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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 178





    METHOMYL








    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 Dr M.L. Lithchfield, Arundel, United Kingdom


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


    World Health Organization
    Geneva, 1996

         The International Programme on Chemical Safety (IPCS) is a joint
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    WHO Library Cataloguing in Publication Data

    Methomyl

    (Environmental health criteria ; 178)

    1.Methomyl - toxicity  2.Insecticides, Carbamate
    I.Series

    ISBN 92 4 157178 0                 (NLM Classification: WA 240)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL

    1. SUMMARY

         1.1. Identity, physical and chemical properties, and analytical
               methods
         1.2. Sources of human and environmental exposure
         1.3. Environmental transport, distribution and transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism in laboratory animals
         1.6. Effects on laboratory mammals and in vitro test systems
         1.7. Effects on humans
         1.8. Effects on non-target organisms in the laboratory and field
         1.9. Evaluation of human health risks and effects on the
               environment
         1.10. Conclusion

    2. IDENTITY PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
               2.4.1. Sample preparation
               2.4.2. Analytical determination

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
               3.2.1. Production processes and levels
               3.2.2. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
               4.1.1. Water
               4.1.2. Soil
               4.1.3. Vegetation
         4.2. Transformation
               4.2.1. Biodegradation
               4.2.2. Abiotic degradation
               4.2.3. Bioaccumulation
         4.3. Interaction with other physical, chemical or biological
               factors

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
               5.1.1. Water
               5.1.2. Soil
               5.1.3. Food crops
               5.1.4. Other crops
               5.1.5. Dairy products
               5.1.6. Animal feed
         5.2. General population exposure
               5.2.1. Food
         5.3. Occupational exposure

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
         6.4. Elimination and excretion
         6.5. Retention and turnover
         6.6. Reaction with body components

    7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

         7.1. Single exposure
         7.2. Short-term exposure
         7.3. Long-term exposure
         7.4. Skin and eye irritation; sensitization
               7.4.1. Skin irritation
               7.4.2. Eye irritation
               7.4.3. Skin sensitization
         7.5. Reproductive toxicity, embryotoxicity and teratogenicity
               7.5.1. Embryotoxicity and teratogenicity
               7.5.2. Reproduction studies
         7.6. Mutagenicity
         7.7. Carcinogenicity
         7.8. Other special studies
               7.8.1. Cholinesterase studies in vivo and in vitro
               7.8.2. Neurotoxicity
               7.8.3. Potentiation studies
               7.8.4. Antidote studies
               7.8.5. Other studies
         7.9. Factors modifying toxicity
         7.10. Mechanisms of toxicity - mode of action

    8. EFFECTS ON HUMANS

         8.1. General population
               8.1.1. Accidental and suicidal poisoning
         8.2. Adverse effects of occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Microorganisms
         9.2. Aquatic organisms
               9.2.1. Algae
               9.2.2. Fish
               9.2.3. Other aquatic organisms
         9.3. Terrestrial organisms
               9.3.1. Terrestrial invertebrates
               9.3.2. Birds
         9.4. Field studies

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

         10.1. Evaluation of human health risks
         10.2. Evaluation of effects on the environment

    11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH

    12. FURTHER RESEARCH

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME

    RESUMEN

    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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                                   *     *     *

       A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
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                                   *     *     *

       This publication was made possible by grant number 5 U01 ES02617-15
    from the National Institute of Environmental Health Sciences, National
    Institutes of Health, USA, and by financial support from the European
    Commission.


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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL

     Members

    Dr T. Bailey, US Environmental Protection Agency, Washington DC, USA

    Dr A.L. Black, Dept. of Human Services and Health, Canberra, Australia

    Mr D.J. Clegg, Carp, Ontario, Canada

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
       Ripton, Huntingdon, Cambridgeshire, United Kingdom  (Vice-Chairman)

    Dr P.E.T. Douben, Her Majesty's Inspectorate of Pollution, London,
       United Kingdom

    Dr P. Fenner-Crisp, US Environmental Protection Agency, Washington DC,
       USA

    Dr R. Hailey, National Institute of Environmental Health Sciences,
       National Institutes of Health, Research Triangle Park, USA

    Ms K. Hughes, Environmental Health Directorate, Health Canada, Ottawa,
       Ontario, Canada

    Dr D. Kanungo, Central Insecticides Laboratory, Government of India,
       Ministry of Agriculture & Cooperation, Directorate of Plant
       Protection, Quarantine & Storage, Faridabad, Haryana, India

    Dr L. Landner, MFG, European Environmental Research Group Ltd,
       Stockholm, Sweden

    Dr M.H. Litchfield, Melrose Consultancy, Denmans Lane, Fontwell,
       Arundel, West Sussex, United Kingdom  (Rapporteur)

    Professor M. Lotti, Institute of Occupational Medicine, University of
       Padua, Padua, Italy  (Chairman)

    Professor D.R. Mattison, University of Pittsburgh, Graduate School of
       Public Health, Pittsburgh, PA, USA

    Dr Jun Sekizawa, National Institute of Health Sciences, Tokyo, Japan

    Dr Palarp Sinhaseni, Chulalongkorn University, Bangkok, Thailand

    Dr Salah A. Soliman, King Saud University, Bureidah, Saudi Arabia

    Dr M. Tasheva, National Centre of Hygiene, Medical Ecology and
       Nutrition, Sofia, Bulgaria

    Mr J.R. Taylor, Pesticides Safety Directorate, Ministry of Agriculture
       Fisheries and Food, York, United Kingdom

    Dr H.M. Temmink, Wageningen Agricultural University, Wageningen, The
       Netherlands

    Dr M.I. Willems, TNO Nutrition and Food Research Institute, Zeist, The
       Netherlands

     Observers

    Dr R. Gardiner, GIFAP, Brussels, Belgium (Representative of GIFAP)

    Dr B. Julin, Du Pont de Nemours (Belgium), Brussels, Belgium
        (Representative of GIFAP)

    Dr S.M. Kennedy, Du Pont de Nemours (Belgium), Brussels, Belgium
        (Representative of GIFAP)

    Dr Ronald L. Mull, Du Pont Agricultural Products, Wilmington, DE,
       United States of America  (Representative of GIFAP)

     Secretariat

    Ms A. Sundén Byléhn, International Register of Potentially Toxic
       Chemicals, United Nations Environment Programme, Châtelaine,
       Switzerland

    Dr P. Chamberlain, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr J. Herrman, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr K. Jager, International Programme on Chemical Safety, World Health
       Organization, Geneva, Switzerland

    Dr P. Jenkins, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr W. Kreisel, International Programme on Chemical Safety,
       World Health Organization, Geneva, Switzerland

    Dr M. Mercier, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland

    Dr M.I. Mikheev, Occupational Health, World Health Organization,
       Geneva, Switzerland

    Dr G. Moy, Food Safety, World Health Organization, Geneva, Switzerland

    Mr I. Obadia, International Labour Office, Geneva, Switzerland

    Dr R. Plestina, International Programme on Chemical Safety, World
       Health Organization, Geneva, Switzerland  (Secretary)

    Dr E. Smith, International Programme on Chemical Safety, World Health
       Organization, Geneva, Switzerland

    Mr J. Wilbourn, International Agency for Research on Cancer, Lyon,
       France

    ENVIRONMENTAL HEALTH CRITERIA FOR METHOMYL

       The Core Assessment Group (CAG) of the Joint Meeting on Pesticides
    (JMP) met in Geneva from 25 October to 3 November 1994. Dr W. Kreisel,
    Executive Director, welcomed the participants on behalf of WHO, and
    Dr M. Mercier, Director, IPCS on behalf of the three IPCS cooperating
    organizations (UNEP/ILO/ WHO).  The CAG reviewed and revised the draft
    monograph and made an evaluation of the risks for human health and the
    environment from exposure to methomyl.

       The first draft of the monograph was prepared by
    Dr M.L. Litchfield, Arundel, United Kingdom.  Extensive scientific
    comments were received following circulation of the first draft to the
    IPCS contact points for Environmental Health Criteria monographs and
    these comments were incorporated into the second draft by the
    Secretariat.

       The fact that E.I. Du Pont de Nemours and Co. made available to
    IPCS and the Core Assessment Group proprietary toxicological
    information on their products is gratefully acknowledged.  This
    allowed the Group to make its evaluation on a more complete data base.

       Dr R. Plestina and Dr P.G. Jenkins, both members of the IPCS
    Central Unit, were responsible for the overall scientific content and
    technical editing, respectively.  The efforts of all who helped in the
    preparation and finalization of the monograph are gratefully
    acknowledged.

    ABBREVIATIONS

    ADI      Acceptable Daily Intake
    ALC      Approximate Lethal Concentration
    CAS      Chemical Abstracts Service
    CCPR     Codex Committee on Pesticide Residues
    EbC50    median effective concentration for inhibition of growth
             based on comparison of areas under the growth curves after
             "b" hours
    ECD      electron capture detector
    FID      flame ionization detector
    FSD      flame photometric detector selective for sulfur
    GC       gas chromatography
    GLC      gas-liquid chromatography
    GOT      glutamic oxaloacetic transaminase
    GPT      glutamic pyruvic transaminase
    HPLC     high performance liquid chromatography
    ISO      International Organization for Standardization
    IUPAC    International Union of Pure and Applied Chemistry
    JMPR     Joint FAO/WHO Meeting on Pesticide Residues
    Kow      octanol/water partition coefficient
    LC50     median lethal concentration
    LD50     median lethal dose
    MATC     maximum acceptable toxicant concentration
    MHTA      S-methyl- N-hydroxythioacetimidate (a metabolite of
             methomyl)
    mPa      millipascal (7.5 × 10-6 mmHg)
    MRL      maximum residue limit
    NOEC     no-observed-effect concentration
    P2S       N-methyl-pyridium-2-aldoxime methane-sulphonate
             (antidote)
    PAM      pyridine-2-aldoxime methiodiode (antidote)
    RTECS    Registry of Toxic Effects of Chemical Substances
    TEAC     tetraethylammonium chloride
    TOCP     tri- o-cresyl phosphate
    TOD      total oxygen demand
    UV       ultraviolet

    1.  Summary

    1.1  Identity, physical and chemical properties, and analytical
         methods

         Methomyl is a white crystalline solid with a melting point of
    77°C and a vapour pressure of 0.72 mPa (25°C).  Its solubility in
    water is 54.7 g/litre and its octanol/water partition coefficient
    (Kow) is 1.24.  It is stable in sterile water at pH 7, but is broken
    down at higher pH values, the half-life being 30 days at pH 9 and
    25°C.

