         papilloma,                       Preussmann et al.
                                                                                            hyperkeratoses,                  (1976)
                                                                                            forestomach

    N-nitroso    Rat, Sprague-Dawley   female   oral gavage,       50 mg      110 weeks     squamous cell      positive      Lijinsky & Taylor
    carbaryl     12                             once a week        (total)                  carcinoma                        (1976)
                                                for 10 weeks                                forestomach,
                                                                                            papilloma,
                                                                                            oesophagus
                 12                    male     oral gavage,       300 mg     90 weeks      squamous cell
                                                twice a week       (total)                  carcinoma
                                                for 20 weeks                                forestomach,
                                                                                            papilloma trachea

    N-nitroso    Rat, Sprague-Dawley   male     oral gavage,       600        80 weeks      carcinoma          positive      Lijinsky &
    carbaryl     16: male;             female   once a week        (total)                  forestomach                      Schmahl (1978)
                 16: female                     for 10 weeks
                                                                                                                                              


    
         In a comparative study of the carcinogenic potency of
     N-nitroso- N-alkylcarbamate esters, Lijinsky & Taylor (1976)
    showed that  N-nitrosocarbaryl was a strong carcinogen, similar in
    action to its highly potent carcinogenic analogue
     N-nitrosomethylurethane. A high incidence (75-80%) of
    squamous-cell carcinomas in the forestomach was detected in female
    Sprague-Dawley rats given 10, weekly, equimolar oral doses
    (0.22 mmol) of both compounds. Nitrosomethylurethane was a more
    potent carcinogen, because the animals with tumours died earlier
    than those in the nitrosocarbaryl group. The same rate of carcinomas
    in the forestomach was induced in male rats treated orally with a
    considerably higher dose of  N-nitrosocarbaryl (1.3 mmol total),
    over twice as long a period (20 weeks). The stronger carcinogenic
    effect of this dose in male animals was expressed by the shorter
    latent period of induced tumours and higher lethality compared with
    female animals. The local carcinogenic effect of  N-nitrosocarbaryl
    in rats, the target organ being the forestomach, was seen in another
    oral carcinogenicity study of a series of nitroso- N-methylcarbamate
    insecticides carried out by Lijinsky & Schmähl, (1978). The oral
    gavage of 10 weekly doses of 60 mg nitrosocarbaryl/kg to both sexes
    of Sprague-Dawley rats led to a high incidence (over 70%) of
    carcinomas in the forestomach, with no evidence of other systemic
    carcinogenic effects.

         No carcinogenic response for carbaryl was obtained with the
    transplacental carcinogenicity test after  in vivo nitrosation in
    pregnant Sprague-Dawley rats (Lijinsky & Taylor, 1976). Pregnant
    animals were given 30 mg carbaryl/rat, orally, for 10 days (4-18
    days of gestation). Two other groups of animals received the same
    dose of carbaryl, together with 0.6-1ml of 4% sodium nitrite on days
    4-6 and 14-18 of pregnancy. The distribution of tumours in the rats
    of various groups was that normally seen in Sprague-Dawley rats. It
    is likely that an insufficient amount of nitrosocarbaryl was formed
    under the conditions of  in vivo nitrosation, or that no
    significant amount of nitrosocarbaryl crossed the placenta.

         A low rate of  in vitro nitrosation of carbaryl under
    conditions similar to those that exist in the human stomach was
    reported by Eisenbrand  et al. (1975). The reaction of
    10-3 mol/litre carbaryl with a 5-fold molar excess of sodium nitrite
    in 0.1N HC1 (pH, 1) led, after 15-60 min, to yields of only 1.2 and
    1.7% of the maximum possible conversion to nitrosocarbaryl.
    Reduction of the concentration of carbaryl and sodium nitrite by a
    factor of 10 decreased the yield of nitrosocarbaryl by about
    one-half. The yields of  N-nitrosocarbaryl obtained by the
     in vitro nitrosation of carbaryl, under the described conditions,
    are low and the potential carcinogenic risk of  in vitro nitrosation
    and similar nitrosation reactions  in vivo is difficult to evaluate
    at present.

    8.7.2.2  Mice

         Nitrosocarbaryl administered for 104 weeks to the skin of
    female CFLP mice (65 mice per group) in three doses (12.5, 50, and
    200 µg/mouse) was found to be more potent regarding dermal
    carcinogenic efficiency than nitrosomethylurea, applied under the
    same conditions, though not as effective as benzo- a-pyrene
    (Deutsch-Wenzel  et al., 1985). Conclusions were drawn on the basis
    of the number of animals bearing carcinomas, total cases with local
    tumours, observed/expected ratios and dose-response relationships of
    incidences of malignant tumours. These results were found to be in
    contrast to the ones obtained by Lijinsky & Winter (1981), who used
    a single total dose of 23 mg and found that nitrosocarbaryl was a
    much less effective inducer of mouse skin tumours than
    nitrosomethylurea.

    8.7.2.3  Overall evaluation of the carcinogenicity of
              N-nitrosocarbaryl

         Sufficient evidence of carcinogenicity at the site of
    application was seen in multiple studies on both sexes of
    Sprague-Dawley rats, by different routes of administration
    (subcutaneous and oral gavage), using different dose levels. The
    non-glandular stomach was the target tumour site when
    nitrosocarbaryl was administered by oral gavage; subcutaneous
    injection of nitrosocarbaryl caused sarcomas at the injection site.

         The local carcinogenic effect of  N-nitrosocarbaryl in rats,
    and the lack of any systemic carcinogenicity, characterizes it as a
    direct-acting alkylating agent.  N-nitrosocarbaryl was active as a
    direct bacterial mutagen and interacted with human DNA  in vitro.
    These data agree with data that show that  N-nitrosocarbaryl is an
    effective  in vivo genotoxin.

    8.7.3  Carcinogenicity of ß-carbaryl

         Beta-carbaryl (N-methyl ß-naphthyl carbamate) was a component
    of technical carbaryl (alpha-carbaryl), suspected of having a
    carcinogenic structure and a tumorigenic potential in mice and rats
    (Zabezhinski, 1970). In life-time studies on mice, strain CC57W (24
    months), and mongrel rats (33 months), using two routes of
    administration, oral gavage (10 mg/kg in mice; 25 mg/kg in rats) and
    subcutaneous injection (20 mg/kg in mice; 50 mg/kg in rats),
    ß-carbaryl showed a weak carcinogenic response. High rates of
    lethality (20-50%) were observed in both mice and rats, by the two
    routes of administration. No data for survival rates and the
    incidence of spontaneous tumours in control animals were presented.
    ß-carbaryl caused a low rate of tumours in rats by both routes of
    administration. The types of tumours (21%) observed after
    subcutaneous injection of ß-carbaryl included: fibrosarcoma at the
    injection site, subcutaneous rhabdomyosarcoma, intestinal sarcoma,

    leukaemia, reticuloses, and reticulosarcoma. The pattern of
    carcinogenic response after orally administered ß-carbaryl (25%)
    involved sarcoma in the liver, fibroadenoma and adenocarcinoma in
    the mammary glands, carcinoma in the thymus, and granulocellular
    carcinoma in the ovaries. No local tumours at the injection site
    were observed in control animals after subcutaneous administration
    of corn oil. The other tumours (carcinoma in the mammary glands and
    thymus, haematopoietic system malignancies) were unusual for control
    animals, as well. ß-carbaryl caused a higher tumour incidence in
    mice than in rats by both subcutaneous (60%) and oral (30%) routes.
    It should be mentioned, however, that most of the tumours observed
    (lung adenomas, leukaemia, and liver haemangiomas) occurred
    spontaneously in untreated mice. Since no control data were
    presented, the carcinogenic response to ß-carbaryl in mice is of
    uncertain significance. Because of these deficiencies, this study is
    inconclusive.

    8.8  Special studies

    8.8.1  Neurotoxicity

         The effect of carbaryl on the nervous system is primarily
    related to ChE inhibition.

         Carpenter  et al. (1961) studied the delayed neurotoxic
    potential of carbaryl in chickens (Rhode Island hens) compared with
    that of triorthocresyl-phosphate. Single doses of 250, 500, 1000, or
    3000 mg/kg body weight, 25-40% in lard were administered
    subcutaneously to chickens. At 2000 mg/kg, weakness was observed on
    day 1 or 2 after dosing. In one case, the chicken was unable to walk
    for 3 days. No evidence of demyelination was observed in any brain
    sciatic nerve or spinal cord section examined microscopically.
    According to the authors, there was a transient cholinergic effect
    caused by the slow absorption of carbaryl.

         The neurotoxic effect of carbaryl was studied in atropinized
    chickens (Gaines, 1969) to protect against acute effects of the
    subcutaneous injection of 800 or 1600 mg carbaryl/kg body weight.
    The higher dose caused leg weakness within 24 h, which recovered by
    day 24.

         Carbaryl solution in corn oil at a daily dose of 100 mg/kg was
    administered orally for 7 consecutive days to 35, 6-day-old, female
    broilers, hybrids between Peterson strain roosters and Hubbard hens
    (Farage-Elawar, 1989). Altered locomotion and abnormally shortened
    gait were observed on the 7th day, and cases of delayed paralysis
    20-40 days, after the last treatment. Locomotion changes were found
    to have no association with the activities of brain
    acetylcholinesterase and neuropathy target esterase, 24 h after the
    first, second, third, and fifth doses as well as 1, 3, 6, 10, 20,

    30, and 40 days after the last treatment, when no statistical
    deviations from the control values of both enzymes were registered.

         A similar, but lesser, effect on gait and stride length was
    observed when 45 mg carbaryl/kg was injected into chick eggs on day
    15 of incubation (Farage-Elawar, 1990). This treatment resulted in
    significant inhibition of brain and plasma cholinesterase, and liver
    carboxylesterase. Administration of the same dose on day 5 of
    incubation resulted in 10% lethality. Brain NTE was not affected.
    The cause of this delayed alteration is not known.

         Effects of long-term carbaryl exposure on the neuromuscular
    system of pigs were reported by Smalley  et al. (1969). Six
    Yorkshire pigs, 3 male and 3 female, received carbaryl in their diet
    (150 mg/kg body weight); the male pigs for 72 days and the female
    pigs for 83 days. Three pigs from the same litter were fed carbaryl
    at 150 mg/kg body weight daily, for 4 weeks, and then 300 mg/kg body
    weight, daily, for 46 days (2 male pigs), and for 85 days (the
    female pig). The signs of intoxication started after about 1´
    months, and were mostly typical of neuromuscular system damage (see
    Table 44; section 8.3). Microscopic examination of the skeletal
    muscle revealed myodegeneration. In the myelinated tracts of the
    cerebellum, brain stem, and upper spinal cord, moderate to severe
    edema was associated with vascular degenerative changes. No
    demyelination of nerve tissue was observed. When carbaryl feeding
    was stopped and hydrochlorothiazide applied as a diuretic, signs of
    toxicity of carbaryl, such as ataxia, and partial paralysis,
    disappeared.

         Carbaryl disturbed the function of the myoneural synapses. It
    produced a decrease in the spontaneous activity and an increase in
    the permeability of the muscular fibre membrane for K+ and Na+
    after multiple oral administrations of 8.5 mg/kg to rats(Kovtum &
    Sokur, 1970).

         Kovtun (1970) while analysing the effects of carbaryl on
    myoneural formations, pointed out that, at a single intake
    (425 mg/kg), multiple intakes during 2 months, or 1/100
    LD50-8.5 mg/kg over 6 months, the frequency of tiny potentials of
    an edge plate was suppressed by 62-65%. On the basis of the data
    obtained it was concluded that carbaryl probably impairs the
    function of presynaptic nerve endings. At the same time, carbaryl
    does not affect the cholinereceptive membrane substance of muscular
    fibres. Carbaryl increases the rest potential of muscular fibres by
    11-35%, depending of the carbaryl dose. This increase can be
    explained through high potassium ion accumulation inside the
    muscular fibres.

         Three different laboratories examined the effects of carbaryl
    on motor activity in rats. All three reported decreased activity

    after intraperitoneal administration, with ED50s that ranged from
    13.3 to 17.6 mg/kg (Crofton  et al., 1991).

         Takahashi  et al. (1991) compared the effects of carbaryl on
    both young (3 months) and old (12 months) rats. A dose of 50 mg/kg
    decreased activity in an open field test, prolonged the duration of
    haloperidol-induced catalepsy, decreased body temperature, and
    increased the nociception threshold, as measured by a hot-plate
    test. A dose of 10 mg also prolonged haloperidol-induced catalepsy.
    The effects on body temperature and nociception were significantly
    greater in older rats.

         Studies were carried out on the mechanical response
    characteristics of the soleus muscle  in situ. Female Holtzman rats
    (6 treated-control pairs) were given 56 mg carbaryl/kg orally.
    Carbaryl increased the tension developed during complete tetanus (by
    electric stimulus) and decreased the time constant of tension
    development (Santolucito & Whitcomb, 1971). The more forceful and
    rapid contraction of the skeletal muscle is probably related to an
    accelerated catecholamine release.

         EEGs on 4 Rhesus monkeys given 0.01 mg carbaryl/kg and on 3
    given 1 mg/kg per day, orally, for 18 months, showed only a
    reduction in the amount of low-amplitude fast waves and an increased
    bilateral synchrony between the right and left hemispheres
    (Santolucito & Morrison, 1971). The authors did not relate these EEG
    changes to the dose.

         Belonozhko & Kuchak (1969) found some changes in the EEG in
    rats, such as desynchronisation of rhythms after a single
    application of carbaryl at 100 mg/kg. During repeated doses of
    35 mg/kg for 90 days, no changes in the EEG were noted, due
    (according to the authors) to adaptation of the nervous system. Oral
    doses of 72 mg carbaryl/kg, administered to rats for 10 days, caused
    a decrease in serotonin and an increase in dopamine levels in the
    brain (Kuzminskaya  et al., 1984).

         Morphological changes in the nervous system caused by carbaryl
    were dose-related. One to six months oral treatment of rabbits with
    0.01 LD50 caused only haemodynamic disorders and cell
    infiltrations, a dose of 0.02 LD50 caused cell dystrophic changes,
    and a dose of 0.1 LD50 caused more progressive and serious
    disorders (Azizova, 1976).

         The behavioural effects of carbaryl were studied in rats and
    monkeys. Disturbance of discrete (shock) avoidance behaviour by
    carbaryl in rats was reported at ip doses > 2.5 mg/kg, the LD50
    being 8 mg/kg (Goldberg  et al., 1965). Carbaryl administered at
    doses of 8, 16, or 28 mg/kg, ip, decreased maze activity in CD male
    rats (10 in each group), whereas doses of 16 and 28 mg/kg reduced
    open field activity. After acute exposure, behavioural changes

    recovered within 60 min, whereas ChE of the blood and brain
    recovered after 240 min (Ruppert  et al., 1983).

         Carbaryl at 10 mg/kg administered subcutaneously in 16, male,
    Long Evans strain rats decreased the number of times they approached
    the novel stimuli and explored the exploratory box, and increased
    habituation. In familiar situations, carbaryl increased activity
    (Albright & Simmel, 1977).

         Anger & Setzer (1979) studied the effects of oral and im
    administration of carbaryl on repeated chain acquisition in 5 male
    monkeys ( Macaccus mascicularis). Oral doses of 50 mg/kg did not
    alter the performance of repeated acquisition tasks. The im
    injection resulted in consistent changes in performance at 5 and
    10 mg/kg, but did not cause any changes at 1 mg/kg.

         Carbaryl affected working memory (continuous delayed response
    and continuous non-match) in 28 male Sprague-Dawley rats (Heise &
    Hudson, 1985a,b). A dose of 10 mg carbaryl/kg, ip, affected
    performance of working memory procedures; with increasing dose,
    carbaryl nonselectively decreased response.

         Administration of 2.24 mg carbaryl/kg, ip for 14 days, did not
    affect the performance of rats in activity wheel cages, 24 h after
    the last treatment. Acute ip administration of 0.54 or 2.24 mg/kg
    significantly decreased the motor activity of rats in activity wheel
    cages. This decrease was reversed by atropine sulfate (Singh, 1973).
    Doses as low as 7.76 mg/kg ip caused mild tremors.

         Oral administration of carbaryl (200 mg/kg, 3 days/week) for a
    period of 90 days, though producing inhibition of ChE in blood (33%)
    and brain (11%), did not result in any kind of overt signs of
    toxicity in male albino rats (Dikshith  et al., 1976).

         Desi  et al. (1974), in long-term studies, investigated the
    effects of carbaryl on the learning process, on the performance of
    previously learned tasks in mazes, and on the EEG in 40 male Wistar
    strain rats. Carbaryl was given at doses of 10 or 20 mg/kg body
    weight per day in the diet (100-200 mg/kg food), for 50 days. Mild,
    but permanent and increased, functional deviations of the nervous
    system were found. Because of increased irritability in the CNS, the
    treated rats took less time than the untreated rats to find their
    food. Later, the task was performed with difficulty when the
    irritability of the CNS was reduced to below the normal level. The
    performance of the learned task was impaired. EEG deviations
    recorded at the end of the maze studies were slight, but permanent.
    They consisted of increased electric activity of the brain,
    increased number of moderately slow beta waves, and light flashes of
    18 Hz accelerated electrical activity.

         Viter (1978) found behavioural changes in rats treated via
    inhalation for several months with 12 or 23 mg carbaryl/m3. The
    latency period of the conditioned reflex on nutrition was prolonged.
    Depression of investigative behaviour and spontaneous motor activity
    were noted.

         The behavioural effects of carbaryl on rats were examined by
    Moser  et al. (1988) using a functional observation battery.
    Carbaryl was administered at doses of 3-30 mg/kg, ip, and tested
    0.5, 3, 24, and 48 h afterwards. Carbaryl decreased spontaneous
    activity, CNS excitability, motor and sensory function, and body
    temperature and weight. Effects indicative of AChE inhibition were
    also observed. All responses were dose dependent.

    8.8.2  Effects on the immune system

    8.8.2.1  Appraisal on immunotoxicology

         The administration of carbaryl, or any other xenobiotic, at
    doses resulting in overt toxicity can be expected to result also in
    a variety of effects on the immune system. Carbaryl, when
    administered  in vivo, at a dose not causing overt clinical signs
    has been reported to produce a variety of non-life-threatening
    effects on the immune system. The effects included cellular as well
    as humoral immunity, and several authors have suggested that they
    were was due to subtle, treatment-related stress. Many of the
    effects described were detected at doses close to the LD50.
    Shortcomings of several of these studies were a lack of consistency
    and, sometimes, overt contradiction between results, which prevents
    the description of a defined immunotoxic mechanism.

         Lifetime exposure to carbaryl did not result in increased
    occurrence of disease in rats or mice. No enhancement of viral
    infections was found with carbaryl, even at dosages close to the
    LD50. Most studies on rabbits and mice, at doses permitting
    survival, did not produce significant effects on the immune system.

          In vitro, a number of researchers have demonstrated viral
    enhancement by prior incubation with carbaryl.  In vitro, carbaryl
    can enhance herpes varicella-zoster, but not herpes simplex. In
    goldfish cell culture, carbaryl has been shown to permit viral
    enhancement by compromising interferon synthesis. Inhibition of
    human serum complement activity as well as interleukine-2 driven
    proliferation of large granular lymphocytes have been demonstrated
     in vitro. These actions could be mediated through the inhibition
    of serine esterases involved in the processes. No increased viral
    infections have been seen in long-term  in vivo feeding studies,
    previously conducted or in progress at present. Carbaryl does not
    enhance transformation of BALB/53T fibroblasts in culture or the
    expression of endogenous murine leukaemia virus.

    8.8.2.2  In vivo studies

         Young mice weighing 10-12 g were infected with influenza by
    applying 3-4 drops (0.05 g) 1% influenza virus in physiological
    solution in the nose. The murine influenza virus strain A.P.R.8 was
    used in the primary dilution 1:32. After 2-3 days, this group of 30
    mice was treated orally with carbaryl in sunflower oil, at a dose of
    500 mg/kg (a dose that killed 3 out of 10 mice). Two control groups
    with the same number of mice, one treated with carbaryl alone, and
    one infected, were compared with the experimental animals for
    survival, blood biochemistry, and pathomorphological changes. The
    greatest number of mice dying were in the experimental group. AChE
    depression was more pronounced and recovery slower, and there were
    more histological changes in the livers of mice infected and
    intoxicated by carbaryl (Moreynis & Estrin, 1965). It is clear from
    this study that a summation of the effects of both factors occurred,
    but, because of the lack of statistical significance, it is
    impossible to judge the eventual effect of the enhancement.

         The effect of carbaryl on an experimental  Erysipelothrix
     rhusiopathiae infection in rats was studied by Shabanov  et al.
    (1983). Rats, treated with doses that increased gradually every 6
    days from 2 to 5 mg/rat (mean weight of rats, 50-60 g) during 30
    days, were infected iv with  Erysipelothrix rhusiopathiae at
    1.5-108 cells/rat. The mortality rate in carbaryl-treated rats was
    36% versus 14% in control rats. Survival time was halved.
    Bacteraemia persisted for 10-12 days in treated groups, and only 5-6
    days in the control group. Both the gross and the histopathological
    changes were more strongly manifested in the treated group.

         Carbaryl, at 0, 2, 20, or 200 mg/kg was administered orally to
    rabbits, daily, for 6 months. A decrease in the phagocytic activity
    of leukocytes and antibody formation (4-5 times) after immunization
    with a murine type of typhoid vaccine, was reported at the dose
    level of 200 mg/kg. At the lower dose of 20 mg/kg, there were
    different phases of reactivity; at the beginning of the first 2
    months, there was an increase and later a decrease in immunological
    reactivity (Perelygin  et al., 1971).

         The effects of oral ingestion of carbaryl on nonreaginic
    antibody production in BALB/c mice were studied after pretreatment
    with 150 mg carbaryl/kg diet for 10 weeks prior to commencement of
    the study. Carbaryl produced significant effects on systemic
    antibody production following oral immunization with sheep red blood
    cells (SRBC). It significantly increased both IgG1 and IgG2b titres.
    No reduction was seen in the synthesis of any antibody class. These
    results suggest that, at the doses used, carbaryl increased systemic
    antibody responses to orally ingested antigens (André  et al.,
    1983).

         Changes in the immunological structures of lymphatic follicles
    in the spleen during carbaryl administration were studied by Dinoeva
    (1974, 1982), who used a micrometric method. Albino rats (30
    treated-control pair) were given 1.5 mg carbaryl/kg, orally, daily
    for 6 months. Plethora in the spleen and retardation in lymphatic
    follicles were observed, which were similar to effects seen in the
    positive control group treated with cyclophosphamide (2 mg/kg).
    There were no changes in the structure and weight of the thymus in
    carbaryl-treated rats, while in the cyclophosphamide positive
    control group, the weight of the thymus was reduced 2.5 times. The
    authors suggested that there is a different mechanism of the
    immuno-suppressive effect of carbaryl that needs further research.

         A single dose of 500 mg carbaryl/kg inhibited the production of
    haemolysins and reduced the number of splenic germinal centres in
    White Leghorn chickens (Roszkowski  et al., 1976). Dose-dependent
    immunosuppressive effects of continued dietary treatment of rabbits
    with carbaryl were studied (Street & Sharma, 1975). Rabbits (male
    White New Zealand, 7 in each group) were fed 0, 4, 20, 45, or 150 mg
    carbaryl/kg diet (corresponding to 0, 0.23, 1.0, 2.3, or 8.38 mg/kg
    body weight per day) for 57 days. The treatment reduced the germinal
    centres in the spleen and caused atrophy of the thymus cortex. The
    antigen-induced increase in serum gamma-globulin was decreased
    significantly (no dose relationship was noted), at 10 days. No
    changes were detected in the number of plasma cells in the lymph,
    haemolysin and haemoglutinin titres, skin sensitivity to tuberculin,
    leukocytes count, body weight, etc.

         Rats pretreated, orally, with 0.05 LD50 carbaryl, daily, for
    2.5 months, were immunized with typhoid antigen. Administration of
    carbaryl continued for an additional 2 months. Signs of
    insufficiency of the immune system, expressed as a reduction in
    specific globulin production, were observed 3.5 months after
    carbaryl application began. Carbaryl did not affect immunogenesis at
    a dose of 0.001 LD50, daily, under the same exposure conditions.
    No overall evaluation was given (Olefir, 1977).

         A humoral immunity study in female BALB/C mice after oral
    administration of carbaryl was performed by Wiltrout  et al. (1978).
    The effects of humoral immune competence were measured by the
    immunoplaque in gel technique. The number of antibody plaque-forming
    cells (PFC) per plate was counted and the PFC/spleen calculated.
    Different groups of mice received carbaryl, orally, at about
    1 LD50 (153 mg/kg body weight), 5 days before immunization (type
    of antigen not specified), on the day of immunization, and 2 days
    after. Only the last treatment resulted in significant suppression
    of the humoral immune response. The ratio (experimental: control) of
    antibody plaque-forming cells was 0.34. The oral administration of
    0.1 LD50 for 8 and 28 days did not cause any significant effects

    on humoral immune competence. Depression of the PFC/spleen level
    corresponds to a decline in the total splenic lymphocyte population.

         Akhundov  et al. (1981) studied the effects of carbaryl on the
    immunological reactivity of 40 rabbits and 40 guinea-pigs given oral
    doses of 15 mg carbaryl/kg for 42 days. Heated vaccine  Salmonella
     typhimurium, at doses of 250 or 500 million microbial cells, was
    applied 3 times at 7-day intervals, 21 days after the beginning of
    carbaryl administration. The auto-sensitizing effect of the vaccine
    was enhanced by carbaryl. Studies on guinea-pigs treated with 15 mg
    carbaryl/kg per day for 3 months showed decreased macrophagial
    migration activity.

         Pipy  et al. (1983) evaluated the cellular and humoral
    mechanisms of carbaryl-induced reticuloendothelial phagocyte
    depression. The function of the reticuloendothelial system (RES)
    involved in specific and non-specific aspects of host resistance to
    infection, neoplasma, etc., was quantitatively evaluated by the rate
    of disappearance of colloids injected into the blood. Colloid
    particles are extracted from the blood exclusively by the RES, in
    particular liver and spleen macrophages. Plasma or serum factors
    called opsonins have a strong stimulatory influence on inert
    particle phagocytosis. Male Sprague-Dawley rats (200-240 g) were
    given single, iv injections of labelled carbaryl at 0.5-32 mg/kg
    body weight (7 different doses). The iv LD50 determined by the
    authors was 50 mg/kg body weight. Colloidal carbon was administered
    simultaneously. In another group, carbaryl was incubated with serum
    from a normal rat for 20 min before the injection. The authors call
    this carbaryl "opsonized". The results showed the ability of
    carbaryl to induce a state of reticuloendothelial phagocytic
    depression, mediated through depletion of opsonins. Carbaryl
    inhibits the cell-bound aromatic amino acid esterase of the serine
    esterase class. The authors concluded that, apart from a slight
    deficiency in plasma opsonins, the inhibitory effect of carbaryl on
    the phagocyte function was primarily due to a selective hepatic and
    splenic macrophage impairment, which could be related to inhibition
    of a cell-bound serine esterase. In another study by Pipy  et al.
    (1982), more details are given of this possible mechanism of
    phagocytoxic blockade by carbaryl. Rats were treated with iv
    carbaryl at 8 or 16 mg/kg body weight. The time-dependence of the
    effects on phagocytic function and the activities of liver serine
    esterases ( N-benzoyl-DL-phenylalanine-ß-naphthyl esterase and
    acethylcholinesterase) was studied. Macrophages of the RES had
    decreased phagocytic capacities after administration of carbaryl.
    Depression of the phagocytosis of colloidal carbon persisted from 1
    to 7 h and 1 to 24 h after administration of 8 and 16 mg/kg
    carbaryl, respectively. Liver ( N-benzoyl-DL-phenylalanine-ß-
    naphthyl esterase (cell-bound serine esterase) was susceptible to
    reversible dose-related inhibition by carbaryl. A correlation
    between the reactivation kinetics of liver serine esterases and
    phagocytic activity was demonstrated.

    8.8.2.3  In vitro studies

         The replication of goldfish virus 2 (GFV-2) was enhanced  in
     vitro by pre-treatment of a piscine culture with subtoxic
    concentrations (1 mg carbaryl/litre) (Shea, 1983). The mechanism of
    enhancement was studied  in vitro in goldfish-derived cell lines
    and Air Bladder III infected with GFV-2 and pretreated with a
    carbaryl solution of 1 µg/ml. Interferon synthesis was studied as a
    possible mechanism of virus enhancement (Shea & Berry, 1984). The
    authors demonstrated that interferon synthesis was induced in CAR
    cells by GFV-2 cells. Antiviral protection provided by supernatants
    from infected CAR cultures with carbaryl, against infection of
    secondary CAR and Air Bladder III cultures was reduced. The authors
    interpreted this phenomenon as a result of general mild suppression
    of cellular metabolism, but other possible mechanisms, such as
    metabolic interaction, were not excluded. In another study, Shea
    (1985) demonstrated quantitative carbaryl inhibition of interferon
    synthesis. Supernatants from infected cultures, not treated with
    carbaryl, provided 10 times as much antiviral protection as compared
    with non-infected cultures. Carbaryl-treated infected culture
    provided only twice as much antiviral protection as uninfected
    cultures. A similar relationship was observed when comparing the
    amount of infectious viral progeny synthesized in the presence of
    supernatant from infected cultures not pretreated with carbaryl
    (10%), and from infected cultures pretreated with carbaryl (60% of
    the amount of virus synthesized in control cultures). The author
    speculated about the possibility of superimposition of a viral
    infection in a population exposed to pesticides.

         Characterization of varicella zoster virus enhancement by
    carbaryl was carried out  in vitro by Abrahamsen & Jerkofsky (1981)
    and Jerkovsky & Abrahamsen (1983). In previous studies, the authors
    demonstrated that the replication of varicella zoster virus (a human
    herpes virus) is increased 12 to 15-fold by pretreatment of cultures
    of human embryonic lung cells (HEL) with carbaryl, and, that
    different strains of this virus show differences in sensitivity to
    enhancement. Wild-type strains recently isolated from clinical
    materials are more sensitive than laboratory adapted strains. In
    this study, the authors demonstrated that the maximum enhancement
    occurred 48-72 h post-inoculation and that the optimal time for the
    pretreatment of monolayers of HEL is 20-24 h. 1-naphthol also
    produced increased amounts of virus, but the treated cells cannot
    pass on to the daughter cells the ability to enhance virus
    replication.

         Rodgers  et al. (1986) determined that the EC50 for the
    inhibition of a T-cell-mediated cytolytic (CTL) response by carbaryl
     in vitro was 65.9 µg/ml. The addition of a supernatant containing
    liver enzymes reduced the effects of several organophosphorous
    pesticides on the CTL response, but had no significant effect on the
    potency of carbaryl.

         Casale  et al. (1989) compared the ability of carbaryl to
    interfere with the human serum complement mediated lysis of sheep
    blood cells. At a concentration of 3 mmol/litre and with 2-h
    preincubation, carbaryl inhibited lysis by 26-45%, depending on the
    antibody concentration. Carbaryl was a more potent lysis inhibitor
    than diisopropyl phosphorfluoridate or four other anticholinergic
    insecticides; the potency was not correlated with anticholinergic
    activity.

          The effects of carbaryl at concentrations of
    0.5-500 µmol/litre on lymphocyte proliferation were studied  in
     vitro (Bavari  et al., 1991). Carbaryl inhibited (3H) thymidine
    incorporation, in a concentration-dependent manner, by as much as
    50%. Alpha-naphthol also had a slight effect at 50 µmol/litre. The
    authors attributed the effect to inhibition of an esterase
    responsible for interleukin activation.

    8.8.3  Effects in blood

         Carbaryl affects the coagulation process. Hyper- and
    hypocoagulation were reported in different studies (Hassan & Cueto,
    1970; Gapparov, 1974; Lox, 1984; Krug & Berndt, 1985; Krug  et al.,
    1988).

         Gapparov (1974) studied the indices of blood coagulation in
    dogs after oral treatment with a daily dose of 2 mg carbaryl/kg body
    weight, over 5 months. A clearly manifested hypercoagulation was
    established, which was connected with a rise in the general
    coagulation activity of the blood, higher thromboplastic activity,
    and prothrombin content, increased number of thrombocytes,
    accelerated coagulation time, and increased activity of the
    fibrinostabilizing factor. Also noted was a decrease in the
    recalcification time of blood plasma, fibrinogen concentration, and
    free heparin quantity, together with an inhibition of the fibrolytic
    activity of the blood. The author interpreted all these changes as
    being connected with the arousal of the parasympathetic system.

         The blood coagulation time was considerably shortened in
    rabbits that were given, orally, a mixture of carbaryl (5 mg/kg),
    DDT (5 mg/kg), and parathion (0.5 mg/kg), for 222 days. This effect
    corresponded to increased levels of 5-hydroxy-3-indolacetic acid
    (5-HIAA) and 4-hydroxy-3-methoxymandelic acid (VMA) in the urine,
    indicating an increased rate of metabolism of serotonin and
    catecholamine (Hassan & Cueto, 1970). The authors suggested that
    this effect was a manifestation of non-specific stress, since
    adrenocortical hormones shorten the coagulation time.

         Fifteen male Sprague-Dawley rats (250-300 g) were given
    drinking-water containing 10 mg carbaryl/litre for 30 days. Platelet
    count, prothrombin time, partial thromboplastin time, fibrinogen,
    and clotting factor activity for coagulation factors II, V, VII,

    VIII, IX, X, and XII were determined. A significant decrease in
    platelet count and in the factor VII clotting activity was observed
    compared with those in the same number of control rats. Microscopic
    evaluation of the liver revealed hepatocyte degeneration, central
    vein congestion, some leukocytic infiltration, and vacuolization of
    the cytoplasm. The author suggested that carbaryl might have harmful
    effects on haemostasis (Lox, 1984).

         Carbaryl has an  in vitro inhibitory effect on arachidonic
    acid-induced platelet aggregation, which corresponds to its
    inhibition of thromboxane B2-formation. The results suggest that
    carbaryl affected platelet aggregation by inhibition of
    cyclooxygenase (the key enzyme of prostaglandin synthesis) by
    carbamoylation (Krug & Berndt, 1985). At a concentration of
    10 µmol/litre, carbaryl completely blocked platelet aggregation and
    cyclo-oxygenase activity (Krug  et al., 1988). The carbamoylation
    of several platelet proteins, including cyclo-oxygenase, may be
    responsible for this effect.

         Carbaryl produced,  in vitro, a dose-dependent increase in
    methaemoglobin (Met Hb) formation at 10 and 100 mg/litre, as well as
    decreases in reduced glutathion levels in the erythrocytes of Dorset
    sheep with low erythrocyte glucoso-6-phosphate dehydrogenase
    (G-6-PD), which is similar to humans who have G-6-PD deficiency.
    Carbaryl posed oxidative stress to G-6-PD-deficient red cells,
    probably due to its major metabolite alpha-naphthol (Calabrese &
    Geiger, 1986). Decreases in the K+ ion concentration in
    erythrocytes (with more than 24%) and in haematocrits (from 43.5 to
    38%) were found by Sokur (1971) in rats fed carbaryl 0.05 LD50/day
    for 2 months.