         The analytical procedure for the determination of methomyl in
    different samples is extraction followed by clean-up and analysis by
    HPLC or GLC.  In some cases methomyl is converted to its oxime
    derivative or a fluorophore derivative (post-column) prior to
    analytical determination.

    1.2  Sources of human and environmental exposure

         Methomyl is produced by reacting  S-methyl  N-hydroxythio-
    acetimidate (MHTA) in methylene chloride with gaseous methyl
    isocyanate at 30-50°C.  It is a carbamate insecticide used on a wide
    range of crops throughout the world. Crops protected include fruit,
    vines, hops, vegetables, grain, soya bean, cotton and ornamentals. 
    Indoor uses include the control of flies in animal houses and dairies.

         The main formulations are water soluble powders and water
    miscible liquids, which are diluted with water for ground or aerial
    spraying of crops.  Typical active ingredient rates are 0.15 to
    1.0 kg/ha.  The main sources of human exposure are during the
    preparation and application of these products and from the ingestion
    of crop residues in foodstuffs (see section 5.3.1.4).

    1.3  Environmental transport, distribution and transformation

         In laboratory studies, methomyl adsorbs poorly to soil.  Weak
    adsorption to clay minerals, particularly illite, has been
    demonstrated; adsorption to soil organic matter is 50 times greater
    but still relatively weak.  Hardly any desorption of bound residue is
    seen.  With these characteristics, methomyl would be expected to be
    mobile in soil.

         Under natural environmental conditions, abiotic degradation of
    methomyl by hydrolysis or photolysis is slow or absent.

         Aerobic degradation in soil is about twice as fast as anaerobic
    degradation.  Reported half-lives of methomyl in soil vary from a few
    days to more than 50 days;  dry conditions delay breakdown.  In
    practice in the field most applications should lead to a half-life of
    around one week.

         In field conditions, methomyl does not leach to levels below 20
    to 30 cm into the soil and does not contaminate ground water.

         When 14C-methomyl is applied to plant leaves it is absorbed but
    not translocated to other parts of the plant.  When applied to the
    root system it is absorbed into the plant where the principle residue
    component is methomyl itself.  Volatile breakdown products are CO2
    and acetonitrile. The remainder of the activity is incorporated into
    natural plant components such as lipids and Krebs cycle acids and
    sugars.  The half-life of methomyl in plant foliage is a few days.

         There was no evidence for accumulation of methomyl in rainbow
    trout exposed to the compound for 28 days in a flow-through system.

    1.4  Environmental levels and human exposure

         Methomyl levels are likely to be either very low or undetectable
    (< 0.02 mg/litre) in ground water on the evidence of analyses of
    various water sources after the application of the compound at
    recommended rates.

         Low residue levels of methomyl are present in food and other
    crops at harvesting, the levels depending upon factors such as the
    applied rate, time interval after the last application and the type of
    crop.  The residue is composed primarily of methomyl.

         Residues of methomyl in dairy products are either undetectable or
    very low.  Lactating cows given methomyl by capsule at a rate
    equivalent to 80 mg/kg in their feed for 28 days showed no detectable
    residues of methomyl or the metabolite MHTA in milk or tissues
    (< 0.02 mg/kg).  No methomyl was detected in eggs or tissues of
    laying hens given 1 or 10 mg/kg in the diet for 4 weeks.

         In total diet or individual food analyses in the USA, the
    concentrations of methomyl in sample surveys were either undetectable
    or very low.  Residue levels are further reduced by processes such as
    washing, peeling and cooking.

         Re-entry exposure studies, specifically for California desert
    conditions, showed that, when workers returned to vineyards where
    dislodgeable foliar residues had fallen to 0.1 µg/cm2, the highest
    exposure occurred on the upper body and head during grape girdling and
    on the upper body and hands during raisin harvesting.  Harvesting and
    packing table grapes resulted in the lowest exposure.  Inhalation
    exposure was minimal.

         After methomyl was sprayed on cucumber and tomato plants, ambient
    air concentrations in the greenhouse ranged up to 4.7 µg/m3 on the
    day after spraying.  Three and 7 days after spraying, breathing zone
    methomyl concentrations ranged up to 14.5 and 0.7 µg/m3,
    respectively.  Hand-wash methomyl values ranged from 10 to 322 µg
    per h work in a greenhouse.  This indicated that dermal exposure was a
    more important route of exposure than inhalation and that re-entry
    intervals should be based on dermal exposure data.

    1.5  Kinetics and metabolism in laboratory animals

         The absorption, metabolism and excretion of methomyl after oral
    administration to rats are very rapid, the processes being completed
    within a few days.  When rats were given radiolabelled methomyl
    (5 mg/kg body weight), 54% of the dose was excreted in urine and 2-3%
    in faeces within 7 days, and 34% in expired air within 5 days.  After
    7 days, 8-9% of the 14C dose remained in the tissues and carcass,
    which was incorporated into endogenous constituents.  The highest
    concentration of radioactivity was in the blood (representing 2% of
    the dose).

         The major metabolic components in expired air of rats were carbon
    dioxide and acetonitrile in the ratio of about 2:1.  The major
    metabolite in urine was the mercapturic acid derivative of methomyl,
    which was equal to 17% of the dose.  Neither methomyl nor its oxime
    derivative was detected.

         The proposed metabolic pathway includes displacement of the
     S-methyl grouping by glutathione followed by enzymic transformation
    to give the mercapturic acid derivative.  Another pathway is by
    hydrolysis to give MHTA, which is rapidly broken down to carbon
    dioxide.  A further possible route is conversion of  syn-methomyl (the
    insecticidal form) to its  anti-isomer, which undergoes hydrolysis,
    rearrangement and elimination reactions to give acetonitrile. 
    Methomyl is similarly metabolized in the monkey, except that the
    mercapturic acid derivative is a minor component in the urine.

         The penetration of 14C-methomyl was estimated to be 85% within
    one hour after dermal application in acetone to mice.  At that time 3%
    of the dose had appeared in blood, 5% in liver and 13% had been
    excreted.  Within 8 h the total excretion was 54.5%.

         The rapid breakdown and elimination of methomyl in the rat,
    together with its lack of accumulation in tissues, are comparable to
    that seen in ruminants.

         Methomyl is completely broken down when cows or goats are dosed. 
    No methomyl or its oxime derivative was detected in milk or tissues. 
    It was shown that the compound was metabolized and incorporated into
    natural constituents of milk and liver.

         No nitrosomethomyl was detected when 14C-methomyl was incubated
    under simulated stomach conditions with sodium nitrite in a cured meat
    macerate.

    1.6  Effects on laboratory mammals and in vitro test systems

         Methomyl has high acute oral toxicity, with an oral LD50 in the
    rat of 17-45 mg/kg body weight.  It is also highly toxic to rats by
    the inhalation route, with a 4-h LC50 of 0.26 mg/litre in aerosol
    form.  Dermal toxicity is very low, with the LD50 exceeding
    2000 mg/kg body weight in the rabbit (intact skin) and > 1000 mg/kg
    body weight in the rat (abraded skin).  Signs of acute toxic action
    are those expected of a cholinesterase inhibitor and include among
    others profuse salivation, lacrimation, tremor and pupil constriction. 
    Recovery from the effects was rapid.  No gross pathological effects
    due to treatment were seen in the organs examined.  Methomyl is not a
    skin irritant or sensitizer and is a mild eye irritant.

         Repeated dietary administration over longer periods did not lead
    to accumulation or increase in toxic effect.  Rats and dogs fed diets
    containing methomyl up to 250 mg/kg and 400 mg/kg in the diet,
    respectively, for 13 weeks did not show any toxic signs or mortality. 
    Rats fed at the 250 mg/kg level showed small decreases in body weight
    gain, lower haemoglobin levels and moderate erythroid hyperplasia in
    the bone marrow.  The NOEL in rats was 50 mg/kg in the diet
    (equivalent to 3.6 mg/kg body weight per day).  Rabbits given repeated
    dermal applications of methomyl at doses up to 500 mg/kg body weight
    per day for 21 days showed hyperactivity and depressed plasma and
    brain cholinesterase activity at the top dose.  The NOAEL was 50 mg/kg
    body weight per day in this study.

         Long-term studies were carried out on rats at methomyl
    dietary levels of 0, 50, 100 or 400 mg/kg and on mice at 0, 50, 75 or
    200 mg/kg.  Effects on rats at the top dose included depressed body
    weight gain and lowered haemoglobin and haematocrit values.  The NOEL
    was 100 mg/kg in the diet, equivalent to 5 mg/kg body weight per day. 
    In the study in mice, an increased mortality rate and decreased
    haemoglobin and red blood cell counts were seen at the two higher dose
    levels.  The NOEL was 50 mg/kg in the diet, equivalent to 8.7 mg/kg
    body weight per day.  In a 2-year toxicity study in dogs (0, 50, 100,
    400 or 1000 mg/kg in the diet), clinical signs of toxicity were noted
    in some animals at the top dose together with slight to moderate
    anaemia.  The NOEL was 100 mg/kg in the diet, equivalent to 3 mg/kg
    body weight per day.

         There was no evidence of treatment-related increases in tumour
    incidences in 2-year studies on rats and mice, indicating that
    methomyl is not carcinogenic. It was not genotoxic in bacterial or
    mammalian cells  in vitro and was negative in tests for primary DNA
    damage in bacterial and mammalian cells  in vitro and in an  in vivo rat
    bone marrow chromosomal study. It showed cytogenetic potential in

    human lymphocytes  in vitro, as shown by increases in micronuclei and
    chromosome aberrations.  Methomyl did not produce embryotoxic or
    teratogenic effects in rats or rabbits at doses up to 400 mg/kg in the
    diet or 16 mg/kg body weight per day by gavage, respectively, at which
    levels toxic effects were present in the dams. In a 3-generation
    reproduction study in rats at dose levels of 50 or 100 mg/kg in the
    diet (equivalent to 5 or 10 mg/kg body weight per day) methomyl did
    not affect fertility, gestation or lactation indices and there were no
    treatment-related gross abnormalities.

         Methomyl did not show delayed neurotoxicity after single or
    repeated administration.  Rats fed 800 mg/kg in the diet showed
    significant depression of blood cholinesterase activity only in the
    early stages of a 5-month study.  In a 28-day dietary study, brain
    cholinesterase activity was only slightly depressed at this dose
    level.  This indicated the rapid reversibility of methomyl-inhibited
    cholinesterase activity in the animals during the feeding periods.  In
    vitro, human erythrocyte cholinesterase activity was six times more
    sensitive to the inhibitory action of methomyl than that of the rat,
    although the rates of spontaneous reactivation were similar.