         In an  in vitro study, Szczepaniak & Jeleniewicz (1981) found
    that carbaryl binds free blood amino acids (plasma and
    erythrocytes). These authors also performed a series of  in vitro
    studies to investigate the effect of carbaryl on amino acids. A
    single application of 475 mg carbaryl/kg on 46 treated and 12
    control rats produced significantly decreased amino acid values in
    the brain, except for valine and phenylalanine. All amino acids
    reached the control level after 72 and 120 h. Two hours after
    administration, erythrocyte amino acids also decreased >50%
    (Szczepaniak & Jeleniewicz, 1980; Jeleniewicz  et al., 1984). A
    slight decrease in erythrocyte amino acid concentrations was
    observed after 30 days with 95 mg carbaryl/kg administered orally
    (Jeleniewicz & Szczepaniak, 1980). Blood serum amino acids in 24
    rats decreased 4 h after a single application of 189.6 mg/kg. There
    was a larger decrease in valine, then in phenylalanine, alanine,
    aspergic acid, serine, and glycine (Szczepaniak  et al., 1980).
    After 15-day dosing of 0.1 LD50(94.8 mg/kg) per day to 12 rats,
    there were no changes in levels in serum and erythrocytes, but after
    30-day dosing in 8 rats, there was a slight decrease in the alanine
    concentration of the erythrocytes (Jeleniewicz & Szczepaniak, 1980).

         The effects of carbaryl on the thermoresistance and fractional
    content of blood serum proteins was studied by Subbotina &
    Belonozhko (1968). A single dose of 150 mg carbaryl/kg administered
    to rabbits and multiple applications of 100 mg carbaryl/kg for 2
    months showed that, with a single application of carbaryl, there was
    an increase in protein thermocoagulation from 28% on day 1 to 67% on
    day 7, and with multiple applications of carbaryl there was a
    lowering of albumin levels and a rise in globulins (mostly
    alpha-globulins) in serum, on day 10. These changes were reversible.
    There was also a decrease in the coefficient of thermal dehydration.
    The changes in proteins in both studies show lowering of their
    lability.

         Carbaryl inhibited the incorporation of 3H-uridine and
    14C-labelled amino acids into RNA and proteins in cultures of HeLa
    cells. The effect was dose-dependent. Incorporation was inhibited by
    50% at a 150 µg/ml concentration after 30 min incubation. At a
    concentration of 350 µg/ml, only 10% of amino acids and 32% of
    uridine incorporation activity were retained (Myhr, 1973). Later,
    Blevins & Dunn (1975) showed that carbaryl caused general metabolic
    changes in Hela cells. A concentration of 1-2 mg carbaryl/litre
    stimulated all divisions and, at 4-8 mg/litre, inhibited growth. A
    decrease in cellular protein at 4 mg/litre was noted. Changes in the
    phospholipid fraction at 8 mg/litre were probably related to the
    alteration of the structure of cellular membranes. Disturbances in
    the development of human cells in culture were also reported by
    Shpirt (1973). An inhibitory effect of carbaryl on cell development
    was demonstrated in Ehrlich ascites tumours in mice. A reduced rate
    of incorporation of labelled uridine-5-3H-thymidine methyl-3H
    and L-leucine 14C in the RNA, DNA, and proteins in Ehrlich cells
     in vitro was also reported (Walker  et al., 1975b). The authors
    suggested that this effect could be a basis for investigating the
    mechanism of the adverse effects that carbaryl has on reproduction.

         Carbaryl and  N-nitrosocarbaryl appeared to have different
    action characteristics with regard to rat liver microsomal membrane
    alterations (Beraud  et al., 1989b); carbaryl was ineffective on
    the lipoperoxidation indices while the nitroso compound had an
    inhibitory action on the formation of malonaldehyde and conjugated
    dienes as well as on the NADPH-dependent reductase activities.

    8.8.4  Effects on the liver and other organs

         Several authors reported data on disturbances in the
    carbohydrate, protein-forming, and detoxicating functions of the
    liver.

         A single application of 300 mg carbaryl/kg in rats produced an
    increase in albumin and alpha-globulins, and a decrease in ß-and
    gamma-globulins (Zapko, 1970).

         Kagan  et al. (1970) studied the effects of carbaryl on the
    liver of 180 rats and 18 rabbits. During an 11-month study, they
    gave a daily, oral dose of 38 mg carbaryl/kg to rats. After 1 month,
    they observed a rise in the alanine-aminotransferase and
    alkaline-phosphatase activities in serum, and a decrease in succinic
    dehydrogenase and glycogen in the liver. Doses of 0.76 mg/kg and
    0.38 mg/kg, given in the diet to rabbits, caused retention of
    bromsulfophthaleine in the blood. The authors also reported a
    changed ratio in the protein fractions in serum and an increase in
    liver weight. The pathomorphological changes in the liver were
    destructive, necrobiotic, and proliferative. An effect on the liver
    was also demonstrated in the study of Lox (1987) (see section
    8.8.3).

         Pavlova  et al. (1968) found that, with acute and long-term
    exposures, carbaryl affected the oxidative processes in tissues,
    because of its direct action on the enzymes of cell respiration and
    possible disturbance in the membrane processes. They performed
    studies on rats treated with 0.2 LD50 for 3 days and on rats
    treated with 0.01 LD50 for 20 weeks. At the higher dose, there
    were decreases in the cytochromoxidase and succinedehydrogenase
    activities in the liver and brain mitochondria. A histochemical
    examination revealed a rather high, irregular activity of the
    cytochromoxidase in the heart, as well as increased succinic
    dehydrogenase activity. With the long-term dosing, the changes were
    not significant, but there was a lowering of the cytochromoxidase
    and succinedehydrogenase activities in the heart mitochondria.
    Development of experimental cholesterol arteriosclerosis in rabbits
    was facilitated by the application of 20 mg carbaryl/kg for 2.5
    months (Lukaneva & Rodionov, 1973). Changes were found in the
    following indices: general cholesterol, ß-lipoproteins, ECG changes,
    and pathomorphological changes in the aorta and coronary vessels.

         Carbaryl (100 mg/kg body weight) given to dogs in their diet
    for 45 days caused disturbances in the secretion of the intestinal
    enzymes. There was an increase in enterokinase secretion, as well as
    in the excretion of alkaline phosphates and lipase into the
    intestinal juice. The no-observed-effect level (NOEL) for these
    effects was 700 µg/kg body weight, which corresponds to 7 mg
    carbaryl/kg diet. Three dogs were used in each group (Georgiev,
    1967).

    8.8.5  Effects on serum glucose

         Orzel & Weiss (1966) found that a rise in blood glucose

    correlated with the onset and duration of tremors and the degree of
    brain ChE inhibition in rats that were treated ip with 5 and 25 mg
    carbaryl/kg. The hyperglycaemic response is blocked by
    adrenal-ectomy and is unaltered by hypophysectomy. The authors
    suggested that the hyperglycaemia was related to increased secretion

    of epinephrine. Hyperglycaemia is thought to result from cholinergic
    stimulations as it is also found in acute intoxications with
    organophosphorous compounds (Kaloyanova, 1963). In their studies,
    Orzel & Weiss did not find changes in liver glycogen. Muscle
    glycogen was decreased only in non-fasted rats. Elevated levels of
    blood glucose and slightly reduced immunoreactive insulin were found
    with repeated oral exposure of rats at 3 mg/rat, weekly, for one
    year (Wakakura  et al., 1978). Glycogen disappeared in most of the
    hepatocytes. The cells mainly contained related granular endoplasmic
    reticulum with swollen mitochondria. A single application of
    30 mg/rat produced transient hypoglycaemia at 20 h followed by
    hyperglycaemia at 44 h. The effects of carbaryl on respiration,
    glycolysis, and glycogenesis in isolated hepatocytes of male Wistar
    rats were studied by Parafita  et al. (1984) and Parafita &
    Fernandez Otero (1984). The cells were treated with concentrations
    of carbaryl of 0.01, 0.1, and 1.0 mmol/litre dissolved in 1%
    dimethylsulfoxide (DMSO). DMSO slightly stimulates the respiratory
    coefficients. Carbaryl decreased the metabolic output of CO2 at
    all concentrations; oxygen consumption was reduced by 40% in
    relation to the DMSO-treated groups only at the highest
    concentration (1.0 mmol/litre). Glucose remained unchanged in the
    presence of carbaryl. Endogenous production of lactic acid was not
    affected, and net metabolic production was strongly inhibited by
    both DMSO and carbaryl. At a maximum carbaryl concentration
    (1 mmol/litre), the net lactic acid production was completely
    blocked. Carbaryl inhibited lactate gluconeogenesis, and, to some
    extent, gluconeogenesis from fructose pyruvate and alanin. Glycerol
    glucogenesis was unaffected. Lactic dehydrogenase activity was
    reduced by 38% and glucose 6-phosphate synthetic activity was
    increased by 1.0 mmol carbaryl/litre. Aspartate aminotransferase
    activities (cytoplasmic and mitochondrial fractions) were inhibited
    by 0.1 and 1.0 mmol carbaryl/litre. The results indicated that
    carbaryl causes a decrease in glucose production by hepatic cells
    and suggested that carbaryl-induced hyperglycaemia in fasted animals
    is caused by deficiencies in the peripheral utilization of the
    glucose.

    8.8.6  Interactions with the drug metabolizing enzyme system

         Carbaryl is a weak inducer of hepatic microsomal
    drug-metabolizing activity. Cress & Strother (1974) reported
    depressed hexobarbital sleeping time in mice given 0.125 or 0.5
    LD50 carbaryl, orally, for 10 days. These authors studied the
    effects of a 2-week dietary administration of high levels of
    carbaryl (10 times higher than the dose given in the earlier study).
    Weanling male Swiss-Webster mice, weighing 17-20 g, were divided
    into 5 groups of 40 animals each. The daily consumption of carbaryl
    by each animal was approximately 119% of the acute LD50. This dose
    was well tolerated with no deaths or overt symptoms of
    cholinesterase inhibition, probably because carbaryl was
    administered over a 24-h period, instead of in a single injection.

    Feeding carbaryl resulted in a 44% increase in the rate of  in vitro
     p-hydroxylation of aniline, and increased  in vitro demethylation
    of benzphetamine. The hepatic levels of cytochrome P-450 and b5
    were increased, but the microsomal protein concentration per gram of
    liver was not affected. No changes were reported in
    1-naphthol-treated mice. Increased metabolic activity was
    demonstrated with phenobarbital and carbaryl. Phenobarbital sleeping
    time was shortened to 45 min (control 74 min) in carbaryl-fed mice.
    The rate of elimination for the carbaryl-treated animals was twice
    as high as that for control animals. The oral LD50 of carbaryl in
    carbaryl-pretreated animals (14 days feeding) was three times as
    high as in the control animals. 1-Naphthol did not affect the levels
    of cytochromes. Sleeping time and the LD50 for carbaryl were not
    different in control and 1-naphthol pretreated animals.

         Liver weight was low in carbaryl-fed mice, but higher as a
    fraction of body weight. The authors concluded that the degree of
    the enzyme induction was not high, because most indicators exceeded
    the control values by 50% only, except for the lethal dose level.

         The pretreatment of rats with 5 daily doses of 10 mg
    carbaryl/kg, administered ip, resulted in a 4.2-fold increase in the
    rate of benzo( a)pyrene metabolism (Lesca  et al., 1984). Total
    microsomal P-450 content and benzphetamine demethylase activity were
    not significantly affected. The increased ability to hydroxylate
    aniline in mice under carbaryl treatment was reported by Guthrie
     et al. (1971).

         Exposure of murine 3T3 fibroblasts to carbaryl at a
    concentration of 10-6 mol/litre was found to increase aryl
    hydrocarbon hydroxylase activity (Lahmy  et al., 1988). The
    magnitude of the effect increased with the duration of exposure.

         Carbaryl induction of microsomal enzyme systems in White
    Leghorn cockerels was demonstrated by Puyear & Paulson (1972). A
    decrease in phenobarbital sleeping time, an increase in liver weight
    and elevation of liver aniline hydroxylase activity were found after
    oral treatment with carbaryl at 100 mg/kg per day (in gelatine
    capsules) for 3 or 6 days. No effect was observed at a dose of
    50 mg/kg. Thus, the sleeping time data indicated that the NOEL of
    carbaryl for Leghorn cockerels was between 50 and 100 mg/kg per day.
    Higher doses caused an increase in liver aminopyrine demethylase
    activity (200 or more mg/kg per day) and in liver cytochrome P-450
    content (300 or 400 mg/kg per day). Microsomal protein was not
    changed. All study parameters returned to control values by day 11
    after the treatment was terminated (Puyear & Paulson, 1972).

         El-Toukhy  et al. (1989) reported that the administration by
    gavage of carbaryl to mice at a dose of 166 mg/kg resulted in small,
    but statistically significant (15-20%), decreases in liver pyridoxal
    phosphokinase and L-tryptophan 2,3-dioxygenase activity.

    Administration over a 5-day period of 83 mg carbaryl/kg per day had
    no significant effect. Hassan  et al. (1990) administered 85 mg/kg,
    orally, either once or five times daily. Both the single and
    repeated regimens resulted in approximately 40% decreases in
    L-tryptophan 2,3-dioxygenase. Carbaryl was also found to be a
    competitive inhibitor of this enzyme  in vitro.

         Inhibition of monoamino-oxidase (MAO) was reported in the
    presence of carbaryl  in vitro in liver homogenate (Hassan  et al.,
    1966). The authors suggested that MAO and the catalase system are
    involved in oxidative demethylation during carbaryl detoxification.

         Exposure of rat liver microsomes to carbaryl  in vitro at a
    concentration of 0.5 mmol/litre resulted in decreases in the
    activities of several monooxygenases (Knight  et al., 1986). The
    ability of carbaryl to inhibit the  N-demethylation of
    ethylmorphine appeared to be competitive with a Ki of
    2.4x10-4 mol/litre. However, when administered to rats at doses of
    up to 25 mg/kg, carbaryl did not have any significant inductive or
    inhibitory effect.

         Lechner & Abdel-Rahman (1986a) reported that the  in vitro
    incubation of 2 and 4 mmol carbaryl/litre for 60 min reduced
    glutathione levels and increased glutathione S-alkyltransferase in a
    rat liver homogenate in a dose- and time-dependent manner. Carbaryl
    had no apparent effect on glutathione levels in whole blood with
    120 min of incubation. Carbaryl inhibited  N-demethylation and
     O-demethylation by rat liver microsomes with apparent Ki of 0.1
    and 0.7 mmol/litre, respectively (Beraud  et al., 1989a).

         Carbaryl had an antagonistic action on the release of
    microsomal ß-glucuronidase by malathion in a microsomal suspension
     in vitro (Lechner & Abdel-Rahman, 1985).

         Jacob  et al. (1985) studied the effects of carbaryl on the
    metabolic activation of the environmental, carcinogenic, polycyclic
    aromatic hydrocarbons. Carbaryl was a weak inducer of metabolism of
    benz( a)anthracence in the rat liver, and altered its metabolite
    profile by shifting from 10, 11-oxidation to 5, 6- and 8,
    9-oxidation. Since carbaryl did not induce bay-region activation,
    the authors concluded that tumour-promoting activity could not be
    expected.

    8.8.7  Effects on the endocrine system

         The effect of carbaryl on the neuroendocrine system was studied
    in rats. Carbaryl was given, orally, at 7, 14, or 70 mg/kg body
    weight to male and female rats (each group contained 24 animals
    weighing 90-130 g) for a period of 1 year. Growth retardation,
    changes in the blood enzymes, and endocrine gland disturbances
    varied with the dosage, being especially marked at the end of the

    study in the group receiving 70 mg/kg body weight per day.
    Acetylcholinesterase and butylcholinesterase activities were
    inhibited significantly in these groups. Spermatozoon motility was
    reduced progressively with the duration of the exposure. In the
    prolonged estrus cycle, the diestrus period was particularly
    affected. An increase in the number of corpora lutea and atrophic
    follicles in the ovaries was correlated with this disturbance. There
    was a dose-dependent increase in the gonadotropic function of the
    hypophysis, which was determined by tests on immature mice.
    Hypophyseal homogenate from a rat given 70 mg carbaryl/kg increased
    the weight of the ovaries by 51.5%, and that of the uterus by 123%,
    compared with the weights in control mice. At all doses,
    histochemical studies of the hypophysis showed changes indicative of
    an increase in the activity of the cells producing a luteinizing
    gonadotrophy, i.e., an increase in the size of the cells, loss of
    granules, and hyalinization of the cytoplasm. Histological
    examination of the adrenal glands revealed an increase in the size
    and mitotic activity of cells in the zone glomerulosa. Enlarged
    cells with a large nucleus or two nuclei were present in the
    fascicular zone. Impairment of thyroid gland functional activity in
    the test group was indicated by the reduction in the rate of
    absorption and excretion of 131I and its rather low recovery, as
    well as by the corresponding histological findings, i.e.,
    enlargement of follicles and more dense and basophilic colloid at
    all doses. Histological findings were more pronounced in the
    70 mg/kg per day groups. It is likely that the effects of carbaryl
    on the reproductive organs is mediated by the endocrine glands.
    However, the possibility of a direct effect was not excluded by the
    authors (Rybakova, 1966; Shtenberg & Rybakova, 1968; Shtenberg
     et al., 1970).

         The effect of carbaryl on the thyroid gland in rats was studied
    by Shtenberg & Hovaeva (1970). Rats were given carbaryl, orally, at
    0.7, 2, 5, or 17 mg/kg per day for 6 months. They were fed a normal
    iodine diet or an iodine-deficient diet. There was an initial
    increase in function in the first 3.5 months of exposure and a
    decrease after 6 months of exposure. Recovery was complete 2 months
    after the end of the exposure. Decrease in iodine uptake and
    reduction of function was 26.5% in rats given 5 mg/kg and 29.5% in
    rats given 15 mg/kg. Rats fed an iodine-deficient diet were more
    sensitive to carbaryl-induced changes in the thyroid.

         The functional states of the thyroid gland and adrenal cortex
    were affected by a daily administration of 36 mg carbaryl/kg to rats
    for 4 months. The maximum accumulation of 131I occurred after 6 h
    and, in the control animals, after 12 h. The 131I absorption rate
    normalized after 45 days, but its excretion was delayed. The
    concentration of sodium in the blood increased by 36.4% after day 15
    and by 74% after 45 days, while the potassium concentrations were
    reduced. The daily excretion of 17-corticosteroids in the urine

    increased by 35.9%. The changes in the thyroid and adrenal glands
    were transient (Dyadicheva, 1971).