         Atropine was shown to be the most consistently effective antidote
    for methomyl poisoning based upon the results of studies in several
    species.

    1.7  Effects on humans

         Reports on accidental and suicidal poisonings with methomyl
    provide some information on effect levels and recovery. Three out of
    five victims of accidental poisoning from a contaminated meal died
    within 3 h of the ingestion.  It was estimated that the victims had
    consumed about 12-15 mg methomyl/kg body weight.  A 31-year-old woman
    and her 6-year-old son, both of whom died as a result of deliberate
    poisoning, showed concentrations of methomyl in the liver of 15.4 and
    56.5 mg/kg, respectively.  The estimated doses were 55 mg/kg body
    weight for the mother and 13 mg/kg body weight for the son.  Six hours
    after ingesting approximately 2.25 g methomyl, a woman's blood
    contained .6 mg methomyl/kg.  Methomyl could not be detected 22 h
    after ingestion, when the woman was recovering.

         A pesticide operator, who did not take any precautions when
    mixing a powdered methomyl formulation for spraying vegetables,
    displayed poisoning symptoms within one hour and showed a blood
    cholinesterase activity 40% of normal after 12 h, with recovery to 80%
    of normal activity within 36 h.  Other operators, following the
    recommended precautions, did not show any symptoms or effects on red
    blood cell or plasma cholinesterase activity during activities with
    the aerial application of methomyl.

    1.8  Effects on non-target organisms in the laboratory and field

         Methomyl showed no effects on soil fungal or bacterial
    populations, nitrification or dehydrogenase activity when applied at
    recommended rates.

         An NOEC for algal growth of 6.5 mg/litre was established for
    methomyl in laboratory studies.

         Methomyl is moderately to highly toxic to fish, the 96-h LC50
    values being in the range of 0.5-2 mg/litre for a variety of species. 
    In a longer-term (21 days) study the LC50 for fingerling trout was
    1.3 mg/litre methomyl when tested as a Lannate 20L (21.5% methomyl)
    formulation.  In an early- life-stage toxicity study over 28 days with
    fathead minnows, the MATC was estimated to be > 57 and < 117 µg/litre.

         In acute toxicity tests with other aquatic organisms,  Daphnia
     magna was one of the most susceptible species to methomyl, the 48-h
    LC50 being 0.032 mg/litre.  In a 21-day study on the survival,
    growth and reproductive capacity of Daphnia magna, the maximum
    acceptable toxicant concentration for methomyl was > 1.6 and
    < 3.5 µg/litre.

         Methomyl is toxic to honey-bees, the reported contact LD50
    being 1.29 µg/bee and the oral LD50 0.2 µg/bee.

         The acute toxicity of methomyl has been assessed in several bird
    species, typical acute oral LD50 values being 10 mg/kg body weight
    for pigeons and 34 mg/kg body weight for Japanese quail.  It is
    relatively less toxic by the dietary route, the 8-day dietary LC50
    being 1100 mg/kg methomyl in the diet for bobwhite quail and
    2883 mg/kg methomyl in the diet for mallard ducks.  In 18-to 20-week
    one-generation studies, the NOEC was 150 mg/kg methomyl in the diet in
    bobwhite quail and mallard ducks.

         No effects were seen on bobwhite quail when they were exposed to
    serial spray applications of methomyl at recommended rates.  Two
    studies on wild bird populations, after methomyl was sprayed over
    forest land or hop fields at recommended rates, did not reveal any
    apparent changes in bird activity and caused no treatment-related
    effect or mortality.  Fat deposits of song birds in treated forests
    were reduced relative to controls; this was considered to be an
    indirect effect through reduction in insect food.

    1.9  Evaluation of human health risks and effects on the environment

         Methomyl is a carbamate cholinesterase inhibitor with a
    well-known mechanism of toxic action.  It is particularly toxic by the
    acute oral and inhalation routes in animal studies, but it has low
    dermal toxicity.  Acute toxic signs in animals are typical of those of
    a cholinesterase inhibitor.  The reversibility of acute toxic action

    is rapid, with survivors showing quick recovery from toxic signs and
    reversal of cholinesterase inhibition in the blood and brain.  The
    quick recovery from toxic effects is due to the rapid reversibility of
    methomyl-inhibited cholinesterase, which is facilitated by the rapid
    clearance of the compound from the body.  Data from accidental and
    intentional human poisonings show that the level of acute methomyl
    toxicity in humans is similar to that found in laboratory animals.

         Because of the rapid reversibility of the action of methomyl
    during periods of feeding, acute toxic signs and blood cholinesterase
    inhibition were rarely seen in dietary studies.  The most consistent
    findings in longer-term studies at the higher dietary levels were
    decreases in body weight gain in rodents and reduced red blood cell
    indices in rodents and dogs.  There was no evidence for carcinogenic
    potential from three long-term studies in rodents.  The compound was
    negative in  in vitro genotoxicity tests that investigated several
    end-points, but methomyl showed cytogenetic potential in human
    lymphocytes.  It was negative in an  in vivo rat bone marrow
    chromosomal study.

         NOELs were identified in each of the long-term animal studies,
    based upon depression of body weight gain and red blood cell indices. 
    These were 5 mg/kg body weight per day in rats, 8.7 mg/kg body weight
    per day in mice and 3 mg/kg body weight per day in dogs.  In the
    absence of any marked species differences in toxic effect in these
    studies, the NOEL in the dog of 3 mg/kg body weight per day should be
    used for the purpose of human risk estimation.

         The adsorption of methomyl to soil is low to moderate with hardly
    any desorption.  Aerobic degradation in soil (with a half-life of
    around one week) is about twice as fast as anaerobic degradation.

         Application of methomyl to plant leaves results in rapid
    absorption of about half the amount applied (the other half being
    adsorbed), and there is no indication of translocation.  Absorbed
    methomyl concentrations in food crops decline rapidly to about 5%
    within one week.

         Several aquatic invertebrates, and particularly daphnids, are
    very sensitive to methomyl with LC50 values in the order of 10 to
    100 µg/litre.

         Fish, both freshwater and estuarine, are less sensitive, the
    LC50 values ranging from 0.5 to 7 mg/litre.  Given the low
    persistence of methomyl and its relatively low acute toxicity to fish,
    the risk is expected to be low.

         At recommended application rates, methomyl does not adversely
    affect microbial activity in temperate soil.

         Methomyl is classified as highly toxic to honey-bees with a
    topical LD50 of around 0.1 µg/bee.

         Acute oral LD50 values for various bird species range between
    10 and 40 mg/kg body weight. Dietary LC50 values (5 days) range from
    1100 to 3700 mg/kg diet.  Methomyl poses an acute risk to birds,
    particularly from granules; dietary intake from contaminated food is
    not expected to kill birds.

         The high acute toxicity of methomyl to laboratory mammals
    indicates a similar hazard to wild mammals.

    1.10  Conclusion

         Considering the qualitative and quantitative characteristics of
    methomyl toxicity, the Task Group concluded that 0.03 mg/kg body
    weight per day will probably not cause adverse effects in humans by
    any route of exposure.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS

    2.1  Identity

    Chemical structure:
                                           O
                                           "
                                 CH3-C=N-O-C-NH-CH3
                                     '
                                     S - CH3

                                 Used in the syn-isomer form

    Molecular formula:           C5H10N2O2S

    Relative molecular mass:     162.2

    ISO common name:             methomyl

    IUPAC chemical name:          S-methyl- N-[(methyl-carbamoyl)oxy]
                                 thio-acetimidate

    CAS chemical name:           methyl N[[(methyl-amino)carbonyl]
                                 oxy] ethanimidothioate

    CAS registry number:         16752-77-5

    RTECS number:                AK 2975000

    Synonyms:                    metomil, mesomil, OMS 1196

    Trade names                  Flytek (Zoecon), Golden Fly Bait
    (manufacturers and           (Sorex), Lannate (Du Pont), Methomex
    suppliers):                  (Makhteshim), Methomyl (various),
                                 Nudrin (Shell), Pillarmate (Pillar)

    Technical product purity:    > 98% w/w

    Technical product             S-methyl- N-hydroxy-thioacetimidate
    impurities:                  (0.2%), 1,3-dimethylurea (0.4%)

    2.2  Physical and chemical properties

         The physical properties of methomyl are listed in Table 1.

    Table 1.  Physical properties of methomyl (Silveira, 1990)
                                                                        

    Physical state                            crystalline solid
    Colour                                    white
    Odour                                     slight sulfurous
    Melting point                             77°C
    Vapour pressure                           0.72 mPa (at 25°C)
    Henry's Law constant                      2.1 × 10-11 atm-m3/mole
    Octanol-water partition coefficient       1.24
    (Kow)
    Solubility:
    water                                     54.7 g/litre
    toluene                                   30   g/litre
    isopropanol                               220  g/litre
    ethanol                                   420  g/litre
    acetone                                   720  g/litre
    methanol                                  1000 g/litre
                                                                        

         Methomyl is stable at temperatures up to 140°C.  It is not
    sensitive to impact, but dusts may form explosive mixtures in air. 
    The autoignition temperature is 265°C.  Methomyl is stable to
    sunlight; it does not decompose when exposed for 120 days.  It is
    stable in sterile buffered water at  25°C (at pH 5 or 7 no breakdown
    occurred within 30 days), but it is increasingly decomposed with
    increasing pH and temperature.  The half-life in water at pH 9 is 30
    days.  Methomyl at concentrations of 10 or 100 mg/litre in water is
    decomposed by artificial sunlight with half-lives of 5.5 and 2 days,
    respectively.  Methomyl itself is not corrosive but aqueous solutions
    may be mildly corrosive to iron (Silveira, 1990).  Irradiation of
    methomyl in aqueous solution at 254 nm for 10 h gave rise to
    acetonitrile (40%), dimethyl disulfide (30%), acetone (15%) and
     N-ethylideneme-thylamine (5%); the rest was unidentified products
    (Freeman & Ndip, 1984).

    2.3  Conversion factors

         1 ppm = 6.62 mg/m3
         1 mg/m3 = 0.151 ppm

    2.4  Analytical methods

         Analytical methods for the detection and determination of
    methomyl in a variety of substrates are shown in Table 2.  In general,
    methomyl is extracted from the sample followed by clean-up and HPLC or
    GLC analysis.  In some cases the methomyl is converted to its oxime
    derivative or a fluorophore derivative (post-column) prior to
    analytical determination.

    2.4.1  Sample preparation

         Solid samples are extracted with organic solvents followed by
    solvent partition and then, usually, a column clean-up.  Water samples
    are mainly submitted directly to solid phase extraction.

    2.4.2  Analytical determination

         The cleaned-up samples are submitted to either HPLC or GLC
    analysis, in some cases after conversion to the oxime derivative. 
    HPLC analysis is coupled with UV detection, sometimes after conversion
    to a fluorescent derivative.  GLC detection is provided by FID, FSD,
    ECD or microcoulometric detectors.  A GC-mass spectrometric detection
    method has been described (Brodsky, 1991).


        Table 2.  Methods for the determination of methomyl
                                                                                                                                                

    Sample type           Sample preparation                              Analytical method              Limit of           Reference
                          extraction/clean-up                                                            detection
                                                                                                                                                

    Technical methomyl    Reverse phase HPLC                              254 nm UV detector             not applicable     Du Pont (1982)
    and formulations

    Plant, animal or      Extract (ethyl acetate), add water,             GLC with                       0.02 mg/kg         Pease & Kirkland
    soil residues         evaporate, acidify, extract & discard           S-microcoulometer detector     (25 g sample,      (1968); Leitch &
                          (hexane), extract (chloroform), concentrate,    or flame photometric           93% recovery)      Pease (1973)
                          derivatize by alkaline hydrolysis               detector

    Crop residues         extract (acetonitrile), partition (hexane),     HPLC, UV detector at           0.02 mg/kg         Clark & Kennedy
                          Florisil clean-up                               233 nm                         (10 g sample,      (1990)
                                                                                                         98% recovery)

    Non-fatty matrix      extract (methanol), 3-step solvent partition    HPLC, post column              < 0.05 mg/kg       Labare (1990)
    residues              Celite/charcoal column clean-up,                derivatization, fluorescent    (150 g sample,
                          concentrate, filter                             detector at 254 nm             89% recovery)

    Vegetables            Homogenized (20 g sample) with                  HPLC/UV                        µg/kg range        Ivie (1980)
                          methylene chloride. Clean-up 10 ml of the       (µ Baudpac C18 column)
                          extract by passing through SEP-PAK silica
                          cartridge. Wash with 2 ml CH2Cl2. Elute
                          with CH2Cl2:CH3OH (1:1 v/v). Evaporate
                          eluate to dryness. Redissolve in 1 ml of
                          CH3CN:H2O(1:1 v/v)
                                                                                                                                                

    Table 2 cont'd).
                                                                                                                                                

    Sample type        Sample preparation                              Analytical method             Limit of             Reference
                       extraction/clean-up                                                           detection
                                                                                                                                                

    Body fluids        derivatize by alkaline hydrolysis, extract      GC/chemical ionization        0.01 mg/kg           Miyazaki et al.
                       (ethyl acetate), concentrate, convert to        mass spectroscopy             (2 g sample,         (1989)
                       trimethysilyl ether derivative                                                95% recovery)

    Soil               samples extracted with ethyl acetate;           HPLC, UV detector at          0.020 mg/kg          Kennedy (1989)
                       filtered; evaporated to 5 ml; silica gel        233 nm                        (5 ml sample,
                       clean-up used when cleaner extract                                            94-102%
                       needed for HPLC                                                               recovery)

    Groundwater        extract (solid phase adsorbent), elute          HPLC, UV detector             < 0.1 µg/litre       Batelle (1991)
                       (acetonitrile), concentrate                                                   (1 litre sample,
                                                                                                     53-62%
                                                                                                     recovery)

    Well water         Filter, automated sample injection, HPLC,       flurometric detector at       1 µg/litre           Hill et al. (1984)
                       post-column alkaline hydrolysis and             230 nm excitation and         (0.5 ml sample,
                       conversion to a fluorophore                     418 nm emission cut-off       95% recovery)
                                                                       filter

    Drinking-water     as above                                        as above                      0.7 µg/litre         Foerst & Moye
                                                                                                     (0.4 ml sample,      (1985)
                                                                                                     90% recovery)
                                                                                                                                                
    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Methomyl does not occur naturally in the environment.

    3.2  Anthropogenic sources

    3.2.1  Production processes and levels

         Methomyl is produced by reacting  S-methyl- N-hydroxythio-
    acetimidate (MHTA) in methylene chloride with gaseous methyl
    isocyanate at 30-50°C.  The unreacted MHTA is recovered and the
    remaining reaction product is subjected to solvent exchange into water
    followed by crystallization and centrifugation.  The ensuing wet cake
    is dried to give technical methomyl (Council of the European
    Communities, 1991).

         The worldwide production has been estimated to be less than 7000
    tonnes (SRI, 1988).

         There are no data available on possible releases to the
    environment from production processes and transportation.

    3.2.2  Uses

         Methomyl was introduced as an insecticide in 1966.  It is used
    for the control of a large variety of insects on a wide range of crops
    throughout the world.  It is particularly active on many lepidopterous
    insects.  It acts by direct contact and following ingestion, through
    the stomach.  Treated crops include fruit, vines, hops, vegetables,
    grain, soya beans, cotton and ornamentals.  Indoor uses include the
    control of flies in animal houses and dairies.

         A global estimate of the amount of methomyl used annually for the
    above purposes is not available.  However, the annual amount used in
    the USA was estimated to be approximately 1300 tonnes in 1987 and
    1992.  The major crops treated in that country are sweet corn, apples,
    lettuce, soya beans, peanuts, tomatoes, cotton, corn, alfalfa, and
    grapes, accounting for nearly 80% of the total amount used (US EPA,
    1988; Gianessi & Puffer, 1992).

         The main formulated products are water-soluble powders (25-90%
    methomyl) and water-miscible liquids (12.5-29% methomyl).  These
    products are diluted with water and applied by ground or aerial spray
    equipment.  Typical methomyl concentrations in the spray solutions are
    200-500 mg/litre. Typical active ingredient rates are 0.15-1.0 kg/ha
    although higher rates, up to 2 kg/ha, may be used for some purposes. 

    Repeat applications, as directed on the label, may be required to
    maintain control of insect infestations.  Examples of crops treated
    and methomyl use rates for the USA and Australia are given by FAO/WHO
    (1990a,b).  Methomyl formulations are compatible in use with many
    other insecticides and fungicides, and combined formulations are
    registered and available for use in many countries.  Methomyl is often
    used with one or more other products in a tank-mix.  Possible
    potentiation by other cholinesterase inhibitors should be considered
    when assessing the safety of use of the tank-mix formulations.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Water

         The transference of methomyl from greenhouse plants to soil and
    to water was assessed on chrysanthemums, grown three times per annum,
    with methomyl applied over a 6-month period at 1-week to 2-month
    intervals at a rate of 1.4 kg/ha.  The three soils investigated were
    frequently irrigated and the drainage water was collected at a depth
    of 0.8 m.  The adsorption isotherms for the three soils indicated that
    the adsorption of methomyl was weak to moderate.  The concentration of
    methomyl in the drainage water was undetectable (< 0.1 µg/litre) in
    60% of the samples and was below 1 µg/litre in the remainder (Leistra
    et al., 1984).

         Methomyl was applied at a high rate of 2.2 kg/ha to a loamy sand
    soil on a farm site with a 10% slope.  No methomyl was detected
    (< 0.01 mg/litre) at the base of the site after a total of about
    80 mm of natural and artificial rain had fallen on the site over a
    period of 15 days (Harvey & Pease, 1973).

         14C-Methomyl was applied at a very high rate of 5 kg/ha to
    cylinders (38 cm deep) containing a fine sand soil or a loamy sand
    soil.  No radioactivity was found in the eluate collected after the
    columns had been subjected to heavy rain (Harvey & Pease, 1973).

         In natural waters, pesticides can be photochemically degraded by
    direct (the pesticide absorbs sunlight) and indirect (other chemicals
    in the water absorb sunlight, and transfer the energy to the
    pesticide) mechanisms. Current regulatory studies only address the
    direct mechanism, and thus neglect an important degradative process. 
    This can result in unrealistically high estimates of persistence of a
    pesticide in surface water.

         These data would suggest that any methomyl residues present in
    agricultural waters would be rapidly degraded, and that methomyl would
    not be expected to have an impact on non-target aquatic organisms.

    4.1.2  Soil

         Batch equilibrium studies were carried out with 14C-methomyl on
    two sandy loams and two silt loams.  Aqueous solutions containing
    0.2-6 mg methomyl/litre of were mixed with the soils and shaken for
    24 h. A separate study was also undertaken on each soil using TLC. 
    Methomyl was shown to be weakly adsorbed on one of the silt loams

    (Ka=1.4), and poorly adsorbed on the other three soils.  Desorption
    was related to soil organic matter content and indicated that methomyl
    is not readily desorbed.  In the TLC assessment the Rf values
    (0.46-0.82) indicated methomyl as Class 4 (mobile) on a sandy loam and
    Class 3 (intermediate mobility) on the other three soils (Priester,
    1984).

         A silty clay loam, a silt loam and two sandy loams were made up
    as slurries and spread on TLC plates.  Methomyl and a minor soil
    metabolite,  S-methyl- N-hydroxy-thioacetimidate (MHTA) were applied
    at 1 µg/spot and the plates developed.  Methomyl and its metabolite
    were considered to be very mobile, with Rf values of 0.64-0.79 and
    0.86-0.93, respectively, in the four soils (US EPA, 1988).

         In a field study on a sandy loam in California, methomyl was
    applied to cabbage by back-pack sprayers at a very high rate of
    10 kg/ha (single application).  Samples of the soil were taken at 0
    and 6 h and then at intervals from 3 to 272 days after application. 
    Analysis showed that methomyl residues remained mostly in the top
    15 cm of soil with deepest penetration into the 15-30 cm layer after
    48 cm rainfall/irrigation.  On this basis the mobility of methomyl was
    considered to be low to moderate under field conditions in this soil
    (Kennedy, 1989).

         In another field study on a soil characterized as a loam and silt
    loam, methomyl was applied to cabbage by back-pack sprayers at the
    high rate of 4.4 kg/ha (single application).  Soil samples were taken
    at 0 and 6 h and then at intervals over a 91-day period after
    application.  Methomyl residues were found only in the top 15 cm of
    soil after 28 cm rainfall/irrigation.  On this basis methomyl was
    considered to be of low mobility in these field conditions (Kennedy,
    1991).