         Hassan (1971) studied the effects of carbaryl on the synthesis
    and degradation of catecholamines in the rat. Rats were given
    carbaryl in the diet at concentrations of 100 or 700 mg/kg for 7
    months, or in peanut oil at single oral doses of 50, 80, or
    250 mg/kg, or 3 single doses of 80 mg/kg body weight. On day 30, the
    rats given 700 mg/kg diet eliminated amounts of urinary
    4-hydroxy-3-methoxy mandelic acid (VMA) increased by more than 300%;
    levels returned to normal after 195 days. A similar effect was
    demonstrated after single oral doses with a dose-effect
    relationship. The amount of 5-hydroxyindole acetic acid (5-HIAA) in
    the urine increased in rats that were treated with a single dose and
    3 successive daily doses of 80 mg/kg per day. Adrenalectomy and
    hypophysectomy did not change the pattern of VMA excretion produced
    by carbaryl. There was an increased turnover rate (68%) of heart
    norepinephrine (NE-3H) in rats treated with 80 mg carbaryl/kg, 2 h
    before application of NE-3H. The corticosterone level was increased
    by about 125% at the same dose level. A carbaryl concentration of
    16.2 µg/ml in the blood was enough to trigger maximal corticosterone
    secretion. The authors suggested a probable activation of the enzyme
    system involved in the catecholamine metabolism, because carbaryl
    may also directly affect the adrenergic nerve endings. Activation of
    the pituitary adrenal axis and an increase in sympaticoadrenergic
    activity with concomitant increased VMA elimination was a
    pharmacological effect due to carbaryl treatment.

         The effect of a single oral dose of 60 mg carbaryl/kg body
    weight on serotonin (5-HT) metabolism in the male Holtzman Albino
    rat brain was studied by Hassan & Santolucito (1971); 2, 4, 6, and
    24 h after carbaryl application, whole brain samples were analysed
    for serotonin, 5-HIAA, and corticosterone. The concentrations of
    5-HT and 5-HIAA in the brain increased by 20-30% (5-HT from 0.61 to
    0.8; 5-HIAA from 0.25 to 0.31 µg/g) from 2 to 6 h and returned to
    normal after 24 h. The plasma corticosterone level was also
    increased by about 125%, 1 h after oral administration of carbaryl,
    and returned to normal after 20 h. The inhibitory effect of
     p-chlorophenylalanine on brain 5-HT formation was diminished by
    carbaryl treatment. The serotonin level in the brain of
    carbaryl-treated animals pretreated with  p-chlorophenylalanine was
    72% higher than in the control animals. Increased 5-HIAA levels were
    probably a result of an increased rate of synthesis of serotonin.
    The authors suggested the possible role of the increased synthesis
    of serotonin and tryptophan-5-hydroxylase activity, which could be
    related to stress conditions. Carbaryl activation of MAO is probably
    related to the increased formation of cerebral 5-HIAA.

         The uptake of noradrenaline  in vitro by hypothalamic slices,
    isolated from rats exposed  in vivo to near lethal levels of

    carbaryl, was increased in a dose-dependent manner (Jablonska &
    Brzezinski, 1990).

         Oral administration of 200 mg carbaryl/kg to rats was reported
    to raise striatal levels of noradrenaline and homovanillic acid, a
    metabolic product of dopamine, when measured 0.5-2 h later (Ray &
    Poddar, 1985b).

         The mechanism of the stimulation of corticosterone secretion is
    not clear.

          In vivo studies on male mice receiving 38 and 68 mg
    carbaryl/kg showed that carbaryl can increase certain hepatic
    androgen hydroxylase activities.  In vitro incubation of carbaryl
    with prostate tissue and testosterone 1,2-3H stimulated the
    formation of dehydrotestosterone-3H, thus, suggesting a direct
    action on steroidogenesis. Comparing these results with the effects
    of other toxic substances, the authors concluded that carbaryl
    cannot exert any major changes in steroid metabolism, nor can it
    reduce hormonal disturbances (Dieringer & Thomas, 1974).

         Attia  et al. (1991) studied the effect of carbaryl on rat
    melatonin production as alterations of the latter were found to have
    marked consequences in reproduction, immunology, and tumour growth.
    Male albino rats ( Rattus rattus), 8 animals in a group, were
    exposed to light/dark cycles of 14/10 h. They were treated by
    gastric gavage with carbaryl dissolved in corn oil for 6 successive
    days. The total doses were 50, 125, and 250 mg/kg. The animals were
    killed 2 and 4 h after the onset of darkness, which was 8 or 10 h
    after the application of the insecticide. Carbaryl was found to
    bring about an augmentation of the pineal melatonin content 4 h
    after the onset of darkness, which coincided with the stimulated
     N-acetyltransferase levels and hydroxyindole- O-methyltransferase
    activity. However, at the same time, carbaryl treatment at all doses
    significantly lowered the circulating melatonin titres; this was
    supposed to be related to increased hepatic melatonin metabolism due
    to the increased activity of the liver drug metabolizing enzyme
    system (Gaillard  et al., 1977). These results and the established
    carbaryl-induced elevated pineal 5-hydroxytryptophan, serotonin, and
    5-hydroxyindole acetic acid contents in the course of the night
    cycle, support the concept that carbaryl has a significant effect on
    pineal melatonin synthesis and secretion.

         Kadir & Knowles (1981) reported that carbaryl inhibited rat
    brain monamine oxidase activity  in vitro.

    8.8.8  Other studies

         Human serum albumin reacted  in vitro with the ester group of
    carbaryl and catalysed the hydrolysis and liberation of 1-naphthol.
    This reaction is similar to an "esterase type" action (Casida &

    Augustinsson, 1959) called carbamoylation (Oonnithan & Casida,
    1968).

    8.9  Factors modifying toxicity, toxicity of metabolites

    8.9.1  Factors modifying toxicity

         The toxicity of carbaryl can be modified by altering liver
    function by tranylcypromine treatment or 70% hepatectomy. A decrease
    in LD50 and increase in ChE activity were more pronounced after
    tranylcypromine treatment (Falzon  et al., 1983).

         The carbaryl LD50 in animals was increased three-fold by
    pretreating animals with small doses of carbaryl (Cress & Strother,
    1974).

         Phenobarbital, administered 24 h before carbaryl treatment,
    decreased the acute ip toxicity of carbaryl in mice, while
    2-diethyl-amino-ethyl-2,2'-diphenyl-valerate-HC1 (SKF 525-A), given
    1 h before carbaryl treatment, increased its acute intraperitoneal
    toxicity (Neskovic  et al., 1978). Enzyme-mediated binding of
    carbaryl to rat hepatic microsomal protein occurred  in vitro in
    the presence of NADPH and oxygen. Incorporation of radioactivity of
    14C-ring labelled carbaryl was studied. A 2- to 3-fold increase in
    binding was produced by pretreatment of animals with MFO inducers,
    e.g., phenobarbital or 3-methylcholanthrene. SKF-525-A inhibited
    binding by approximately 77% of the radioactivity. It is likely that
    binding of active carbaryl metabolites formed by MFO occurs. The
    radiolabelled metabolic products were covalently bound to amino acid
    residues of microsomal protein: 99.3-99.7% of the bound
    radioactivity (Miller  et al., 1979). A 50% decrease in microsomal
    ß-glucuronidase activity was observed 1 h after a single oral
    administration of 50 mg carbaryl/kg to female, Sprague-Dawley rats.
    The whole liver homogenate ß-glucuronidase content was reduced by
    40% after daily treatment with the same dose of carbaryl for 7 days.
    This effect was attributed to the decreases in mitochondrial
    lysosomal and microsomal ß-glucuronidase. The action of carbaryl in
    depleting the endoplasmic reticulum of ß-glucuronidase led to an
    increase in serum ß-glucuronidase activity. This was demonstrated in
    an  in vitro microsomal suspension study which showed that
    incubation of 4 mmol carbaryl/litre with microsomal suspensions
    effected a release of the ß-glucuronidase enzyme. The effect on the
    endoplasmic reticulum was further exemplified by the induction in
    microsomal UDP-glucuronyl transferase activity after 7 days of daily
    treatment with carbaryl at a dose of 25 mg/kg. Thus, carbaryl
    modifies the enzyme activities associated with the endoplasmic
    reticulum by decreasing specific activity (90%) towards
    ß-glucuronidase enzyme and activating the synthesis of endoplasmic
    reticulum protein connected with drug metabolism, such as the
    UDP-glucuronyl-transferase enzyme (Abdel-Rahman  et al., 1985;
    Lechner & Abdel-Rahman, 1985).

         Osman & Brindley (1981) conducted bioassays to determine the
    carbaryl susceptibility and synergism with piperonyl butoxide in
    natural populations of three species of Lobops grassbugs, in order
    to estimate monoxygenase detoxification. Pretreatment of the insects
    with piperonyl butoxide inhibited the mixed-function oxidase system
    and decreased the values of the LC50 for the insects (Osman &
    Brindley, 1981). Mixed-function oxydase involvement in the
    biochemistry of synergistic insecticides (including carbaryl) has
    been reviewed by Casida (1970).

         Diet may modify carbaryl toxicity. Boyd & Boulanger (1968)
    reported an increased susceptibility to carbaryl toxicity in Albino
    rats (272 Wistar strain rats were used) fed a protein-deficient
    diet. Boyd & Krijnen (1969) also reported that the LD50 decreased
    from 589 mg/kg in rats fed an 81% casein diet to 67 mg/kg in rats
    fed a 0% casein diet; 285 male rats were used in this study.

         The combined effects of different ambient temperature levels
    and carbaryl were studied by Ahdaya  et al. (1976). The LD50
    values in mice injected ip were 263 mg/kg at 1 °C and 122 mg/kg at
    38 °C (588 mg/kg is the LD50 at 27 °C). The thermoregulation
    ability of mice treated with carbaryl was affected more than that of
    mice treated with parathion which is a stronger inhibitor of ChE.
    The authors suggested that this effect was due to an overall
    reduction in the basal metabolic rate.

         Atropine sulfate decreased signs of parasympathetic stimulation
    in a group of pigs acutely poisoned with 1-2 g carbaryl/kg (Smally,
    1970). During multiple administrations of carbaryl, drug-induced
    (hydrochlorothiazide) diuresis helped in the detoxification
    processes. ChE reactivations are contraindicated because they may
    aggravate the signs of carbaryl intoxication (Sanderson, 1961;
    Podolak & Warchocki, 1980).

         Application of atropine or trepazin, 20 min before oral

    intoxication with carbaryl in mice, decreased toxicity about 2
    times. The results were similar when cholinolytics were applied
    2 min after administration of carbaryl (Vyatchanikov & Alexachina,
    1968). Atropine administered iv to rats at a dose of 8 mg/kg
    increased the carbaryl ip LD50 by a factor of about 7 (70 to
    460 mg/kg) (Harris  et al., 1989). Co-administration of either of
    two different oximes (2-PAM and HI-6) with atropine was found to
    provide significantly less protection than that afforded by atropine
    alone, indicating that oxime therapy is not a useful treatment for
    carbaryl poisoning.

         Co-administration of an oral dose of 10 mg malathion/kg in rats
    significantly reduced the rates of both absorption and elimination
    of an oral dose of 10 mg carbaryl/kg (Lechner & Abdel-Rahman,
    1986a). Peak plasma levels of labelled carbaryl were observed about

    1 h after the administration of carbaryl alone, and after 2 h when
    malathion was administered simultaneously. The terminal rate of
    elimination of carbaryl was decreased by a factor of about 4, with
    the half-life increasing from 16.96 h to 64.41 h.

         Concentrations of cimetidine in the range of 60-240 µg/ml were
    observed to decrease the clearance rate of carbaryl by perfused rat
    liver in a dose-dependent manner (Ward  et al., 1988).

         Ray & Poddar (1985a,b, 1990) reported that the intraperitoneal
    administration of 1 mg haloperidol/kg, 12.5 to 100 mg
    5-hydroxy-tryptamine (5-HTP)/kg, or 100 mg L-tryptophan/kg increased
    the incidence of tremors in rats following an oral dose of 50-200 mg
    carbaryl/kg. The potentiation of the tremorogenic effect of carbaryl
    by 5-HTP was demonstrated to be dose dependent. The potentiating
    effects of 5-HTP and haloperidol could be blocked by the
    coadministration of the serotonergic antagonist methysergide
    (20 mg/kg, ip) or the dopaminergic antagonist bromocriptine
    (10 mg/kg, ip), respectively. These results suggest the possible
    involvement of a central cholinergic, dopaminergic interaction in
    the carbaryl-induced tremor.

         The effects of humic acids in the detoxification of carbaryl
    during oral application are very slight: only 9.9-18.6% decrease in
    toxicity was observed (Golbs  et al., 1984).

         The combined effects of carbaryl and sodium nitrite have been
    studied (Podolak-Majczak & Tyburczyk, 1984, 1986; Tyburczyk &
    Podolak-Majczak, 1984a,b; Tyburczyk & Podolak-Majczak, 1986). Dosing
    Wistar rats for 3 months with sodium nitrite at 20 mg/kg per day,
    and carbaryl at 0.1 LD50/day (60 mg/kg), the brain
    gamma-aminobutyryl acid level, methaemoglobin, blood serotonin, free
    blood tryptophan, serum and liver alanine amino-transferase activity
    levels increased and blood cholinesterase activity decreased.
    Decreases were observed in the vitamin E and A levels,
    glucose-6-phosphate dehydrogenase activity, and liver aminohexoses
    and hydroxyproline levels with a simultaneous increase in the serum
    aminohexoses level. This finding may indicate the increasing process
    of connective tissue catabolism and lisosomal membranes
    labilization.

    8.9.2  Toxicity of metabolites

         Hydrolysis of the carbamate ester bond of carbaryl results in
    detoxification. The carbamate moiety is decomposed to carbon dioxide
    and methylamine, and the phenolic part is conjugated and excreted.
    Kuhr (1971) summarized the data on the toxicity of carbaryl
    metabolites (Table 53).

        Table 53.  Toxicity of carbaryl and some of its metabolitesa
                                                                                     
                                   LD50 (mg/kg)          7-day    Molar I50 bovine
                                                         NOELb    anticholin-esterase
                                             Mouse       (mg/kg)
                            Rat oral    Intraperitoneal   Rat
                                                                                     

    Carbaryl                    270          29-42        125-250      5 x 10-8

    4-Hydroxycarbaryl          1190           74           > 1000      4 x 10-7

    5-Hydroxycarbaryl           297           56           > 1000      4.6 x 10-8

    7-Hydroxycarbaryl          4760                        > 1000

    Hydroxymethylcarbaryl    > 5000         630-780       250-500      1.4 x 10-5

    1-Naphthol                 2570                      500-1000      1 x 10-3
                                                                                     

    aFrom: Kuhr (1971).
    bNOEL = No-observed-effect level.
    
         Many of the known metabolites are much less toxic than
    carbaryl. The pharmacological study of carbaryl in rats showed that
    the metabolites with a methylcarbamate moiety are inhibitors of
    plasma cholinesterase (Fernandez  et al., 1982). None of the
    carbaryl metabolites was appreciably more active as a cholinesterase
    inhibitor than carbaryl itself (Oonnithan & Casida, 1968).

    8.9.3  N-nitrosocarbaryl

         Carbaryl is a secondary amine and is, therefore, capable of
    nitrosation in the presence of nitro donor groups, such as sodium
    nitrate, to give a nitrosamide. This nitrosamide, nitrosocarbaryl,
    has been proved to be mutagenic and carcinogenic, at high doses in
    animals. Conditions of this nitrosation include a strongly acidic pH
    (less than 2), which is comparable with the pH in the human stomach.
    However, nitrosocarbaryl is not stable at this pH. Its maximum
    stability is between pH 3 and 5, pHs at which no significant amounts
    of carbaryl can be nitrosated. Carbaryl has been nitrosated in
    several studies,  in vitro as well as  in vivo, in the guinea-pig,
    which has a stomach acidity close to that in man. If significant
    yields of nitrosocarbaryl have been shown in these circumstances,
    the significance of these findings is still not clear for human risk
    evaluation. The pH in the human stomach is variable during food
    intake and probably, more importantly, the stomach contains a lot of
    food, which will minimize the contact between naturally occurring

    nitrite and carbaryl residues, but which will also afford a lot of
    nucleophilic sites for nitrosocarbaryl to react with. It is also
    noteworthy that all studies that were conducted with jointly
    administered carbaryl and nitrite yielded negative results for
    oncogenicity. Cranmer (1986) estimated the potential intake of
    nitrosocarbaryl at 6x10-9 mg/kg per day. Using different
    mathematical models, Cranmer estimated a cancer risk for
    nitrosocarbaryl between 10-6 (one-hit model) and 10-9 (probit
    model). However, if such oncogenic nitroso-carbamates were to be
    found in such quantities in the human stomach, an increased
    incidence of stomach cancer would have been expected during the
    period when drug and pesticide carbamates were widely used. However,
    during this period, the incidence of gastric cancer in the USA
    declined considerably.

         The bacterial metabolite  N-nitrosocarbaryl may act as a
    noncompetitive inhibitor of the  in vitro metabolism of
    aminopyrine,  p-nitroanisole, and aniline by rat liver microsomes
    (Beraud  et al., 1980, 1989a,b).  N-nitrosocarbaryl was more
    effective as an inhibitor of microsomal activity than the parent
    compound.

    8.10  Mechanism of toxicity - mode of action

         The mechanism of toxicity and the mode of action of carbaryl
    and carbamates, in general, have been described in EHC 64 (WHO,
    1986).

    8.10.1  Inhibition of cholinesterase activity

         As a carbamate compound, carbaryl is an inhibitor of
    cholinesterase (ChE) activity (for details see Reiner & Aldridge
    (1967) and Aldridge (1971)).