         Cox et al. (1993) studied methomyl adsorption to 14 soils from
    southern Spain. These varied in pH from 5.3 to 7.9, in percentage of
    organic matter from 0.59 to 2.5%, in cation exchange capacity from 4.2
    to 28.5, and in the percentage of clay minerals.  The methomyl
    concentration in soil and water components following shaking for 24 h
    was measured by HPLC.  Simple and multiple regression analysis was
    used to evaluate which factors affected methomyl adsorption.  Soils
    were equilibrated with both 20 and 50 µM methomyl (high purity); there
    was no significant difference between concentration at the same
    soil/solution ratio, indicating poor affinity of methomyl for the
    soils.  Both simple and multiple regression indicated soil organic
    matter, clay content and clay minerals, methomyl in soil and illite
    content as the major features of soil affecting adsorption of

    methomyl.  Further studies examined adsorption to individual soil
    components.  Humic acid showed by far the highest affinity for
    methomyl with Kd values 50 times greater than for clay minerals. 
    Montmonillonites showed a similar Kd to illite in these studies,
    contrary to findings with whole soils.  The authors suggest, on the
    basis of maturation studies, that adsorption to clay may occur in the
    interlamellar space of the minerals.

    4.1.3  Vegetation

         When 14C-methomyl was applied to the surface of tobacco plant
    leaves the compound was absorbed in the leaf but not translocated to
    other parts of the plant (Harvey & Reiser, 1973).

         In a study by Fung et al. (1978), each tobacco seedling received
    250 ml of water containing 500 µg methomyl/litre (equivalent to about
    0.5 kg active ingredient per hectare of 17 000 plants) after
    transplantation.  The concentration of methomyl peaked at 15 mg/kg in
    the leaves and at 2.5 mg/kg in the growing tips 2 weeks after
    treatment.  Subsequently, the concentration decreased, which could be
    explained almost entirely by growth dilution.  At 9 weeks after
    transplantation, the plants were sprayed with a solution of 500 mg
    methomyl/litre.  Three weeks after this (i.e. 12 weeks after
    transplantation), another similar application was made.  Some plants
    received an additional application of 250 ml of a 500 mg
    methomyl/litre solution on each side of the row of plants. 
    Concentrations increased sharply after these treatments and dropped
    afterwards: levels in the leaves of plants with both foliar
    application peaked at 9 and 6 mg/kg;  levels in leaves which received
    foliar and root applications peaked at 18 and 11 mg/kg.  Part of the
    decrease after application could again be explained by growth
    dilution.  It appears, therefore, that translocation of methomyl from
    roots to leaves can occur (Fung et al., 1978).

         A sandy loam soil was treated with 14C-methomyl at a rate of
    4.4 kg/ha and, 30-120 days later, cabbage, red beet and sunflower
    seeds were sown and the plants grown to maturity.  Thirty days after
    treatment the soil contained 26% of the original methomyl whereas
    after 120 days it contained only 8%.  All crops, sown at 30 or 120
    days, contained only very small residues of methomyl and/or
    metabolites, equivalent to 0.01 mg/kg or less at harvest (Harvey,
    1978).

    4.2  Transformation

    4.2.1  Biodegradation

         In a study by Harvey (1972a), 14C-methomyl (1 mg/litre) in
    river water (pH 6.3) was exposed for 8 weeks from JulySeptember in the
    USA.  The compound degraded with a half-life of about one week.  The
    initial degradation product was MHTA followed by breakdown to carbon
    dioxide, which accounted for 65% of the original radioactivity after 8
    weeks. The S-oxide of MHTA was also detected in small amounts.  At
    termination, 9% of the original activity was present in sediment and
    the biological film on the walls of the container.

         Laboratory studies were carried out on a non-sterile silt loam at
    its natural pH of 4.7 and at an adjusted pH of 7.9; an alkaline soil
    (pH 7.9) was also evaluated.  All soils were treated with
    14C-methomyl at a high rate equivalent to 4.4-6.1 kg/ha and the
    breakdown was assessed over 42 days.  Methomyl degraded (52-69%) in 42
    days, carbon dioxide (31-45%) being the main decomposition product. 
    Small amounts of MHTA (1-2%) were present in the soil at termination. 
    It was shown that the 14CO2 could be reincorporated into soil
    organic matter (Harvey & Pease, 1973) (J. Harvey, Jnr (1976):
    supplement to "Decomposition of methomyl in soil"; personal
    communication by Du Pont to IPCS, dated 28 July 1976).

         Under field conditions the decomposition of methomyl was more
    rapid, with a 71% loss from a silt loam soil within one month; none
    was detected after one year.  MHTA was present in trace amounts at 1
    and 3 months but was not present at one year.  Most of the residual
    application was found in the top 75 mm of soil, and none was found
    below 200 mm.  Decomposition was rather more rapid in fine sand and
    loamy sand soils (Harvey & Pease, 1973).

         When applied at a concentration of 4.1 mg/kg to a microbially
    active loam soil (equivalent to a very high rate of 9 kg/ha),
    14C-methomyl was metabolized with a half-life of approximately
    11 days.  The decomposition followed first-order kinetics and the main
    end product was 14CO2 (Zwick & Malik, 1990a). These results were
    in agreement with the studies described above and with other aerobic
    soil metabolism studies conducted on soils of high or low organic
    matter content and various pHs (Harvey, 1972b; 1977a,b).

         Dissipation studies of methomyl in loam soils in California and
    Mississippi resulted in half-lives of 8 weeks and 5 days, respectively
    (Kennedy, 1989; 1991). In addition to differences in temperature,
    field moisture differences during the experiment seem largely

    responsible for these differences in half-life, because adjusting
    field moisture of the California soil to 75% of its capacity in the
    laboratory reduced the half-life to 11 days (Kennedy, 1991).  Field
    moisture conditions greatly decrease the air content of the soil.  In
    anaerobic soils it has been shown that ferrous ions facilitate the
    rapid degradation of methomyl (Bromilow et al., 1986).

         Methomyl is also degraded under anaerobic soil conditions.  An
    alkaline soil with low organic matter content was incubated with
    methomyl (4.1 mg/kg) aerobically for 14 days and then anaerobically
    for 60 days.  The half-life under anaerobic conditions was
    approximately 14 days and 14CO2 was a major break-down product,
    equivalent to 23.4% of the applied activity during the 60 days of
    anaerobic incubation.  Unextractable activity was 30% of the total at
    7 days and 24% after 60 days of anaerobic treatment. Most of this was
    associated with soil organic matter (Zwick & Malik, 1990b).

         Anaerobic degradation (Eh 80-310 mV) was studied in samples of
    sand, loamy sand and fine sand, taken from below the soil water table
    at four locations in the Netherlands  (Smelt et al., 1983).  In each
    case, methomyl was incubated at 10°C and when pH was between 7.4 and
    7.7 the half-life was less than 0.2 day (one hour after the start of
    the experiment, 38-63% of the applied dose was recovered, and after
    24 h, 0.15-5% of the applied dose was recovered.  When the fine sand
    sample was incubated at 10°C and pH 5.0, methomyl could be detected
    for 3 days, and the rate of decrease corresponded to a half-life of
    7 h.

         The role of microbial action was shown by perfusing two soil
    samples (fine sandy loam at pH 6.1 and fine sandy clay loam at pH 5.87
    with organic matter content in both of 2.1-2.3%) with methomyl
    solution (6 mg/litre) with and without sodium azide (Fung & Uren,
    1977).  The contribution of adsorption or dissipation of methomyl from
    solutions was small when compared with that of microbial
    transformation.  The latter amounted to 25-45% in 42 days after a lag
    phase of 7-14 days.  When previously perfused soil was re-exposed to
    fresh methomyl solution, 60-75% was lost in 42 days without any lag
    phase.

         The metabolic fate of methomyl has been investigated in tobacco,
    corn and cabbage (Harvey & Reiser, 1973).  Tobacco was grown from
    seedlings, and when the plants were 18 cm high the roots were treated
    with 14C-methomyl (10 mg/litre solution).  Cabbage (42 days old) and
    corn (28 cm high) plants were treated with 14C-methomyl via foliar
    application.  Each plant was placed in a glass metabolism apparatus
    for radioactivity measurement of volatile products and plant material. 
    Tobacco absorbed 20-25% of the available activity over a 4-week
    period.  One quarter of this was retained in plant tissue and the
    remainder volatilized.  The principal component of plant tissue

    activity was methomyl.  The volatile components were carbon dioxide
    and acetonitrile in equal proportions.  Of the applied activity, 47%
    was lost from the growing shoots of young corn as volatile components
    within 10 days.  This was composed of CO2 and acetonitrile in the
    ratio of 1:4.  One week after treatment of cabbage leaves, 20% of the
    activity was lost as CO2 and acetonitrile in equal proportions.  The
    extracts of the treated plants were investigated for the presence of
    three possible metabolites, MHTA and the S-oxide and S,S-dioxide
    derivatives of methomyl.  There was no evidence for the presence of
    these compounds.  The only terminal residue specifically detected was
    methomyl.  The remainder of the radioactivity was incorporated into
    natural plant components such as lipids and Krebs cycle acids and
    sugars.

         The biodegradation of methomyl was also studied in corn and
    cabbage under field conditions after the application of the
    radiolabelled compound.  The outer leaves of cabbage contained most of
    the radioactive residue of which a small proportion (3-4%) was
    identified as methomyl.  In corn, the outer portions contained most of
    the radioactive residue with about 2 mg methomyl/kg being present
    (Harvey & Reiser, 1973).

         The half-life of methomyl was determined in cotton leaves sampled
    during periods without rainfall after a single application at
    0.75 kg/ha, the maximum label rate.  The foliar half-life was
    estimated to be between 0.6 and 2.2 days, with an average of 1.1 days
    (Eble & Tomic, 1991).  Bull (1974) applied radiolabelled
    14C-methomyl to leaves of tobacco in aqueous solution.  Almost half
    of the applied methomyl penetrated the leaves within the first few
    hours.  Surface residues were largely lost within 48 h and the parent
    compound was the only radioactive component of the unabsorbed dose. 
    The absorbed methomyl was degraded within 8 days (mostly within 48 h). 
    No S-oxide, S,S-dioxide or oxime derivatives were found in the plants,
    the methomyl being degraded to acetonitrile and CO2.  After methomyl
    was applied directly to tobacco leaves, its half-life was 3-7 days
    (Harvey & Reiser, 1973).  Studies describing the decline of
    dislodgeable foliar residues on various crops are reviewed in
    section 5.3.

    4.2.2  Abiotic degradation

         When a 3% solution of methomyl in distilled water was stored for
    168 days, 90% of the compound was recovered at the end of the period. 
    The remainder was recovered as MHTA (Harvey, 1967).

         The hydrolysis of methomyl was studied at pH 5, 7 and 9, at
    concentrations of 10 and 100 mg/litre, and at 25°C.  The compound was
    stable for 30 days at pH 5 and 7 but broke down at pH 9 with a
    half-life of about 30 days.  The hydrolysis product was MHTA
    (Friedman, 1983).