         A number of studies have been performed by Carpenter  et al.
    (1961) to assess the extent of ChE inhibition by carbaryl in
    mammals. A single oral dose of carbaryl of 560 mg/kg produced a 43%
    inhibition of the erythrocyte ChE in rats in 0.5 h, and a 30%
    inhibition in brain AChE. However, they returned to normal in rats
    that survived 24 h after administration of the dose. Carbaryl did
    not depress plasma ChE significantly. Two groups of Beagle dogs were
    injected once, iv, with 10 or 15 mg/kg as an 8% solution in 95%
    alcohol. No significant effects were found on either erythrocyte or
    plasma ChE. On the 5th day, several administrations of the same
    doses depressed plasma ChE by 24% and erythrocyte AChE by 40%. It is
    doubtful that a long incubation time for the samples (2 h for
    plasma) played a role in the slight depression of ChE. Comparative
    data on ChE inhibition in the brain, plasma, and erythrocytes of
    rats that received single doses of carbaryl were reported by Mount
     et al. (1981). As shown in Table 54, there was a dose-dependent
    decrease in ChE in the brain, plasma, and erythrocytes.

         Brain AChE was significantly different in dead rats and in
    surviving rats given 800 mg/kg. AChE depression in the brain was
    >70% in the lethally poisoned rats. The inhibition of red blood
    cell AChE activity was the same as in plasma.

    Table 54.  Inhibition of ChE in % in comparison with the controlsa
                                                                       

    Sprague-Dawley rats    Post-dosing    Brain    Red blood   Plasma
                               (h)                   cells
                                                                       

    Controls 10 rats                        0          0          0

    450 mg/kg                   0.5        56         44         51
    (24 rats sacrificed)        1          74         29         53
                                2          74         42         68
                                4          66         48         61
                                8          55         25         31
                               24          27         60         38
                               48          22         23         46
                               96           6         19        -19

    800 mg/kg                   0.5        66         32         47
    (34 rats sacrificed)        1          70         44         50
                                2          79         73         69
                                4          50         72         70
                               12          50         72         50
                               28          58         63         68
                               48          17         26         40
                               96          16         -6         16

    800 mg/kg                   3          80          -          -
    (24 rats died)              4          85          -          -
                               18          88          -          -
                               25          71          -          -
                               29          88          -          -
                               30          84          -          -

    1200 mg/kg               1-36       88-91          -          -
    (15 died)
                                                                       

    aAdapted from: Mount  et al. (1981).


         The affinity of AChE of human brain caudate nucleus for
    carbaryl was studied  in vitro and some inhibition constants were
    determined (Patocka & Bajgar, 1971). The value of the I50 affinity
    constant was calculated from the dependence of AChE inhibition on
    the molar concentration of the inhibitor in probit logarithm

    transformation. The Hill coefficient was obtained from Hill plots.
    The affinity constant for carbaryl pI50 was 5.59 and the Hill
    coefficient was 1.50. According to the authors, some results of this
    study suggest that AChE may be an allosteric enzyme.

         Intravenous administration of colloidal carbon in the rat,
    inhibiting the phagocytic activity of the RES, prolonged the
    duration of the anticholinesterase effect of carbaryl (Pipy  et al.,
    1979). The authors speculated that the metabolism of carbaryl was
    decreased by the RES inhibition and, as a result, the reactivation
    speed of ChE was slower.

         Pregnant rats were treated orally with 1 or 5 mg carbaryl/kg
    from day 11 to the last day of gestation (Declume & Benard, 1977b;
    Declume  et al., 1979). No cholinesterase depression in blood,
    brain, and liver were observed in either the dams or the newborn
    offspring. However, after administration of 50 mg/kg from day 19 to
    the last day of gestation, ChE inhibition was seen in both the
    mother and newborn offspring.

         Cambon  et al. (1978) reported decreased cholinesterase
    activity in the blood, brain, and liver in the mother and the fetus
    after treatment of the dams at 6.25, 12.5, 25, and 50 mg/kg.
    Variability of cholinesterase levels in the controls and
    short-comings in the cholinesterase analysis protocol make these
    results difficult to interpret.

    9.  EFFECTS ON HUMAN BEINGS

    9.1  General population exposure

    9.1.1  Acute toxicity, poisoning incidents

         The clinical picture of carbaryl intoxication results from the
    accumulation of ACh at nerve endings (WHO, 1986). The signs and
    symptoms can be categorized into the following 3 groups:

          (a) Muscarinic manifestations
         -    increased bronchial secretion, excessive sweating,
              salivation, and lacrimation;
         -    pinpoint pupils, bronchoconstriction, abdominal cramps
              (vomiting and diarrhoea); and
         -    bradycardia.

          (b) Nicotinic manifestations
         -    fasciculation of fine muscles (in severe cases, diaphragm
              and respiratory muscles also involved); and
         -    tachycardia.

          (c) Central nervous system manifestations
         -    headache, dizziness, anxiety, mental confusion,
              convulsions, and coma; and
         -    depression of respiratory centre.

         All these signs and symptoms can occur in different
    combinations and can vary in onset and sequence, depending on the
    chemical, dose, and route of exposure. The duration of symptoms is
    usually shorter than that observed in organophosphorus poisoning.
    Mild poisoning might include muscarinic and nicotinic signs only.
    Severe cases always show central nervous system involvement; the
    clinical picture is dominated by respiratory failure sometimes
    leading to pulmonary oedema, due to the combination of the
    above-mentioned syndromes.

         A review of carbaryl-related poisoning from 1966 to 1980 was
    made by US EPA. During this period, 193 cases of over-exposure to
    carbaryl as the sole active ingredient in the poisoning and 144
    cases of over-exposure to a combination of carbaryl with other
    active ingredients were recorded (Weston, 1982). Not all case
    histories have been confirmed. There were 5 deaths. There is no
    evidence that carbaryl was involved in these deaths, except for one,
    which was acknowledged by the manufacturer.

         Hayes (1963) reported two incidents of poisoning: one, a
    19-month-old child who swallowed an unknown amount of carbaryl, and
    the other, a man who swallowed 250 mg of carbaryl. Both developed
    moderately severe ChE inhibition symptoms within 20 min: constricted
    pupils, salivation, muscular incoordination in the child, and

    epigastric pain, profuse sweating, lassitude, and vomiting in the
    man. Both recovered after atropine treatment. Blood cholinesterase
    was inhibited.

         One death from carbaryl ingestion while drunk was reported by
    Farago (1969) who concluded that 2-PAM application hastened the
    fatal outcome (due to pulmonary oedema), 6 h after ingestion.
    Carbaryl was found in various tissues.

         Acute intoxication during the loading of an airplane was
    reported by Long (1971).

         In a case report of a suicide attempt involving about 25 g
    (500 mg/kg) of carbaryl, dicumarin and boric acid, Dickoff  et al.
    (1987) described the occurrence of a peripheral neuropathy that
    resembled the syndrome observed following exposure to some
    organophosphorus compounds. Recovery continued for 9 months.
    Electrophysiological findings were consistent with axonal peripheral
    neuropathy. The cause-effect relationship was confounded because of
    combined exposure.

    9.1.2  Controlled human studies

         Wills  et al. (1968) carried out controlled studies in human
    volunteers, aged 25-57 years. In a preliminary study, oral doses of
    0.5, 1, and 2.0 mg carbaryl/kg in capsules (single application to 2
    subjects) were tolerated without any subjective or objective
    symptoms. In the main study, one group (5 subjects) took 0.06 mg
    carbaryl/kg daily, and one group (6 subjects) took 0.13 mg
    carbaryl/kg for 6 weeks. Physical examination, BSP removal from
    blood, EEG examination, routine blood and urinalysis were performed,
    and ChE of plasma and red blood cells was examined. No changes were
    found in the low-dose group. An increase in the ratio of amino acid
    nitrogen to creatinine in the urine, at the high dose, may represent
    a decrease in the ability of the proximal convoluted tubule to
    reabsorb amino acids. This change was reversible.

         The urine of some subjects was analysed (Knaak  et al., 1968).
    The overall recovery (by the fluorometric method) of the carbaryl
    equivalents in the urine was 26-28%, and, with the colorimetric
    method, 37.8%, in subjects treated with 2 mg carbaryl/kg. The
    following metabolites were found chromatographically in a 4-h urine
    sample: alpha-naphthol glucuronide (10-15%), and sulfate (6-11%) and
    4-(methylcarbamoyloxy)-alpha-naphthyl glucuronide (4%). Another
    metabolite, alpha-naphthyl methylimido-carbonate  O-glucuronide,
    was identified by fluorometry.

         A human ingestion study was conducted to determine the
    relationship between a single oral dose of carbaryl and the rate of
    its urinary excretion as metabolites. Elimination was apparently
    first order over the dosage range of the studies (0.25-1 mg/kg). The

    model predicts that, 24 h after ingestion, approximately 41% of the
    dose can be accounted for as urinary metabolites (Hansen, 1978).

         In a study involving one subject, Ward  et al. (1988) observed
    that pretreatment with a clinical regimen of cimetidine (3x200 mg
    over a three-day period) reduced presystemic (first-pass) clearance
    of a dose of 1 mg carbaryl/kg by about 46%.

         A scientist studying the anthelminthic activity of carbaryl,
    tested its human safety by ingesting 250 mg (about 2.8 mg/kg). After
    20 min, he experienced epigastric pain and began to sweat profusely.
    He was treated with a total dose of 3 mg atropine and recovered
    completely 2 h after taking the carbaryl. Another scientist ingested
    420 mg carbaryl (4.45 mg/kg), and after 85 min he had vision
    troubles, weakness, profuse sweating, and felt lightheaded. He was
    treated with a total dose of 4.8 mg atropine and recovered 4 h after
    the onset of symptoms (Hayes & Laws, 1991).

    9.1.3  Long-term exposure

         Branch & Jacqz (1986a,b) reported the case of a 75-year-old man
    who was exposed to carbaryl for 8 months, inside his home, after
    repeated excessive applications of 10% dust formulation. He
    experienced a series of signs and symptoms compatible with
    cholinesterase depression in addition to a 40-lb (18-kg) weight
    loss. After exposure ceased, the patient's condition improved
    markedly. However, a few months later he started to experience
    modification of his sleep pattern and peripheral neuropathy and
    cerebral atrophy were demonstrated. Other pathologies, such as
    recurrent gastric ulcer, cardiac fibrillations, a recent head injury
    due to an automobile accident, and other less defined pathologies
    were present in this patient which provide other, more likely,
    causes for these later symptoms.

         The uncertainties associated with long-term exposure to levels
    sufficient to result in sustained suppression of plasma
    pseudocholinesterase activity and possible brain damage are
    discussed by Avashia (1987) and Branch (1987).

    9.2  Occupational exposure

    9.2.1  Epidemiological studies

         The first report on workers exposed to carbaryl was published
    by Best & Murray (1962). For 19 months, from the start of carbaryl
    production, they studied men working on the production, handling,
    and shipping of carbaryl. The most exposed group were bagging
    workers occasionally exposed to carbaryl dust under abnormal
    conditions (40 mg/m3). These showed a slight depression in blood
    ChE activity, but this was below the rate at which clinical symptoms
    might be expected. They found that 41% of 689 urine specimens

    contained >1000 µg/100 ml total 1-naphthol (>400 µg/100 ml
    indicates absorption), with no clinical or subjective symptoms. In
    cases of acute intoxication, 3140 µg 1-naphthol/100 ml urine were
    found. Knaak  et al. (1965) using fluorometric analysis in
    conjunction with chromatographic separation, found 5 times more
    sulfate (25 mg/litre) than glucuronides (5 mg/litre) of 1-naphthol
    in the urine of exposed workers.

         Vandekar (1965) in a village-scale trial in Nigeria, assessed
    the risk for the population of exposure to carbaryl. A slight
    depression of plasma ChE was found in all spraymen, the day after
    the spraying. Levels of 1-naphthol derivatives in their urine did
    not increase on days 1 and 2 after spraying but increased slightly
    on day 6.

         In a study on 19 agricultural workers (Yakim, 1967), whole
    blood ChE activity was measured before, and after, 3-4 days exposure
    to airborne carbaryl. Men exposed to a mean airborne carbaryl
    concentration of 2 mg/m3 showed a decrease of 20-24% in ChE
    activity. Signalmen exposed to 4 mg/m3 (mean) showed a 13-30%
    decrease in ChE activity. No objective signs of ill health were
    observed. In the same study, a mean carbaryl concentration of
    0.7 mg/m3 was reported in the cabin of an aeroplane used to apply
    carbaryl, but no changes were reported in the biological parameters
    of the pilots. During the agricultural application of carbaryl dust
    at a maximum exposure level of 19 mg/m3 dust on cotton fields,
    Adylov (1966) reported a decrease in catalase activity, and a 20%
    decrease in ChE activity on day 14.

         In cases of occupational overexposure to carbamates, mild
    symptoms appear long before a dangerous dose is absorbed, which is
    why severe occupational intoxications with carbaryl are rare. Tobin
    (1970) gives reasons for the lack of severe intoxications: (1) there
    is a very short time (´ h or less) between exposure to carbamates
    and the onset of symptoms; (2) lack of symptoms progression, because
    of a large margin between the median effective dose and the lethal
    dose of carbamates and the early detection of intoxication.

         Workers exposed to carbaryl used on pets for flea control,
    experienced diarrhoea, increased salivation, cough, difficulty in
    breathing, and phlegm (Ames  et al., 1989).

         Vandekar (1965) reported a skin rash in a sprayman who was
    accidentally splashed with a carbaryl formulation. Although
    carbamate compounds generally have not caused dermatitis or allergic
    skin reactions, Vandekar suggested that they can appear in certain
    individuals after unusually heavy exposure.

         One out of a group of 30 farmers with contact dermatitis was
    identified by a patch test as having a positive allergic reaction to
    a 1% solution of carbaryl (Sharma & Kaur, 1990). No allergic
    reaction were observed in a control population (No.=20).

         To identify possible effects on reproduction, Whorton  et al.
    (1979) studied a cohort of 47 male workers who had worked for at
    least 1 year in the production and packaging of carbaryl. A semen
    sample was used for sperm count. Testosterone follicle-stimulating
    hormone, and luteinizing hormone were determined by
    radioimmunoassay. The range of airborne carbaryl concentrations in
    the workplace was 0.03-14.21 mg/m3 with a mean of 4.9 mg/m3.
    This cohort showed no seminal or blood abnormalities related to
    carbaryl exposure. Although a small excess (not significant at
    alpha=0.05) was observed in a small number of oligospermic men in
    the exposed group, there was no evidence that testicular function or
    fertility in the male workers was affected under these conditions of
    exposure.

         Wyrobek  et al. (1981) used the same cohort of exposed workers
    to study sperm abnormalities. Semen was collected from 50 men,
    occupationally exposed to carbaryl for 1-18 years. Semen samples
    were analysed for changes in sperm motility, sperm count,
    morphology, and frequency of sperm-carrying double fluorescent
    bodies (YFF). The YFF test represents sperm with two Y chromosomes
    due to meiotic nondysjunction. The exposed workers showed changes in
    sperm morphology with a higher proportion of sperm with abnormal
    head shapes in comparison with the control group of newly hired
    unexposed workers. There was no dose dependence as judged by job
    classification. A negative correlation between number of years
    working in the carbaryl area and the percentage of abnormal sperm
    was observed. Workers who had once been exposed to carbaryl, but who
    had not been exposed for an average of 6.3 years, showed a
    marginally significant elevation in sperm abnormalities, possibly
    not reversible. MacLeod (1982) reviewed the Wyrobek  et al. (1981)
    study and did not find any essential differences in the distribution
    of the sperm types in the control and the carbaryl-exposed groups.
    No significant changes in sperm count and fertility were reported in
    100 workers (Thomas, 1981).

    10.  PREVIOUS EVALUATION BY INTERNATIONAL BODIES

         The latest IARC evaluation of carbaryl was made during 1987
    (IARC, 1987). It was concluded that there were no data on cancer in
    humans and inadequate evidence of carcinogenicity in experimental
    animals. Carbaryl could not be classified with regard to its
    carcinogenicity to humans (Group 3).

         The FAO/WHO Joint Meeting on Pesticide Residues (JMPR)
    evaluated carbaryl at its meetings in 1963, 1965, 1966, 1967, 1968,
    1969, 1970, 1971, 1973, 1975, 1976, 1977, 1979 and 1984 (FAO/WHO,
    1964, 1965, 1967, 1968, 1969, 1970, 1971, 1972, 1974, 1976, 1977,
    1978, 1980, 1985). Since 1973, an acceptable daily intake (ADI) of
    0-0.01 mg/kg body weight has been established. This estimate is
    based on the following experimental data: no-effect level for rats:
    200 mg/kg in the diet = 10 mg/kg per day; for dogs: 100 mg/kg in the
    diet = 1.8 mg/kg per day; and for human beings: 0.06 mg/kg per day
    (FAO/WHO, 1965, 1967, 1974).

         Maximum residue levels (MRLs) for carbaryl were recommended by
    FAO/WHO (1986b) (see Table 55). The values recommended for tolerance
    levels represent the sum of free carbaryl, combined carbaryl,
    conjugated naphthol, and conjugated methylcarbaryl, expressed as
    total toxic residues of carbaryl.

         A WHO study group on occupational health recommended 5 mg
    carbaryl/m3 as a tentative, health-based, maximum permissible
    level in the working environment. A biological limit of 30%
    inhibition of ChE activity in whole blood, plasma, or red cells with
    respect to pre-exposure levels should not be exceeded (WHO, 1982).

         In the WHO recommended classification of pesticides by hazard,
    technical carbaryl is classified in Class II as moderately hazardous
    in normal use (WHO, 1992). WHO/FAO (1975) issued a data sheet on
    carbaryl (No. 3).

         IRPTC in its series "Scientific reviews of Soviet literature on
    toxicity and hazards of chemicals" has published a review on
    carbaryl (IRPTC, 1982, 1989).