         The photolysis of methomyl was studied at initial concentrations
    of 10 and 100 mg/litre and at pH 5 under UV light.  Methomyl
    photolysed rapidly at both concentrations with a half-life of 2-3 days
    at 100 mg/litre.  The principal photo-product was acetonitrile
    (Harvey, 1983).

         In a study by Swanson (1986), 14C-methomyl was applied to a
    thin layer of a silt loam soil on glass plates and exposed to natural
    sunlight for 30 days at 24-28°C.  The compound decomposed with an
    estimated half-life of 34 days.  The principal decomposition product
    was acetonitrile.  Duplicate preparations, kept in the dark, did not
    decompose.

         Methomyl degraded rapidly in slightly alkaline solution (pH 8.85)
    with a chlorine/methomyl ratio of 10.  The degradation rate increased
    with increasing temperature, increasing chlorine concentration, and
    decreasing pH.  The reaction rate with free chlorine was 1000-fold
    faster than with chloramine. Methomyl degraded to acetic acid,
    methanesulfonic acid and dichloromethylamine after forming methomyl
    sulfoxide and  N-chloromethomyl (Miles & Oshiro, 1990).  Mason et al.
    (1990) also reported that the removal of methomyl can be effectively
    achieved by some disinfectants (Cl2, O3) but not by ClO2.

    4.2.3  Bioaccumulation

         Rainbow trout were exposed to 0.075 and 0.75 mg methomyl per
    litre in a flow-through test system for up to 28 and 21 days,
    respectively, and then placed in clean water (pH 7.3, total hardness
    25 mg CaCO3/litre at 18°C).  At the higher concentration, fish
    tissue contained 0.36-0.45 mg methomyl/kg during the exposure period
    and, at the lower concentration, 0.04-0.07 mg/kg.  Within one day of
    depuration the methomyl tissue levels fell to below 0.02 mg/kg in both
    exposure groups.  There was therefore no indication of bioaccumulation
    of methomyl in these studies (Sleight, 1971).

    4.3  Interaction with other physical, chemical or biological factors

         When 14C-methomyl was incubated with a rumen microorganism
    culture at a level of 1 mg/kg and at 38°C for 24 h, 90% was
    metabolized to a volatile component which was identified as
    acetonitrile by gas chromatography.  Less than 0.1% of the total
    activity was recovered as methomyl or MHTA (Belasco, 1972b).

         No nitrosomethomyl was detected (< 1 µg/kg) when 14Cmethomyl
    (1 mg/kg) was incubated under simulated stomach conditions (pH 2) with
    sodium nitrite (16-20 mg/kg) in a macerate of cured meat for 1 or 3 h
    at 37°C (Han, 1975).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Water

         In 60% of drain water samples from greenhouses containing treated
    plants in an area south of The Hague, The Netherlands,  methomyl could
    not be detected (< 0.1 µg/litre). In the remaining 40% samples its
    concentration was < 1 µg/litre (Leistra et al., 1984).

         Out of 22 404 wells sampled and analysed for methomyl in the US
    EPA pesticide monitoring programme, 85 showed detectable methomyl
    concentrations within the range of trace to 20 µg/litre, i.e. within
    the lifetime health advisory figure of 200 µg/litre (US EPA, 1991).

         After a cedar swamp had been sprayed with Lannate LV formulation
    (29% a.i.) at a rate of 0.28 kg methomyl/ha, no methomyl could be
    detected (< 0.02 mg/litre) in surface water at any time between 1 and
    58 days after treatment (Du Pont, 1978).

    5.1.2  Soil

         Soil samples taken from a tobacco farm in Maryland, USA, after a
    single application of methomyl (Lannate 90% a.i.; 13.4 kg/ha)
    contained 0.6 mg methomyl/kg at 0-15 cm depth after 8 days.  At a
    depth of 15-30 cm, 0.1 mg/kg was detected after 17 days.  No methomyl
    (< 0.02 mg/kg) was detected after 47 days at either level.  Lannate
    is applied as an incorporation to a depth of 10 cm (Pease, 1968).

         Levels of methomyl in soil after an upland forest and a cedar
    swamp had been sprayed with Lannate LV at a rate of 0.28 kg
    methomyl/ha were either very low (< 0.07 mg/kg) or undetectable
    (< 0.02 mg/kg).  No residues were detected (< 0.02 mg/kg) at an
    application of half the above rate (Du Pont, 1978).

    5.1.3  Food crops

         Methomyl is used as a broad spectrum insecticide on many food
    crops, hence low residues may be present at harvesting.  The amount of
    residue at harvest depends upon factors such as the application rate,
    time interval between the last application and harvest, and the type
    of crop. The residue is composed mainly of methomyl itself.  The
    residue levels expected in food crops at harvest can be derived from
    the numerous supervised trials which have been carried out on many
    crops in countries worldwide (FAO/WHO, 1988a,b; 1990a,b).  Pre-harvest
    intervals are also set on the basis of the results of supervised
    trials, e.g. 7 days for lettuce and onions in USA, 1 day for brassicas
    and tomatoes in Australia (FAO/WHO, 1990a,b).

         The decline of methomyl residues on food crops after application
    was demonstrated by the field treatment of broccoli followed by
    harvesting at intervals thereafter.  The results of treatment at
    0.55 kg/ha (6 applications) are shown in Table 3 (Du Pont, 1973).

    Table 3.  The decline of surface and absorbed methomyl residues in
              broccoli (Du Pont, 1973)
                                                       

    Days after treatment              Residue (mg/kg)
                                                       

             1                           1.0

             3                           0.15

             7                           0.04

             10                          0.02
                                                       

         Similar examples of the decline of methomyl residues have been
    shown for lettuce and cauliflower (Braun et al., 1980), celery (Braun
    et al., 1982), wheat (Du Pont, 1973; FAO/WHO, 1988a,b) and tomatoes
    (FAO/WHO, 1990a,b).

         Treated food crops processed after harvesting generally do not
    show a concentration of methomyl residues in the processed fractions.
    Unwashed whole oranges were found to contain 0.96 mg/kg at harvest and
    0.88 mg/kg after washing. The dried peel contained 2.8 mg/kg whereas
    the pulp, juice, cold process oil and molasses contained no detectable
    residue (< 0.02 mg/kg).  Similarly, tomatoes analysed after harvest
    contained 0.38 mg/kg while the processed fractions, wet pomace, dry
    pomace, juice and puree contained < 0.02 mg/kg (Kennedy & Hay, 1991a;
    Marxmiller & Hay, 1991).  Mint oil produced from the distillation of
    methomyl-treated plants and wine produced from treated grapes
    contained no detectable residues (< 0.04 and < 0.02 mg/kg,
    respectively) of methomyl (Kiigemagi et al., 1973; Brodsky, 1991).

    5.1.4  Other crops

         Environmental levels of methomyl on treated crops such as cotton
    and tobacco may be deduced from supervised trials.

         After 14 applications of methomyl at 0.5 kg/ha and two at the
    high rate of 1.65 kg/ha, cotton contained 0.17 mg methomyl/kg 15 days
    after the last application.  Processed fractions showed < 0.02 mg/kg
    in oil, 0.065 mg/kg in meal and 0.14 mg/kg in hulls (Kennedy & Hay,
    1991b).

         The residue levels in tobacco leaves immediately after the
    application of methomyl at the recommended rate of 0.56 kg/ha were 44
    and 88 mg/kg at two sites in the USA.  After five days these levels
    had dropped to 0.7 and 1.4 mg/kg.  Approximately 96% of the methomyl
    was lost during flue-curing (Leidy et al., 1977).

    5.1.5  Dairy products

         There are no reports of methomyl residues in dairy produce.

         Groups of lactating cows (three/group) were dosed methomyl by
    capsule at a rate equivalent to 8, 24 or 80 mg/kg in their feed for
    28 days.  Milk collected during the dosing period and tissues taken at
    termination contained no detectable residues of methomyl or its
    metabolite MHTA.  Acetonitrile was detected in the milk of cows dosed
    with methomyl at 8 mg/kg, the milk concentration of acetonitrile
    reaching a plateau of 0.04-0.1 mg/kg by day 4.  This component was
    also present in liver (0.08 mg/kg) and kidney and muscle (0.04 mg/kg)
    at this dose level.  Acetamide concentrations in milk and tissue of
    cows dosed with 80 mg/kg were the same as those found in control
    animals.  Radiolabel assessment showed that the acetamide derived from
    methomyl was < 1% of the total dose (Powley, 1991). In another study,
    methomyl was fed to cows at 2 or 20 mg/kg in feed and no methomyl
    (< 0.02 mg/kg) was detected in milk over a 30-day period nor in meat
    tissue at termination (Du Pont, 1967).

         The 14C-residue in milk was equivalent to 0.13 mg/kg 4 days
    after two goats had been fed 14C-methomyl at 8 mg/kg diet.  Methomyl
    itself could not be detected.  Total 14C-residues in a range of
    tissues were very low (< 0.001-0.003 mg/kg) (Osman et al., 1983).

    5.1.6  Animal feed

         Some indication of methomyl residues expected in those portions
    of treated crops used for animal feed can be deduced from the
    following studies. Methomyl concentrations were 0.35 mg/kg in forage,
    0.14 mg/kg in cannery waste and < 0.02 mg/kg in kernels from sweet
    corn treated with methomyl at 0.9 kg/ha and harvested 9 days after the
    last of four applications (Harvey & Yates, 1967).  Methomyl residues
    on sweet corn forage harvested immediately after the last of nine
    foliar applications at 0.5 or 1 kg/ha were 0.15-0.60 mg/kg and
    0.2-0.72 mg/kg, respectively (US EPA, 1988).  The residues on samples
    of wheat straw taken 7 days after foliar application of 0.55 kg
    methomyl/ha were < 0.02-6.5 mg/kg, and after 14-18 days they were
    < 0.02-0.8 mg/kg (US EPA, 1988).

    5.2  General population exposure

         Information available on general population exposure is limited
    and derives primarily from only one country.  More complete exposure
    information via various routes specific to regions and countries is
    required to assess the risk of occupational exposure and intake of
    residues.

    5.2.1  Food

         The market baskets collected for the US FDA total diet study
    prior to 1991 consisted of 234 food items.  Of these, a total of 72
    items (69 adult foods, 2 baby foods and water) were analysed by
    methodology known to be capable of determining methomyl. Methomyl was
    detected only in 11 food items collected from 1987 to April 1991 (20
    market basket studies): watermelon, pear, strawberries, grapes,
    cantaloupe, raisins, lettuce, celery, cauliflower, cucumber, and green
    sweet peppers.  The levels detected in these food samples ranged from
    trace to 0.630 mg/kg, well below the tolerances established by US EPA
    (US FDA, 1993a).

         The total number of domestic and imported food samples analysed
    by methodology known to be capable of determining methomyl in US FDA
    regulatory monitoring programmes during the period 1988-1992 was 7765. 
    Of these, methomyl residues were detected only in 112 samples.  Four
    samples were found to be violative: one domestic sample of strawberry
    (4.53 mg/kg) and one  imported cantaloupe (0.28 mg/kg) exceeded the
    USA tolerances and there were two imported samples for which no USA
    tolerances have been established (okra, 0.05 mg/kg and pepino,
    0.46 mg/kg) (US FDA, 1993b).

         Residues in foodstuffs are reduced by domestic processing such as
    washing, peeling and cooking.  For example, 50-90% of methomyl
    residues on celery was removed by trimming (FAO/WHO, 1986).  Methomyl
    residues declined by 70-93% in tomatoes, peas or cabbage after 30 min
    cooking in boiling water in open containers (Holt, 1971).  Methomyl
    was added to spinach puree to give a concentration of 50 mg/kg and
    then processed in closed cans for 40 min at 122°C.  No methomyl was
    detected (< 0.05 mg/kg) at the end of this period (Niven, 1971).

         Methomyl has not been detected in wine or mint oil prepared from
    crops previously treated with methomyl (see section 5.1.3).

         No methomyl could be detected (< 0.02 mg/kg) in eggs or tissues
    of laying hens given 1 or 10 mg methomyl/kg diet for 4 weeks (Sherman,
    1972).

    5.3  Occupational exposure

         A series of studies was carried out to determine worker re-entry
    times after the application of methomyl to grape vines in California,
    USA (Dong et al., 1992; Reeve et al., 1992).  These studies were
    specific to the desert conditions found in California and should not
    be compared to studies on other crops or in other climates. Methomyl
    was applied at different times of the growing season at 1 kg/ha and
    the dislodgeable foliar residues were measured at time intervals after
    application to estimate how long it would take to reach the desired
    level of 0.1 µg/cm2 on the leaves.  Under desert conditions with
    water supplied only by furrow or drip irrigation, it was found that it
    required about 5 days to reach this level in June, when grape girdling
    was carried out, and about 10 days in September, at harvesting
    (Powley, 1989, 1990a,b).

         A worker re-entry study was undertaken to estimate exposure after
    entry into vineyards when dislodgeable foliar residues had fallen to
    0.1 µg methomyl/cm2 or less.  Each worker wore ankle length tights
    (except raisin grape harvesters) and long sleeved T-shirt, both worn
    under normal work clothes.  Each wore a personal air sampling pump and
    two patches were attached to work hats.  Sample patches were worn on
    the thigh and ankle on the normal work clothes by most workers during
    girdling operations.  Work continued for 3-4 h.  Methomyl exposure
    when girdling field grapes ranged from 315-1214 µg/h with highest
    values on the upper body and head.  Exposure was highest to the upper
    body and hands of raisin harvesters where overall daily exposure was
    463-865 µg/h.  Harvesting and packing table grapes resulted in the
    lowest methomyl exposures of 219 and 102 µg/h, respectively. 
    Inhalation exposure was minimal (Merricks, 1990).

         It should be emphasized that the rate of decay of methomyl in the
    Californian studies described above is not representative of the
    situation in grape culture in other areas of the world or for other
    crops, as, due to irrigation and other cultural practices, Californian
    grape vines are quite large and have lush foliage which maximizes
    exposure.  Methomyl does not hydrolyse readily in the hot dry
    desert-like conditions and this gives rise to atypical transfer rates.

         Dislodgeable foliar residue from cotton plants was the subject of
    three studies in Arizona, USA (Cahill et al., 1975; Ware et al, 1978,
    1980).  In each case, methomyl was applied at 0.55 kg/ha and leaf
    samples were taken for analysis of dislodgeable residues up to 96 h
    after. In each study the methomyl residues had declined to 0.1 µg/cm2
    or less within 48 h.

         Dislodgeable foliar residues were determined after spraying mint
    to estimate possible exposure to workers moving irrigation pipes. 
    After spraying methomyl at l kg/ha from the air, dislodgeable residues
    were 1.5 µg/cm2 at 4 h and 0.32 µg/cm2 at 48 h, and, after
    applying 2 kg/ha, residues were 2.3 µg/cm2 at 4 h and 0.6 µg/cm2 at
    48 h (Kiigemagi & Deinzer, 1979).

         A pilot study was undertaken in Thailand with a methomyl 90%
    soluble powder formulation to assess the use of food dyes as markers
    for pesticide exposure.  Pesticide operators prepared and sprayed the
    diluted methomyl formulation containing the dyes on low (broccoli,
    chinese kale), medium (tobacco) or tall (citrus) crops with knapsack
    or high pressure power sprayers.  Measurement of dye content of the
    outer garments showed that exposure occurred mainly to the lower body
    and legs when spraying low crops and mainly to the upper body and arms
    when spraying tall crops.  Some correlation was shown between the
    amounts of methomyl and dye deposited on the outer garments.  However,
    the number of participants (two per group) was too small to draw
    definite conclusions, and more work needs to be done to establish
    these correlations (Ambridge, 1992).

         Methomyl was not detected in air samples from the working zones
    of operators during normal closed transfer, mixing-loading operations. 
    During application, methomyl air concentrations of up to 7.5 µg/m3
    were found in applicator working zones (Knaak et al., 1980).

         In order to establish a post-application re-entry interval for
    workers employed in greenhouse operations, methomyl dislodgeable
    foliar residue data were collected from rose foliage.  It was shown
    that after a single high rate of application of 3.2 kg/ha it took
    nearly 5 days for the dislodgeable residue to decline to the required
    level of 0.1 µg/cm2.  It was estimated that for the application rate
    of 1 kg/ha, the highest normally used for rose treatment, a re-entry
    interval of 48 h would be required (Oswald et al., 1991).

         The concentration of methomyl in greenhouse air was measured
    directly by an atmospheric pressure chemical ionization mass
    spectrometer system.  The atmosphere was monitored during spraying of
    roses and for 26 h thereafter.  Samples taken at head height during
    spraying showed methomyl levels of about 33.1-39.7 µg/m3 (5-6 ppb). 
    A few hours later, at the end of the day's operations, concentrations
    were about 19.9-26.5 µg/m3 (3-4 ppb).  When monitoring resumed the
    following morning the air concentrations were still at about the same
    level indicating that methomyl, deposited in aerosol droplets on the
    roses, had not fully evaporated (Williams et al., 1982).

         Ambient air and breathing zone samples were analysed in four
    greenhouses 1 day before and 7 days after methomyl was sprayed on
    cucumber and tomato plants.  Ambient air methomyl concentrations
    ranged up to 4.7 µg/m3 on the first day after spraying.  Three and

    seven days after spraying, breathing zone methomyl concentrations
    ranged up to 14.5 and 0.7 µg/m3, respectively.  Hand-wash methomyl
    values ranged from 10 to 322 µg/h of work in a greenhouse.  The
    authors considered that dermal exposure, as indicated by the hand-wash
    data, was a more important factor than air exposure and that re-entry
    intervals should be set according to information derived from the
    former (Boleij et al., 1991).

         Ambient air in a pesticide storage building was monitored over a
    3-h period using high volume air samplers and absorption on XAD-4 or
    XE-340 resins. Methomyl was stored in the building as a liquid
    concentrate along with other pesticide formulations.  The average
    methomyl air concentration over the sampling period was 13.7 ng/m3. 
    This represents a value of 0.18 µg/m3 when converted to a 40-h
    working week and can be compared with the ACGIH TLV of 2500 µg/m3
    (Yeboah & Kilgore, 1984).

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS

         The term 14C-methomyl in this section refers to
    S-methyl-[1-14C]-N-[(methylcarbamoyl)oxy] thioacetimidate, unless
    otherwise stated.

    6.1  Absorption

         The absorption of 14C-methomyl was very rapid after oral dosing
    of 5 mg/kg to male or female rats.  About 80% of the activity was
    excreted within 24 h as metabolic products in urine and expired air. 
    Only 2-3% was found in faeces (Harvey et al., 1973; Hawkins et al.,
    1991).

         A similar pattern was seen in the cynomolgus monkey following a
    single 5 mg/kg oral dose.  More than 60% of the dose was eliminated in
    expired air and urine within 24 h as metabolic products.  Only about
    3% of the dose was found in faeces over a period of 168 h after dosing
    (Hawkins et al., 1992).

         In an assessment of dermal penetration, 14C-methomyl was
    applied in acetone to a 1 cm2 shaved area of skin of mice (7-8 weeks
    old) at a rate of 1 mg/kg.  The mice were then placed in metabolism
    chambers and killed for radioactivity measurements at intervals up to
    48 h.  Within 5 min, 14C activity was detected in blood and liver. 
    In 60 min, 2.9% of the original 14C dose was present in blood, 5%
    was in the liver, and 12.9% had been excreted (urine plus CO2 plus
    faeces).  Very little methomyl remained at the application site after
    60 min, when penetration was estimated to be approximately 85%.  The
    half-life, as a measure of penetration rate, was approximately 13 min
    (Shah et al, 1981).

    6.2  Distribution

         After 5 mg 14C-methomyl/kg had been dosed orally to five male
    and five  female rats, 8-9% of the initial activity was found in the
    tissues and carcass 7 days later.  The highest concentration of
    activity was found in blood (2 mg/kg equivalents) with a distribution
    of 3-4 mg/kg in red cells and 0.7-0.9 mg/kg in plasma. The
    radioactivity concentrations were lower in other tissues (< 1 mg per
    kg).  As a proportion of the original dose, blood contained
    approximately 2%, liver 0.4%, gastrointestinal tract 0.6% and other
    individual tissues < 0.1% each. There was no significant difference
    in distribution between males and females (Hawkins et al., 1991).

         14C activity was distributed among a range of tissues after two 
    rats had been fed 200 mg methomyl/kg diet for 8 days and then given
    5 mg 14C-methomyl/kg orally.  Of the 14C dose, 9% was found in the
    tissues and carcass within one day and 10% within 3 days (Harvey et
    al., 1973).

         When cynomolgus monkeys were given a single oral dose of 5 mg
    14C-methomyl/kg, approximately 5% of the radioactivity was retained
    in the tissues after 168 h.  The highest concentrations of activity
    were in the liver (0.7-0.9 mg/kg equivalents), fat (0.4-0.7 mg/kg
    equivalents) and kidney (0.4-0.5 mg/kg equivalents).  Lower
    concentrations found in other tissues were generally higher than blood
    levels of 0.1-0.2 mg/kg equivalents (Hawkins et al., 1992).