        Table 55.  Maximum Residue Limits (MRLs) established by the Codex
               Alimentariusa
                                                                                  

    Commodity                                                               MRL
                                                                          (mg/kg)
                                                                                  
    Animal feedstuffs (green alfalfa, clover, corn, forage, cow pea        100
    foliage, grasses, peanut hay, sorghum forage, soybean vines,
    sugarbeet tops, bean and pea vines)

    Bran (wheat)                                                            20

    Apricots, blackberries, boysenberries, nectarines, peaches,             10
    raspberries, asparagus, okra, leafy vegetables (except
    brassica), nuts (whole), olives (fresh), sorghum grain, cherries,
    plums, kiwi fruit

    Blueberries, citrus fruit, cranberries, strawberries                     7

    Apples, bananas (pulp), grapes, beans, peas (including pod),             5
    brassica, tomatoes, peppers, aubergines, pears, poultry skin,
    barley, oats, rice (in husk and hulled), rye, wheat

    Cucumbers, melons (Cantaloupe), pumpkins, squash                         3

    Root crop vegetables (beets, carrots, radishes, rutabagas,               2
    parsnips), peanuts (ground-nuts, whole), wholemeal flour

    Cottonseed (whole), sweet corn (kernels), nuts (shelled), olives         1
    (processed), soybeans (dry mature seed), cow-peas

    Poultry meat, eggs (without shells)                                      0.5

    Potatoes, meat of cattle, sheep, and goats, sugarbeets, wheat            0.2
    flour (white)

    Milk and milk products                                                   0.1
                                                                                  

    aFrom:FAO/WHO (1986b).
    
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    Zepp RG & Cline DM (1977) Rates of direct photolysis in the aquatic
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    ANNEX I.  TREATMENT OF CARBAMATE PESTICIDE POISONING IN MAN

    (From EHC 64: Carbamate Pesticides - A General Introduction)

         All cases of carbamate poisoning should be dealt with as an
    emergency and the patient should be hospitalized as quickly as
    possible.

         Extensive descriptions of the treatment of poisoning by
    anticholinesterase agents are given in several major references
    (Kagan, 1977;Taylor, 1980; Plestina, 1984).

         The treatment is based on:

         (a) minimizing the absorption;

         (b) general supportive treatment; and

         (c) specific pharmacological treatment.

    I.1  Minimizing the absorption

         When dermal exposure occurs, decontamination procedures include
    removal of contaminated clothes and washing of the skin with
    alkaline soap or with a sodium bicarbonate solution. Particular care
    should be taken in the cleaning of the skin area where venupuncture
    is performed. Blood might be contaminated with carbamates and
    therefore inaccurate measures of ChE inhibition might result.
    Extensive eye irrigation with water or saline should also be
    performed. In the case of ingestion, vomiting can be induced, if the
    patient is conscious, by the administration of ipecacuanha syrup
    (10-30 ml) followed by 200 ml of water. However, this treatment is
    contraindicated in the case of pesticides dissolved in hydrocarbon
    solvents. Gastric lavage (with the addition of bicarbonate solution
    or activated charcoal) can also be performed, particularly in
    unconscious patients, taking care to prevent aspiration of fluids
    into the lungs (i.e., only after a tracheal tube has been put in
    place).

         The volumes of the fluids introduced in the stomach should be
    recorded and samples of gastric lavage frozen and stored for
    subsequent chemical analysis. If the formulation of the pesticide
    involved is available, it should also be stored for further analysis
    (i.e., detection of toxicologically relevant impurities). A purge to
    remove the ingested compound can be administered.

    I.2  General supportive treatment

         Artificial respiration (via a tracheal tube) should be started
    at the first sign of respiratory failure and maintained for as long
    as necessary.

         Cautious administration of fluids is advised as well as general
    supportive and symptomatic pharmacological treatment and absolute
    rest.

    I.3  Specific pharmacological treatment

    I.3.1  Atropine

         Atropine should be given, beginning with 2 mg iv repeated at 15
    to 30-min intervals. The dose and the frequency of atropine
    treatment varies from case to case, but should maintain the patient
    fully atropinized (dilated pupils, dry mouth, skin flushing, etc.).

    I.3.2  Oxime reactivations

         Although it might be suspected that oxime cholinesterase
    reactivators would be as helpful in carbamate poisoning as they are
    in organophosphorous poisoning, this is not the case. There is
    experimental evidence that the pyridinium oxime 2-PAM is not
    effective in carbamate poisoning and there is some evidence that it
    makes poisoning by certain carbamates, including carbaryl, worse.

    I.3.3  Diazepam

         Diazepam should be included in the therapy of all but the
    mildest cases. Besides relieving anxiety it appears to counteract
    some aspects of CNS-derived symptoms that are not affected by
    atropine. Doses of 10 mg sc or iv are appropriate and may be
    repeated as required.

         Other centrally acting drugs and drugs that may depress
    respiration are not usually recommended in the absence of artificial
    respiration procedures.

    References to Annex I

    KAGAN, J.S. (1977) [The toxicity of organophosphorus pesticides.]
    Moscow (in Russian).

    PLESTINA, R. (1984) Prevention, diagnosis, and treatment of
    insecticide poisoning. Geneva, World Health Organization. 
    (Unpublished WHO document VBC/84.889).

    TAYLOR, P. (1980) Anticholinesterase agents. In: Goodman, L.S. &
    Gilman, A., ed. The pharmacological basis of therapeutics. 6th ed.,
    New York, Macmillan Publishing Co., pp. 100-119.

    RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    1.  Résumé et évaluation

    1.1  Identité, propriétés et méthodes d'analyse

         Carbaryl est la dénomination commune d'un dérivé de l'acide
    carbamique, le  N-méthylcarbamate de 1-naphtyle. Le produit
    technique consiste en un solide cristallin blanc, peut volatil et
    peu soluble dans l'eau, qui est stable à la lumière et à la chaleur
    mais qui s'hydrolyse facilement en milieu alcalin. Il existe une
    norme FAO pour le carbaryl qui stipule un degré de pureté de 98%,
    avec une limite pour les impuretés ( N-méthylcarmate de ß-naphtyle)
    de 0,05%.

         Pour les analyses portant sur le carbaryl et ses métabolites,
    il existe de nombreuses méthodes: chromatographie sur couche mince,
    spectrophotométrie, chromatographie en phase gazeuse,
    chromatographie en phase liquide à haute pression et spectrométrie
    de masse à ionisation chimique. La limite de détection peut
    descendre en-dessous du nanogramme et le taux de récupération
    dépasse généralement 80%.

    1.2  Production et usages

         On utilise le carbaryl depuis une trentaine d'années comme
    insecticide agissant par contact et par ingestion avec certaines
    propriétés endothérapiques; il permet de lutter contre de nombreux
    vecteurs et ravageurs. La principale unité de production se trouve
    aux Etats-Unis d'Amérique. Plus de 290 fabricants proposent une
    gamme de formulations de carbaryl qui dépasse les 1500 produits.

    1.3  Transport, distribution et transformation dans l'environnement

         Dans la plupart des conditions, le carbaryl ne persiste pas
    dans l'environnement. Dans l'eau, son temps de demi-hydrolyse dépend
    de la température, du pH et de la concentration initiale; il varie
    de quelques minutes à plusieurs semaines. Le principal produit de
    décomposition est le 1-naphtol.

         L'accumulation du carbaryl, exprimée sous la forme d'un facteur
    de bioconcentration dans l'environnement aquatique, et plus
    précisément chez les poissons d'eau douce, varie de 14 à 75. Le
    carbaryl s'adsorbe plus facilement sur les sols à forte teneur
    organique que sur les sols sableux. Aux doses d'emploi usuelles, et
    lorsqu'il est appliqué conformément "aux bonnes pratiques
    agricoles", il se dissipe rapidement, avec une demi-vie de 8 jours à
    un mois dans les conditions normales. Il arrive que le carbaryl soit
    entraîné par les pluies ou par les travaux agricoles de la surface
    vers les couches sous-jacentes (à un mètre de profondeur).

         Le carbaryl peut contaminer la végétation, soit au cours de
    l'épandage soit par migration à partir d'un sol contaminé.

         La décomposition du carbaryl dans l'environnement dépend de son
    degré de volatilisation, de photodécomposition et de dégradation
    chimique ou microbienne dans le sol, l'eau et les végétaux. la
    vitesse de décomposition est plus rapide en climat chaud.

    1.4  Concentrations dans l'environnement et exposition humaine

         Dans la population générale, le carbaryl est principalement
    absorbé par la voie alimentaire.

         Les résidus présents dans des échantillons de rations totales
    sont relativement faibles, et ils vont de traces à 0,05 mg/kg. Aux
    Etats-Unis d'Amérique, on estime que pendant les premières années
    d'utilisation du carbaryl, l'ingestion journalière de carbaryl était
    de 0,15 mg/personne/jour (dans 7,4% des composites); cette dose est
    tombée à 0,003 mg/personne/jour en 1969 (dans seulement 0,8% des
    composites). Pendant la période d'épandage, on peut retrouver
    parfois du carbaryl dans les eaux de surface et les retenues d'eau.

         La population peut être exposée au carbaryl lors d'opérations
    de lutte de contre les ravageurs ou les vecteurs tant au domicile
    que sur les aires de loisir.

         Les travailleurs peuvent être exposés au carbaryl lors de la
    fabrication, de la formulation, de l'emballage, du transport et du
    stockage du produit ainsi que pendant son épandage. Les
    concentrations dans l'atmosphère des lieux de travail au cours de la
    production varient de < 1 mg/m3 à 30 mg/m3. Il peut y avoir une
    importante exposition cutanée chez les travailleurs de l'industrie
    et les ouvriers agricoles en cas de mesures de protection
    insuffisantes.

    1.5  Cinétique et métabolisme

         Le carbaryl est rapidement absorbé au niveau des poumons et des
    voies digestives. Une dose de carbaryl dans l'acétone appliquée sur
    la peau de volontaires humains a été absorbée par voie percutanée à
    raison de 45% en 8 heures. Toutefois, les données obtenues  in vitro
    concernant la pénétration cutanée ainsi que les données
    toxicologiques indiquent que l'absorption percutanée s'effectue
    généralement à un rythme beaucoup plus lent.

         Les principales voies métaboliques du carbaryl consistent en
    une hydroxylation du cycle et une hydrolyse. Il en résulte la
    formation de nombreux métabolites qui subissent ensuite une
    conjugaison avec formation de sulfates, de glucuronides et de
    mercapturates hydrosolubles qui sont excrétés dans l'urine.
    L'hydrolyse conduit à la formation de 1-naphtol, de dioxyde de

    carbone et de méthylamine. L'hydroxylation produit du
    4-hydroxycarbaryl, du 5-hydroxycarbaryl, du
     N-hydroxyméthylcarbaryl, du 5,6-dihydro-5,6-dihydroxycarbaryl et
    du 1,4-naphtalènediol. Le principal métabolite chez l'homme est le
    1-naphtol.

         Dans les conditions normales d'exposition, il est improbable
    que le carbaryl s'accumule chez les animaux. Il est excrété
    principalement par la voie urinaire étant donné que la
    détoxification de son produit d'hydrolyse, le 1-naphtol, s'effectue
    essentiellement par la formation de conjugués hydrosolubles. Dans le
    cas des métabolites du carbaryl, le cycle entérohépatique joue
    également un rôle considérable, en particulier après administration
    par voie orale.

         Le produit d'hydrolyse, l'acide  N-naphtolcarbamique, se
    décompose spontanément en méthylamine et dioxyde de carbone. La
    méthylamine subit ensuite une déméthylation en dioxyde de carbone et
    formiate, ce dernier étant ultérieurement excrété, en majeure partie
    dans l'urine.

         Des métabolites du carbaryl sont également présents en faible
    proportion de la dose absorbée dans la salive et le lait.

    1.6  Effets sur les êtres vivants dans leur milieu naturel

         Les valeurs de la CL50 pour les crustacés varient de 5 à 9
    µg/litre (puces d'eau et mysidés), 8 à 25 µg/litre (orchesties) et
    500 à 2500 µg/litre (écrevisses). Chez les insectes aquatiques, les
    limites de sensibilité sont du même ordre. Les plécoptères et
    éphémèroptères (perles et éphémères) en constituent les groupes les
    plus sensibles. Les mollusques sont moins sensibles avec des valeurs
    de la CE50 de l'ordre de quelques mg/litre. Dans le cas des
    poissons, la plupart des valeurs de la CL50 se situent entre 1 et
    30 mg/litre. Les salmonidés constituent le groupe le plus sensible.

         La toxicité aiguë est faible pour les oiseaux. La DL50 pour
    la sauvagine et le gibier à plumes en général est > 1000 mg/kg.
    D'après les tests, l'oiseau le plus sensible est un francolin
    (Francolinus levaillanti) (DL50 = 56 mg/kg). Rien n'indique que
    les oiseaux aient eu à souffrir de l'effet des épandages effectués
    sur les zones forestières à la dose de 1,1 kg de carbaryl/ha.

         Le carbaryl est très toxique pour les abeilles et les lombrics.
    Dans le cas des abeilles, la DL50 par voie orale est de 0,16
    µg/insecte (soit 1-2 mg/kg).

         On est fondé à penser que le carbaryl puisse avoir une
    influence temporaire sur la composition en espèces des écosystèmes
    terrestres et aquatiques. Par exemple, une étude a montré que les

    effets exercés sur certaines communautés d'invertébrés terrestres
    pourraient persister au moins 10 mois après un seul épandage.

    1.7  Effets sur les animaux d'expérience et les systèmes d'épreuve
         in vitro

         La toxicité aiguë, exprimée sous la forme de la DL50, varie
    considérablement selon l'espèce, la formulation et le véhicule du
    produit. La DL50 estimative par voie orale pour le rat varie de
    200 à 850 mg(kg. Les chats sont plus sensibles, avec une DL50 de
    150 mg/kg. Les porcs et les singes le sont moins, avec une DL50 >
    1000 mg/kg.

         Une concentration de 792 mg de matière active par m3, qui
    constitue la valeur maximale qu'on puisse obtenir pour un aérosol, a
    produit, au cours d'une exposition de 4 heures, une mortalité de 20%
    (1/5) chez des rattes. A des concentrations de 20 mg/m3, des
    aérosols de carbaryl ont provoqué une réduction de l'activité
    cholinestérasique chez des chats lors d'une exposition de 4 heures,
    mais cette concentration n'a eu aucun effet observable chez des
    rats.

         Le carbaryl est légèrement irritant pour l'oeil et n'a que peu
    ou pas de pouvoir sensibilisateur. Lors d'études à long terme, la
    concentration sans effet nocif observable a été évaluée à 10 mg/kg
    de poids corporel (200 mg/kg de nourriture) pour le rat et à 1,8
    mg/kg de poids corporel (100 mg/kg de nourriture) pour le chien.
    Chez le chat, soumis à une exposition de longue durée par
    inhalation, la concentration sans effet nocif observable est de 0,16
    mg/m3. Le carbaryl a un faible potentiel d'accumulation.

    1.7.1  Reproduction

         On a montré que le carbaryl avait des effets indésirables sur
    la reproduction des mammifères et le développement périnatal chez un
    certain nombre d'espèces. Ces effets sur la reproduction consistent
    en une réduction de la fécondité, une diminution de l'effectif des
    portées et une réduction de la viabilité postnatale. Les effets
    toxiques du carbaryl sur le développement se traduisent pas un
    certain nombre de morts foetales, une réduction du poids foetal et
    la présence de malformations. A l'exception d'un petit nombre
    d'études, les effets nocifs sur la reproduction et le développement
    n'ont été constatés en totalité qu'à des doses manifestement
    toxiques pour la mère, et dans un certain nombre de cas, la mère
    était plus sensible au carbaryl que l'embryon ou le foetus. Ces
    effets toxiques sur la femelle gestante consistaient en une
    mortalité accrue, une réduction de la croissance et des dystocies.
    Les données indiquent que, par rapport à l'organisme adulte, la
    fonction de reproduction et le processus de développement des
    mammifères n'est pas particulièrement sensible au carbaryl.

    1.7.2  Mutagénicité

         Un certain nombre de tests  in vitro et  in vivo ont été
    effectués sur la carbaryl afin d'en évaluer le pouvoir mutagène;
    divers points d'aboutissement de ces effets ont été étudiés sur
    divers systèmes (bactéries, levures, végétaux, insectes et
    mammifères).

         Les données disponibles montrent que le carbaryl n'a aucune
    tendance à endommager l'ADN. On ne dispose d'aucun rapport
    confirmant les caractères mutagènes suivants: induction de
    recombinaisons mitotiques, conversion génique, et synthèse non
    programmée de l'ADN chez les procaryotes  (H. influenzae, B.
     subtilis) ni chez les eucaryotes ( S. cerevisiae, A. nidulans,
    lymphocytes humains en culture et hépatocytes de rat)  in vitro.

         La recherche de mutations géniques, qui a donné lieu à un grand
    nombre d'épreuves sur systèmes bactériens, a toujours donné des
    résultats négatifs, sauf dans deux cas. Lors de plusieurs études
    portant sur les mutations géniques et effectuées sur des cellules
    mammaliennes  in vitro, le carbaryl n'a donné qu'un seul résultat
    positif équivoque dans une de ces études. Toutefois, cette étude
    présentait un certain nombre de défauts et ce résultat n'a pas été
    confirmé par ceux d'autres études comparables.

         Des lésions chromosomiques ont été observées  in vitro sur des
    cellules humaines, des cellules de rat et de hamster ainsi que des
    cellules végétales exposées à des fortes doses de carbaryl. Aucun
    effet de ce genre n'a été observé lors d'épreuves  in vivo sur des
    systèmes mammaliens, même à des doses atteignant 1000 mg/kg.

         On a montré que le carbaryl perturbe le mécanisme d'élongation
    des fibres du fuseau chez les cellules végétales et mammaliennes  in
     vitro. On ne sait pas encore très bien si les résultats des
    épreuves effectuées sur des végétaux sont extrapolables à l'homme.

         Compte tenu de la base de données sont on dispose actuellement,
    on peut conclure que rien n'autorise à soupçonner le carbaryl de
    présenter un risque d'effets mutagènes pour les cellules somatiques
    ou germinales de l'homme.

         Un dérivé nitrosé du carbaryl, le  N-nitrosocarbaryl, peut
    provoquer des recombinaisons mitotiques et des conversions géniques
    chez les procaryotes  (H. influenzae, B. subtilis) et les
    eucaryotes  (S. cerevisiae) in vitro, et il donne des résultats
    positifs lors de "spot tests" effectués sur  E. coli.

         En outre, les résultats expérimentaux indiquent que le
     N-nitrosocarbaryl se lie à l'ADN provoquant la formation de
    liaisons alcalino-sensibles et des cassures monocaténaires.

         Il n'est pas établi que le nitrosocarbaryl soit un agent
    clastogène  in vivo (cellules de la moelle osseuse et cellules
    germinales) même à doses toxiques élevées.

    1.7.3  Cancérogénicité

         De nombreuses études ont été consacrées au pouvoir cancérogène
    du carbaryl chez le rat et la souris. La plupart de ces études ont
    donné des résultats négatifs mais il s'agit de travaux anciens qui
    ne satisfont pas aux normes actuelles. Quoiqu'il en soit, de
    nouvelles études portant sur ces mêmes animaux et qui, elles,
    satisfont aux exigences modernes, sont actuellement en coursa. La
    dernière évaluation du CIRC (CIRC, 1987) a conclu que l'existence de
    cancers imputables au carbaryl n'était pas documentée chez l'homme
    et qu'on ne possédait pas de preuves suffisantes d'un pouvoir
    cancérogène de cette substance chez les animaux de laboratoire. Il
    n'a donc pas été possible de classer le carbaryl en fonction de son
    pouvoir cancérogène pour l'homme (Groupe 3).

         On a montré que le  N-nitrosocarbaryl induisait des tumeurs
    locales chez les rats (sarcomes au point d'injection ou carcinomes
    spinocellulaires au niveau de la portion cardiaque de l'estomac,
    lorsque la substance est administrée par voie orale). Etant donné la
    biochimie du carbaryl chez l'homme, on peut considérer comme
    négligeable le risque de cancérisation par le  N-nitrosocarbaryl
    résultant d'une exposition humaine au carbaryl.

    1.7.4  Effets sur les différents organes et systèmes

    a) Système nerveux

         Les effets du carbaryl sur le système nerveux tiennent
    essentiellement à l'inhibition de la cholinestérase qui est
    généralement passagère. Ces effets ont été étudiés sur des rats et
    des singes. Des doses de 10 à 20 mg de carbaryl par kg, administrées
    pendant 50 jours par voie orale, ont provoqué des perturbations dans
    l'apprentissage et l'exécution de certaines épreuves par les rats
    traités.

    ______________

    a  Ces études n'ont pas encore fait l'objet d'un examen par le
         PISC.  La société qui effectue ces travaux indique qu'aux doses
         les plus fortes étudiées, on note une augmentation
         significative de la fréquence des tumeurs chez les deux
         espèces.

         Lors d'une petite étude portant sur des porcs, du carbaryl
    administré pendant 72 à 82 jours en mélange avec la nourriture à
    raison de 150 mg/kg de poids corporel, a produit un certain nombre
    d'effets neuromusculaires. On a observé en outre chez des poulets
    ayant reçu de fortes doses de carbaryl, une faiblesse réversible des
    pattes. Aucun signe de démyélinisation n'a été observé dans le
    cerveau, le nerf sciatique ou les coupes de moelle épinière
    examinées au microscope. On n'a pas observé d'effets de ce genre à
    l'issue d'études à long terme sur des rongeurs.

    b) Système immunitaire

         Administré  in vivo à des doses provoquant des signes
    cliniques manifestes, le carbaryl exerce divers effets sur le
    système immunitaire. Nombre de ces effets ont été observés à des
    doses voisines de la DL50. Dans la plupart des études où les doses
    utilisées permettaient la survie des lapins et des souris examinés,
    on n'a pas observé d'effets significatifs sur le système
    immunitaire. Plusieurs de ces travaux présentaient des défauts, par
    exemple un manque de cohérence et parfois des contradictions
    manifestes dans les résultats, défauts qui ne permettent pas de
    dégager des résultats obtenus un mécanisme immunotoxique bien
    défini.

    c) Sang

         Le carbaryl affecterait l'hémostase mais les résultats
    concernant le sens de cet effet sont contradictoires. On a observé
    que le carbaryl produisait une augmentation de la formation de
    méthémoglobine liée à la dose dans des érythrocytes de moutons
    présentant un déficit en glucose-6-phosphate-déshydrogénase. La
    sérum-albumine humaine réagit  in vitro sur le groupement ester du
    carbaryl. Le carbaryl se lie aux acides aminés libres.

    d) Foie

         On a fait état de troubles affectant le métabolisme des
    glucides et la synthèse des protéines au niveau du foie ainsi que
    d'une perturbation de la fonction détoxifiante de cet organe chez
    les mammifères. Le carbaryl induit faiblement l'activité
    pharmacométabolisante des microsomes hépatiques. Il y a
    raccourcissement de la durée du sommeil induit par le phénobarbital.
    Les taux hépatiques de cytochrome P-450 et b5 sont augmentés. Ces
    modifi-cations du métabolisme hépatique pourraient expliquer en
    partie le triplement de la DL50 pour le carbaryl observé chez des
    rats préalablement traités par cette substance.

    e) Fonction gonadotrope

         Il a été signalé que le carbaryl augmentait la fonction
    gonadotrope de l'hypophyse chez le rat.

    1.7.5  Mécanisme fondamental de la toxicité

         Le carbaryl est un inhibiteur de l'activité cholinestérasique.
    Cet effet est lié à la dose et rapidement réversible. On n'a pas
    observé de vieillissement de la cholinestérase carbamylée. Tous les
    métabolites reconnus du carbaryl ont une activité
    anticholinestérasique sensiblement plus faible que le carbaryl
    lui-même.

    1.8  Effets sur l'homme

         Le carbaryl est facilement absorbé par inhalation et après
    administration par voie orale mais moins facilement pas la voie
    percutanée. Etant donné que l'inhibition de la cholinestérase est le
    principal mécanisme de l'action du carbaryl, le tableau clinique
    d'une intoxication par cette substance est dominé par les symptômes
    correspondants, à savoir: augmentation de la sécrétion bronchique,
    sueurs profuses, salivation et larmoiement; myosis,
    bronchoconstriction, crampes abdominales (vomissements et diarrhée);
    bradycardie; fasciculation des petits muscles (dans les cas graves
    le diaphragme et les muscles respiratoires sont également atteints);
    tachycardie, céphalées, vertiges, angoisses, confusion mentale, coma
    et dépression des centres respiratoires. Ces signes d'intoxication
    se manifestent rapidement après l'absorption et disparaissent aussi
    vite une fois que l'exposition a cessé.

         Des études contrôlées sur des volontaires humains ont montré
    que des doses uniques inférieures à 2 mg/kg étaient bien tolérées.
    Une dose unique de 250 mg (2,8 mg/kg) a suscité des symptômes
    modérés d'inhibition cholinestérasique (douleurs épigastriques et
    sueurs) en l'espace de 20 minutes. Les sujets ont complètement
    récupéré dans les 2 heures suivant un traitement par le sulfate
    d'atropine.

         En cas d'exposition excessive d'origine professionnelle au
    carbaryl, on observe des symptômes légers bien avant qu'une dose
    dangereuse ne soit absorbée, ce qui explique que les cas graves
    d'intoxication professionnelle par le carbaryl soient rares. Lors
    des épandages agricoles, l'exposition percutanée peut être
    importante. Cependant on n'observe en général aucun effet irritant
    local, encore que l'on ait décrit des éruptions cutanées à la suite
    l'éclaboussures accidentelles de carbaryl en formulation liquide.

         Les données concernant les effets du carbaryl sur le nombre de
    spermatozoïdes et la modification de leur morphologie chez les
    travailleurs de l'industrie sont contradictoires. Aucun effet
    indésirable sur la reproduction n'a été signalé.

         L'indicateur biologique le plus sensible de l'exposition au
    carbaryl est l'apparition de 1-naphtol dans les urines et la
    diminution de l'activité cholinestérasique du sang. On peut donc

    utiliser la concentration urinaire du 1-naphtol comme indicateur
    biologique à condition qu'il n'y ait pas de 1-naphtol sur le lieu de
    travail. Lors de certains cas d'exposition professionnelle, on a
    constaté que 40% des échantillons d'urine contenaient plus de 10 mg
    de 1-naphtol total par litre. Dans un cas d'intoxication aiguë, on
    en a trouvé 31 mg/litre d'urine. On considère qu'il y a danger à
    partir de 10 mg/litre et que les symptômes apparaissent à partir de
    30 mg de 1-naphtol par litre d'urine (Fiche d'information sur le
    carbaryl, OMS, 1973, VBC/DS/75.3).

         La mesure de l'activité cholinestérasique peut constituer un
    test très sensible pour la surveillance médical des travailleurs, à
    condition que le dosage soit effectué peu après l'exposition.

    2.  Conclusions

         On estime que le carbaryl est peu dangereux pour l'homme en
    raison de sa faible tension de vapeur, de sa décomposition rapide,
    de la désinhibition spontanée également rapide de la cholinestérase
    et en raison du fait que les symptômes d'intoxication apparaissent
    bien avant qu'une dose dangereuse ne se soit accumulée dans
    l'organisme. On ne dispose pas encore de bonnes études de
    cancérogénicité qui satisfassent aux normes actuelles en la matière.

    2.1  Exposition de la population générale

         Les quantités résiduelles de carbaryl qui demeurent dans les
    denrées alimentaires et l'eau de boisson après l'utilisation normale
    de cet insecticide en agriculture, sont très inférieures à la dose
    journalière acceptable (DJA) (0,01 mg/kg de poids corporel/jour) et
    il est improbable qu'elles puissent constituer un risque pour la
    santé de la population dans son ensemble.

    2.2  Sous-groupes de population exposés à un risque élevé

         Lorsqu'on utilise du carbaryl à des fins de santé publique,
    soit au domicile soit sur des aires de loisir, il y a un risque
    d'exposition excessive si l'on ne suit pas les règles concernant son
    emploi.

    2.3  Exposition professionnelle

         En faisant respecter des méthodes de travail raisonnables et
    notamment un certain nombre de précautions de sécurité et des
    mesures de protection individuelle, avec une surveillance
    convenable, il n'existe aucun risque qui puisse résulter d'une
    exposition professionnelle au cours de la fabrication, de la
    formulation et de l'épandage du carbaryl. Les produits non dilués
    doivent être manipulés avec de grandes précautions car toute faute
    de manipulation peut entraîner une contamination cutanée. Sur le

    lieu de travail, la concentration atmosphérique ne doit pas dépasser
    5 mg/m3.

    2.4  Effets sur l'environnement

         Le carbaryl est toxique pour les abeilles et les lombrics. On
    ne doit pas procéder à son épandage pendant la floraison.

         En utilisation normale, le carbaryl ne devrait pas poser des
    problème écologique. Il est adsorbé en grande partie sur les
    particules de sol et il ne passe pas facilement par lessivage dans
    les eaux souterraines. Il subit une décomposition rapide dans
    l'environnement et n'est donc pas persistant. L'emploi de carbaryl
    ne devrait pas entraîner d'effets nocifs à court terme sur
    l'écosystème.

    3.  Recommandations

    *    La manipulation et l'épandage du carbaryl doivent s'effectuer
         en  observant les précautions qui s'imposent pour tous les
         pesticides. On suivra rigoureusement les instructions
         d'utilisation qui  figurent sur l'emballage.

    *    La fabrication, la formulation, l'emploi et l'élimination du 
         carbaryl doivent se faire avec toutes les précautions voulues
         pour  réduire au minimum la contamination de l'environnement.

    *    Les travailleurs qui sont soumis à une exposition régulière 
         doivent faire l'objet d'un contrôle médical périodique.

    *    La chronologie des épandages de carbaryl doit être réglée de 
         manière à éviter tout effet sur les espèces non visées.

    *    Il importe d'effectuer des études de cancérogénicité
         satisfaisant  aux normes modernes.

    RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES

    1.  Resumen y evaluación

    1.1  Identidad, propiedades y métodos analíticos

         El 1-naftil  N-metil carbamato, derivado del ácido carbámico,
    se conoce por el nombre común de carbarilo. El producto de calidad
    técnica es un sólido cristalino blanco, de baja volatilidad y escasa
    hidrosolubilidad, y estable a la luz y al calor, pero fácilmente
    hidrolizable en medio alcalino. La FAO ha establecido una
    especificación mínima de pureza del 98%, con un límite de impureza
    del 0,05% para el ß-naftil  N-metil carbamato. 

         Para analizar el carbarilo y sus metabolitos, se pueden
    utilizar numerosas técnicas, como la cromatografía de capa fina, la
    espectrofotometría, la cromatografía de gases, la cromatografía
    líquida de alta presión y la espectrometría de masas con ionización
    química. Pueden alcanzarse límites de detección inferiores a un
    nanogramo, y la recuperación supera por lo general el 80%.

    1.2  Producción y usos

         El carbarilo se viene utilizando desde hace unos 30 años como
    insecticida de contacto y de ingestión, posee algunas propiedades
    sistémicas y permite combatir una amplia serie de plagas. La planta
    de fabricación más importante está en los Estados Unidos. Más de 290
    fabricantes transforman el carbarilo para integrarlo en más de 1500
    productos diferentes.

    1.3  Transporte, distribución y transformación en el medio ambiente

         En la mayoría de las situaciones, el carbarilo no persiste en
    el entorno. En el agua, su semivida por hidrólisis depende de la
    temperatura, del pH y de la concentración inicial, y varía entre
    varios minutos y varias semanas. El principal producto de
    degradación es el 1-naftol.

         Se ha estudiado la acumulación de carbarilo en peces de agua
    dulce, y expresada como factor de bioconcentración en el medio
    acuático se ha cifrado en valores comprendidos entre 14 y 75. El
    carbarilo es adsorbido más fácilmente en los suelos que poseen un
    alto contenido orgánico que en los suelos arenosos. A un ritmo
    habitual de aplicación conforme con unas "prácticas agrícolas
    adecuadas", la disipación es rápida, con una semivida de entre 8
    días y un mes en condiciones normales. Ocasionalmente, por efecto de
    la lluvia y del cultivo agrícola, el carbarilo es transportado de la
    superficie al subsuelo (a un metro de la superficie).

         El carbarilo contamina la vegetación durante el rociamiento o
    por desplazamiento hasta las plantas a través del suelo contaminado.

         La degradación del carbarilo en el entorno depende del grado de
    volatilización, fotodescomposición y degradación química y
    microbiana que se produzca en el suelo, el agua y las plantas. La
    descomposición es más rápida cuando el clima es cálido.

    1.4  Niveles ambientales y exposición humana

         La principal fuente de ingestión de carbarilo entre la
    población general son los alimentos.

         Los residuos hallados en muestras de la ingesta alimentaria
    total son relativamente escasos, pues oscilan entre cantidades
    ínfimas y 0,05 mg/kg. En los Estados Unidos, la ingesta diaria
    durante los primeros años de aplicación de carbarilo fue de 0,15
    mg/día por persona (lo contenían el 7,4% de los compuestos); la
    cifra se redujo a 0,003 mg/día por persona en 1969 (sólo lo
    contenían un 0,8% de los compuestos). Durante el periodo de
    aplicación se encuentra carbarilo ocasionalmente en las aguas
    superficiales y los embalses.

         La población general puede estar expuesta al carbarilo durante
    las operaciones de lucha contra las plagas, en su vivienda o en
    zonas recreativas.

         Los trabajadores pueden estar expuestos al carbarilo durante su
    fabricación, formulación, envasado, transporte y almacenamiento, así
    como durante y después de su aplicación. Las concentraciones
    halladas en la atmósfera del lugar de trabajo durante su producción
    oscilaron entre < 1 mg/m3 y 30 mg/m3. Si las medidas de
    protección son inadecuadas, los trabajadores industriales y
    agrícolas pueden sufrir exposiciones cutáneas importantes.

    1.5  Cinética y metabolismo

         El carbarilo es absorbido rápidamente por los pulmones y el
    tracto digestivo. En voluntarios se observó una absorción cutánea
    del 45% a las 8 horas de aplicar una dosis del producto diluida en
    acetona. Sin embargo, los datos referentes a la penetración cutánea
     in vitro y a la toxicidad indican que la absorción cutánea se
    produce por lo general a una velocidad mucho menor.

         Las principales vías metabólicas del carbarilo son la
    hidroxilación del anillo y la hidrólisis. El resultado son numerosos
    metabolitos que experimentan conjugación, con formación de sulfatos,
    glucurónidos y mercapturatos hidrosolubles, que se excretan por la
    orina. Como resultado de la hidrólisis se forman 1-naftol, dióxido
    de carbono y metilamina. La hidroxilación da lugar a
    4-hidroxicarbarilo, 5-hidroxicarbarilo,  N-hidroximetilcarbarilo,
    5-6-dihidro-5-6-dihidroxicarbarilo y 1,4-naftalendiol. El metabolito
    principal en el hombre es el 1-naftol.

         En condiciones normales de exposición, el carbarilo rara vez se
    acumula en los animales. El producto se excreta principalmente por
    la orina, debido a que la detoxificación del producto de su
    hidrólisis, el 1-naftol, se produce principalmente por
    transformación en conjugados hidrosolubles. La circulación
    enterohepática de los metabolitos del carbarilo es también
    considerable, sobre todo tras su administración oral.

         El producto de la hidrólisis, el ácido carbámico  N-naftol, se
    descompone espontáneamente en metilamina y dióxido de carbono. La
    posterior desmetilación de la metilamina da lugar a dióxido de
    carbono y formato, siendo este último excretado principalmente por
    la orina.

         Un pequeño porcentaje de las dosis de carbarilo absorbidas
    aparecen como metabolitos en la saliva y la leche.

    1.6  Efectos en otros organismos en el medio ambiente

         En los crustáceos, las CL50 oscilan entre 5 y 9 µg/litro
    (pulgas de agua, mísidos), 8 y 25 µg/litro (anfípodos), y 500 y 2500
    µg/litro (cangrejos de río). El margen de sensibilidad es parecido
    en los insectos acuáticos; Plecoptera y Ephemeroptera (gusarapa y
    cachipollas) son los grupos más sensibles. Los moluscos son menos
    sensibles, situándose su CE50 en niveles de unos pocos mg/litro.
    En cuanto a los peces, la mayoría de las CL50 están comprendidas
    entre 1 y 30 mg/litro; el grupo más sensible son los salmónidos.

         En el caso de las aves la toxicidad aguda es baja. La DL50
    para las aves de caza, sean acuáticas o terrestres, es > 1000
    mg/kg. El ave más sensible analizada es el mirlo de alas rojas
    (DL50 = 56 mg/kg). En zonas forestales rociadas con 1,1 kg de
    carbarilo por hectárea no se observó ningún efecto en las aves
    locales.

         El carbarilo es muy tóxico para las abejas y las lombrices de
    tierra. La DL50 oral para las primeras es de 0,18 µg/abeja
    (aproximadamente 1-2 mg/kg).

         Hay indicios de que el carbarilo puede alterar temporalmente la
    composición de especies en los ecosistemas tanto terrestres como
    acuáticos. Por ejemplo, un estudio reveló que en determinadas
    colonias de invertebrados terrestres sus efectos pueden persistir
    durante por lo menos 10 meses tras una sola aplicación.

    1.7  Efectos en animales de experimentación y en sistemas de prueba
         in vitro

         La toxicidad aguda, expresada como DL50, varía
    considerablemente según las especies, fórmulas y vehículos. Las
    estimaciones de la DL50 oral en la rata oscilan entre 200 y 850

    mg/kg. Los gatos son más sensibles, pues presentan una DL50 de 150
    mg/kg. Los cerdos y los monos son menos sensibles, pues su DL50 es
    > 1000 mg/kg.

         La exposición a 792 mg de ingrediente activo de carbarilo
    nebulizado, que es la máxima concentración a la que se llegó durante
    4 horas, provocó la muerte de una de cinco ratas hembra. Aerosoles
    de carbarilo a concentraciones de 20 mg/m3 dieron lugar a una
    disminución de la actividad colinesterasa (ChEA) en gatos durante
    exposiciones únicas de 4 horas, pero esa misma concentración no tuvo
    efectos observables en ratas.

         El carbarilo produce leves irritaciones oculares y tiene un
    potencial de sensibilización escaso o nulo. Estudios prolongados
    revelaron un NOEL de 10 mg/kg de peso corporal (200 mg/kg ingesta
    alimentaria) en las ratas, y de 1,8 mg/kg de peso corporal (100
    mg/kg dieta) en los perros. El NOEL por inhalación prolongada es de
    0,16 mg/m3 en los gatos. El potencial de acumulación de carbarilo
    es bajo. 

    1.7.1  Reproducción

         Se ha demostrado que el carbarilo tiene efectos adversos sobre
    la reproducción y el desarrollo perinatal en diversas especies de
    mamíferos. Los efectos sobre la reproducción comprenden problemas de
    infertilidad, una disminución del tamaño de las camadas y una
    reducción de la viabilidad postnatal. Los efectos tóxicos sobre el
    desarrollo observados son un aumento de la mortalidad  in utero,
    una disminución del peso del feto y la aparición de malformaciones.
    Salvo en un reducido número de estudios, todos los efectos adversos
    sobre la reproducción y el desarrollo se observaron sólo a dosis
    manifiestamente tóxicas para la madre, y en varios casos ésta
    resultó ser más sensible al carbarilo que su prole. Entre los
    efectos tóxicos para la madre cabe citar la letalidad, una
    disminución del crecimiento y la distocia. Los datos disponibles
    indican que los procesos de reproducción y desarrollo de los
    mamíferos no son especialmente sensibles al carbarilo en comparación
    con la susceptibilidad del organismo adulto.

    1.7.2  Mutagenicidad

         Se ha evaluado la posible mutagenicidad del carbarilo mediante
    diversas pruebas  in vitro e  in vivo, empleando para ello
    bacterias, levadura, plantas, insectos y mamíferos, y analizando
    diversos puntos finales.

         Según los datos disponibles, el carbarilo no es lesivo para el
    ADN. No se ha notificado ningún dato que confirme que ha habido
    inducción de la recombinación mitótica, conversión génica o síntesis
    imprevista de ADN en procariotas  (H. influenzae, B. subtilis) y

    eucariotas ( S. cerevisiae, A. nidulans, linfocitos humanos en
    cultivo, y hepatocitos de rata)  in vitro.

         Se obtuvieron resultados negativos en las pruebas de detección
    de mutaciones génicas en un gran número de ensayos realizados con
    bacterias, salvo en dos casos. En varios estudios de mutagenicidad
    del carbarilo llevados a cabo con células de mamífero  in vitro, se
    obtuvo sólo un resultado positivo equívoco en un estudio de células
    en cultivo. Ese estudio, sin embargo, presentaba varias deficiencias
    y sus resultados no han sido confirmados en estudios comparables.

         Se han notificado lesiones cromosómicas a altas dosis de
    carbarilo en células humanas y de rata y hámster  in vitro, así
    como en plantas. No se han observado efectos de ese tipo en pruebas
     in vivo con mamíferos, ni siquiera a dosis de hasta 1000 mg/kg.

         Se ha mostrado que el carbarilo altera el mecanismo de las
    fibras del huso en células de plantas y mamíferos  in vitro. Es
    dudoso el interés de realizar ensayos con plantas para extrapolar
    sus resultados al hombre.

         Cabe concluir que los datos disponibles no corroboran la
    suposición de que el carbarilo plantea un riesgo de inducción de
    cambios génicos en las células somáticas o germinales del hombre.

         El producto nitrosado del carbarilo, el  N-nitrosocarbarilo,
    puede inducir fenómenos de recombinación mitótica y conversión
    génica en los procariotas  (H. influenzae, B. subtilis) y
    eucariotas  (S. cerevisiae) in vitro, y arroja resultados positivos
    en las pruebas  in situ con  E. coli.

         Además, resultados experimentales indican que el
     N-nitrosocarbarilo se une al ADN, causando la ruptura de los
    enlaces alcalisensibles y de las cadenas simples.

         No se ha demostrado que el nitrosocarbarilo sea clastógeno  in
     vivo (médula ósea y células germinales), ni siquiera a dosis
    tóxicas elevadas.

    1.7.3  Carcinogenicidad

         Se han realizado numerosos estudios en la rata y el ratón para
    determinar los posibles efectos carcinógenos del carbarilo. Los
    resultados de la mayoría de esos estudios fueron negativos, pero se
    trata de trabajos realizados hace muchos años y que no satisfacían
    los criterios actuales. Se están realizando nuevos estudios

    conformes con los actuales criterios en ratones y ratas.a En la
    más reciente evaluación del CIIC (CIIC, 1987) se llegaba a la
    conclusión de que no había información sobre el cáncer en el hombre
    y de que los indicios de carcinogenicidad en animales de
    experimentación eran insuficientes. No se podía clasificar el
    carbarilo en lo que se refiere a su carcinogenicidad para la especie
    humana (Grupo 3).

         Se ha mostrado que el  N-nitrosocarbarilo induce la aparición
    de tumores localmente en la rata (sarcoma en el lugar de la
    inyección o carcinoma de células escamosas del antro cardiaco al
    administrarlo por vía oral). Teniendo en cuenta las transformaciones
    químicas que sufre el carbarilo en el hombre, el riesgo de
    carcinogenicidad por  N-nitrosocarbarilo como consecuencia de la
    exposición a esta sustancia puede considerarse insignificante.

    1.7.4  Efectos en distintos órganos y sistemas

    a) Sistema nervioso

         Los efectos del carbarilo sobre el sistema nervioso se deben
    principalmente a la inhibición de la colinesterasa y son por lo
    general temporales. En unos estudios sobre los efectos en el sistema
    nervioso central de ratas y monos se observó que la administración
    oral de 10-20 mg/kg durante 50 días provocaba trastornos del
    aprendizaje y del comportamiento en las ratas. 

         En un pequeño estudio realizado con cerdos, el carbarilo (150
    mg/kg de peso corporal en la alimentación durante 72-82 días) tuvo
    diversos efectos neuromusculares. Se observó una debilidad
    reversible de las patas en pollos sometidos a altas dosis de
    carbarilo. No se observaron signos de desmielinización en los cortes
    de cerebro, nervio ciático o médula espinal examinados al
    microscopio. Tampoco se notaron efectos de esa índole en estudios
    prolongados realizados con roedores.

    b) Sistema inmunitario

         Se ha notificado que el carbarilo administrado  in vivo a
    dosis que producen claros signos clínicos tiene diversos efectos en
    el sistema inmunitario. Muchos de los efectos descritos se
    detectaron a dosis cercanas a la DL50. La mayoría de los estudios
    llevados a cabo con conejos y ratones a dosis compatibles con la
    supervivencia no han revelado efectos de importancia en el sistema

    ______________

    a  El IPCS aún no ha examinado esos estudios.  La sociedad
         encargada de realizarlos ha indicado que se observa un aumento
         significativo de tumores a la dosis màs elevada en las dos
         especies.

    inmunitario. Sin embargo, varios de esos estudios adolecían de
    incoherencia y a veces de contradicción patente entre los
    resultados, lo cual no permite describir un mecanismo inmunotóxico
    bien definido.

    c) Sangre

         Se ha señalado que el carbarilo afecta a la coagulación, pero
    existe cierta controversia en cuanto al tipo de efecto. En
    eritrocitos de oveja con déficit de glucosa-6-fosfato
    deshidrogenasa, el carbarilo provocó un aumento dosis-dependiente de
    la formación de metahemoglobina (Met-Hb). La albúmina sérica humana
    reaccionó  in vitro con el grupo éster del carbarilo. El carbarilo
    se une a los aminoácidos libres de la sangre.

    d) Hígado

         Se han señalado trastornos del metabolismo de los carbohidratos
    y de la síntesis de proteínas, así como de la función de
    detoxificación en el hígado de ciertos mamíferos. El carbarilo es un
    inductor ligero de la actividad de metabolización de medicamentos
    que reside en los microsomas hepáticos. Se observa un acortamiento
    del periodo de sueño inducido por el fenobarbital. Los niveles
    hepáticos de citocromo P-450 y b5 aumentan. Los cambios del
    metabolismo hepático son tal vez parcialmente responsables de la
    triplicación de la DL50 por carbarilo en ratas tratadas
    previamente con dicho compuesto.

    e) Función gonadotrópica

         Se ha señalado que el carbarilo estimula la función
    gonadotrópica de la hipófisis de la rata.

    1.7.5  Mecanismo principal de toxicidad

         El carbarilo inhibe la acción de la colinesterasa, efecto que
    depende de la dosis y es fácilmente reversible. No se observó ningún
    fenómeno de "maduración" de la colinesterasa carbamilada. Todos los
    metabolitos identificados del carbarilo son

    considerablemente menos activos que éste como inhibidores de la
    colinesterasa.

    1.8  Efectos en el hombre

         El carbarilo es fácilmente absorbido por inhalación y por vía
    oral, y menos fácilmente por vía cutánea. Como su principal
    mecanismo de acción es la inhibición de la colinesterasa (ChE), en
    el cuadro clínico de la intoxicación predominan los síntomas de esa
    inhibición, tales como: hipersecreción bronquial, aumento de la
    sudación, de la salivación y del lagrimeo; pupilas puntiformes,

    broncoconstricción, espasmos abdominales (vómitos y diarrea);
    bradicardia; fasciculación de los músculos finos (que también afecta
    en los casos graves al diafragma y a los músculos respiratorios);
    taquicardia; cefalea, vértigo, ansiedad, confusión mental,
    convulsiones y coma; y depresión del centro respiratorio. Los signos
    de intoxicación aparecen rápidamente tras la absorción y desaparecen
    pronto al cesar la exposición.

         En estudios controlados realizados con voluntarios se observó
    una buena tolerancia a dosis únicas inferiores a 2 mg/kg. Una dosis
    única de 250 mg (2,8 mg/kg) provocó síntomas moderados de inhibición
    de la ChE (dolor epigástrico y sudación) al cabo de 20 minutos. La
    recuperación completa se produjo tras dos horas de tratamiento con
    sulfato de atropina.

         En los casos de sobreexposición ocupacional al carbarilo, se
    observan síntomas leves mucho antes de que llegue a absorberse una
    dosis peligrosa; de ahí que raras veces se produzcan casos graves de
    intoxicación ocupacional por este compuesto. Durante las
    aplicaciones agrícolas, la exposición cutánea puede desempeñar un
    papel importante. No suelen observarse efectos irritantes locales,
    pero se ha descrito la aparición de exantema cutáneo tras la
    salpicadura accidental con formulaciones de carbarilo.

         Los datos acerca de los efectos del carbarilo sobre el número y
    la morfología de los espermatozoides en trabajadores industriales
    son discordantes. No se han notificado efectos adversos sobre la
    reproducción.

         El indicador biológico más sensible de la exposición al
    carbarilo es la aparición de 1-naftol en la orina y una disminución
    de la actividad ChE de la sangre. Si no hay 1-naftol en el entorno
    de trabajo, los niveles urinarios de este producto se pueden emplear
    como indicador biológico. Durante la exposición ocupacional, el 40%
    de las muestras de orina contenían más de 10 mg de 1-naftol/litro.
    En un caso de intoxicación aguda se hallaron 31 mg/litro en la
    orina. El nivel de riesgo es > 10 mg/litro, y el nivel de aparición
    de síntomas, 30 mg 1-naftol/litro de orina (hoja de datos sobre el
    carbarilo, OMS, 1973, VBC/DS/75.3).

         El análisis de la actividad ChE puede ser una prueba de gran
    sensibilidad a efectos de vigilancia, siempre que se realice poco
    después de la exposición.

    2.  Conclusiones

         Se considera que los riesgos que plantea el carbarilo para el
    ser humano son escasos, debido a su baja presión de vapor, a su
    rápida degradación y a la recuperación espontánea y rápida de la
    colinesterasa inhibida, así como al hecho de que los síntomas
    aparecen normalmente mucho antes de que pueda haberse acumulado en

    el organismo una dosis peligrosa. Aún no se dispone de estudios
    satisfactorios sobre la carcinogenicidad conformes con los criterios
    actuales.

    2.1  Exposición de la población general

         Los niveles de residuos de carbarilo presentes en los alimentos
    y el agua de bebida, resultantes de su uso normal en la agricultura,
    son muy inferiores a la ingesta diaria admisible (IDA) (0,01 mg/kg
    de peso corporal al día), y difícilmente pueden representar un
    riesgo para la salud de la población general.

    2.2  Subpoblaciones de alto riesgo

         El uso del carbarilo con fines de salud pública en la vivienda
    o en zonas recreativas puede ser causa de sobreexposición si se
    descuidan las normas aconsejadas para su aplicación.

    2.3  Exposición ocupacional

         Si se vela por el cumplimiento de unas prácticas laborales
    razonables, en particular las medidas de seguridad, la protección
    del personal y una supervisión adecuada, la exposición ocupacional
    durante la fabricación, formulación y aplicación de carbarilo no
    planteará riesgos. Las concentraciones no diluidas se deben manejar
    con sumo cuidado, dado que unas prácticas laborales incorrectas
    pueden ser causa de contaminación cutánea. Las concentraciones en el
    aire del lugar de trabajo no deberían superar los 5 mg/m3.

    2.4  Efectos en el medio ambiente

         El carbarilo es tóxico para las abejas y las lombrices. No
    debería aplicarse a los cultivos durante la floración.

         Si se emplea normalmente, el carbarilo no debería suscitar
    preocupación desde el punto de vista del medio ambiente. El
    carbarilo se adsorbe en buena parte en el suelo y no se lixivia
    fácilmente hacia las aguas subterráneas. Se degrada rápidamente en
    el entorno, por lo que no tiende a persistir. El uso de carbarilo no
    debería tener efectos nocivos a corto plazo en el ecosistema.

    3.  Recomendaciones

    *    La manipulación y la aplicación del carbarilo se deberían
         realizar  adoptando las precauciones previstas para todo
         plaguicida y  siguiendo minuciosamente las instrucciones
         suministradas en el  envase para emplear correctamente el
         producto.

    *    Deberían controlarse cuidadosamente la fabricación, la
         formulación, el uso y la eliminación del carbarilo, con objeto
         de  reducir al mínimo la contaminación del medio ambiente.

    *    Los trabajadores expuestos regularmente al producto deberían 
         someterse a chequeos periódicos.

    *    Debería determinarse la época de aplicación del carbarilo de 
         manera que no afecte a las especies que no se desee combatir.

    *    Deberían realizarse estudios de carcinogenicidad que satisfagan 
         los criterios actuales.


    See Also:
       Toxicological Abbreviations
       Carbaryl (HSG 78, 1993)
       Carbaryl (ICSC)
       Carbaryl (PIM 147)
       Carbaryl (FAO Meeting Report PL/1965/10/1)
       Carbaryl (FAO/PL:CP/15)
       Carbaryl (FAO/PL:1967/M/11/1)
       Carbaryl (FAO/PL:1968/M/9/1)
       Carbaryl (FAO/PL:1969/M/17/1)
       Carbaryl (AGP:1970/M/12/1)
       Carbaryl (WHO Pesticide Residues Series 3)
       Carbaryl (WHO Pesticide Residues Series 5)
       Carbaryl (Pesticide residues in food: 1976 evaluations)
       Carbaryl (Pesticide residues in food: 1977 evaluations)
       Carbaryl (Pesticide residues in food: 1979 evaluations)
       Carbaryl (Pesticide residues in food: 1984 evaluations)
       Carbaryl (Pesticide residues in food: 1996 evaluations Part II Toxicological)
       Carbaryl (JMPR Evaluations 2001 Part II Toxicological)
       Carbaryl (IARC Summary & Evaluation, Volume 12, 1976)