         One hour after the dermal applications of 14C-methomyl to mice
    (see section 6.1), 2.9% of the dose was present in blood, 5% in liver
    and 56% in the remaining carcass.  After 8 h the distribution was 6.1%
    in blood, 3.3% in liver, 3.8% in the gastro-intestinal tract and
    smaller amounts (< 1%) in other individual tissues.  The remaining
    carcass contained 15% of the original dose (Shah et al., 1981).

    6.3  Metabolic transformation

         In an initial investigation, two male rats were fed a diet
    containing 200 mg methomyl/kg for 8 days, followed by intra-gastric
    intubation of 1.2 mg 14C-methomyl (=5 mg/kg).  One male rat was
    treated similarly except that the 14C-methomyl was given after 19
    days.  Urinary and volatile metabolite identification was carried out
    1 or 3 days after the 14C dose.  Volatile products, trapped in
    caustic soda solution or in cold traps, were identified as carbon
    dioxide and acetonitrile, the latter confirmed by mass spectroscopy. 
    Countercurrent distribution of the urine showed that nearly all the
    radioactivity was present as polar material.  Methomyl, its
    S,S-dioxide and MHTA were not detected.  The methomyl S-oxide could
    not be detected by TLC (Harvey et al., 1973).

         A more detailed study (Hawkins et al., 1991), with five male and
    five female rats receiving single oral doses of 14C-methomyl
    (5 mg/kg), confirmed that the expired metabolites (over 120 h) were
    carbon dioxide (22%) and acetonitrile (12%).  The radioactive
    components of the 0-24 h urine were separated by reverse phase HPLC,
    ion partition chromatography and TLC. The major metabolite in urine
    was identified by NMR and mass spectroscopy as the mercapturic acid
    derivative of methomyl, equivalent to about 17% of the 14C-dose.
    There were 10 minor components which included, on tentative
    identification, acetonitrile, acetate and methomyl oxime sulfate. 
    Methomyl, MHTA and the anti-isomer form of methomyl were not detected.

         Metabolic pathways for methomyl in the rat include the
    displacement of the S-methyl moiety by glutathione and enzymic
    transformation to give the mercapturic acid derivative.  Another
    pathway involves hydrolysis to give MHTA which is rapidly
    broken down to carbon dioxide (Fig. 1).

         Another proposed pathway involves the conversion of the
    syn-isomer of methomyl (the insecticide form) to its anti-isomer.  The
    latter has been shown to produce acetonitrile as the main volatile
    metabolite when given orally to rats (see section 6.4).  It is
    proposed that the anti-isomer hydrolyses to the anti-MHTA,
    which then undergoes a Beckmann re-arrangement and elimination
    reaction to form acetonitrile (Huhtanen & Dorough, 1976).

         It is also likely that certain metabolic products such as
    acetonitrile undergo further reactions, with the carbon components
    being incorporated into natural body constituents such as fatty acids,
    neutral lipids and glycerol, as shown in ruminants (see section
    4.2.1).

         It is probable that two of the main metabolic pathways also
    operate in the monkey.  When an oral dose of 14C-methomyl
    (5 mg/kg body weight) was given to cynomolgus monkeys, the
    major metabolites were CO2 (32-38%) and acetonitrile (4-7%) in the
    expired air.  These were derived, presumably, by the same processes as
    described for the rat above.  A combination of HPLC and TLC
    characterized 18 radioactive metabolites in urine, with no metabolite
    representing more than 4% of the dose.  Small amounts of acetonitrile,
    acetate, acetamide and MHTA sulfate were among the products found. 
    The mercapturic acid derivative of methomyl (a major rat urinary
    metabolite) accounted for about 1% of the dose.  The presence of these
    minor metabolites are presumably the result of extensive metabolism of
    primary metabolites (Hawkins et al., 1992).

         A lactating cow was dosed twice daily by capsule for 28 days 
    with 14C-methomyl at a rate equivalent to 8 mg/kg in feed.  Milk
    samples were collected each day and selected tissues were taken within
    24 h of the last dose.  Radioactivity appeared in milk within one day
    and reached a plateau of 0.5 mg/kg (equivalents) within 6 days.  This
    activity was mostly due to the reincorporation of the radiolabel into
    fatty acids, lactose and other acetate derived products.  No methomyl
    or MHTA was detected; acetonitrile accounted for about 25% of the
    radioactivity.  The liver showed the greatest concentration of
    radioactivity, equivalent to 9.23 mg/kg; kidney contained only
    2.01 mg/kg and there were lower concentrations in fat and muscle. No
    methomyl was detected in tissue; most of the radioactivity was
    considered to be the result of reincorporation of the radiolabel as
    acetate into natural constituents (Monson & Ryan, 1991).

    FIGURE 1

         A lactating goat was given 14C-methomyl by capsule, twice a
    day, for 10 days at a dose rate equivalent to 20 mg/kg in feed.  Milk,
    blood, urine and faeces were sampled daily and selected tissues taken
    within one day of the last dose.  No methomyl or the metabolite MHTA
    was detected in any of the samples.  Approximately 16% and 7% of the
    activity was excreted in urine and faeces, respectively, and about 8%
    appeared in the milk and 17% in expired air.  The milk activity
    reached a plateau after 3 days and was equivalent to approximately
    2 mg/kg.  At this time the lactose component contained about 11-13% of
    the milk activity.  Hexane extracts, containing the triglyceride
    components, contained 26-37% of the milk activity and the casein
    component 8-9%.  This indicates that methomyl had been completely
    broken down and incorporated into natural constituents of milk.
    Acetonitrile was identified as a volatile metabolite in milk and blood
    (Harvey, 1980).

         The examination of the liver fractions showed that the
    radio-activity derived from methomyl was found in glycerol,
    glycerol-3-phosphate, fatty acids, neutral lipids and insoluble
    protein.  This indicates a metabolic pathway via acetonitrile and
    acetate into the natural occurring constituents in the liver.  The
    breakdown of methomyl and distribution of metabolic products in the
    liver was shown to be similar in the cow (Monson, 1989).

         Acetonitrile, CO2 and reincorporation products derived from
    acetate found after the application of methomyl to plants (section
    4.2.1) are similar to those identified in the above animal studies.

         The proposed metabolic pathway for methomyl in animals is shown
    in Fig. 1.

    6.4  Elimination and excretion

         Rat and monkey studies show that methomyl is very rapidly
    metabolized and eliminated, the processes being largely completed
    within 24 h.

         Rats fed 200 mg methomyl/kg in diet and then given 5 mg
    14C-methomyl/kg orally (see section 6.3 for detail) showed a 50%
    elimination of 14C in expired air in 3 days in the form of carbon
    dioxide and acetonitrile in the proportion of 1:2. Urinary excretion
    of 14C was 27% in one day (Harvey et al, 1973).

         In a more detailed study, where male and female rats were given
    5 mg 14C-methomyl/kg orally (see section 6.3), approximately 53% of
    the radioactivity was excreted in urine over 7 days, 45% of the dose
    being excreted in the first 6 h.  Faecal excretion contributed only
    2-3% over 7 days. The other major path of elimination (over 5 days)
    was via expired air as carbon dioxide (22% of dose) and acetonitrile

    (12% of dose).  Of this, 18% of the dose was expired as CO2 within
    6 h and 10% as acetonitrile in 24 h.  Overall, most of the
    radiolabelled dose (80%) had been eliminated in 24 h with an estimated
    half-life of 5 h.  There was no obvious difference in the amount or
    rate of excretion between males and females.  The single oral dose
    given to these animals (5 mg/kg) produced mild clinical signs of
    cholinesterase inhibition which disappeared within 2 h of dosing
    (Hawkins et al., 1991).

         When methomyl was radiolabelled on the carbonyl group, the
    elimination of 14CO2 was very rapid and equivalent to about 85% of
    the oral dose in male and female rats.  When the labelling was at the
    - 14C=N group, the overall elimination in expired air in 24 h was
    30% in the form of CO2 and acetonitrile (in the proportion of 2:1). 
    When 14C-MHTA was administered in the same way the expired component
    was mainly 14CO2, equivalent to 22% of the dose.  The anti-isomer
    of methomyl mainly produced acetonitrile in the expired air,
    equivalent to 28% of the dose given orally to rats. Rats given the
    anti-MHTA by intraperitoneal injection produced ten times more
    acetonitrile than those given the syn-MHTA.  The urine from rats
    treated orally with 14C-methomyl or MHTA contained 25-35% of the
    radioactivity over a 24-h period (Huhtanen & Dorough, 1976).

         In monkeys given 5 mg 14C-methomyl/kg orally, approximately 32%
    of the dose was excreted in urine in 7 days, with 34% as CO2 and 5%
    as acetonitrile in the expired air.  Most of this was excreted in the
    first 24 h.  Faecal excretion amounted to only 3-4% (Hawkins et al.,
    1992).

         After dermal application of 14C-methomyl to mice (see section
    6.1), the total excretion (urine plus CO2 plus faeces), as a
    proportion of the applied dose, was 0.2% in 15 min, 12.9% in 60 min
    and 54.5% in 480 min (Shah et al., 1981).

    6.5  Retention and turnover

         The absorption, metabolism and excretion of methomyl in the rat
    are very rapid.  No methomyl can be detected within the tissues or
    excretory products within a few hours of dosing.  Most of the dose is
    eliminated within 24 h with an estimated half-life of 5 h (Hawkins et
    al., 1991).  Metabolic products, mainly in urine and expired air, are
    also eliminated rapidly; tissue concentrations are very small and
    lower than blood levels.  There is no evidence for accumulation in
    tissues. A similar picture exists for the metabolism of methomyl in
    ruminant species.

    6.6  Reaction with body components

         Methomyl is a potent direct inhibitor of acetylcholinesterase in
    both insects and mammals.  The carbamylated enzymes undergo rapid
    spontaneous reactivation (see section 7.8.1).

    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

         The results of the single exposure of technical methomyl by the
    oral, dermal and inhalation routes in various species are shown in
    Table 4.

         Methomyl is very toxic by the oral route.  In the rat, the signs
    of toxicity are those expected from a cholinesterase inhibitor and
    include profuse salivation, lacrimation, tremor, abnormal posture,
    pupil constriction, diarrhoea and prostration.  At lethal doses the
    rats died within hours.  Survivors began to recover within several
    hours and had fully recovered within days.  No compound-related
    changes were seen in organs subjected to histopathological
    examination.

         The acute dermal toxicity of methomyl is very low.  No deaths
    occurred in rats or rabbits at the doses shown in Table 4.  The
    compound has high toxicity by the inhalation route in the rat, with
    affected animals showing typical signs of cholinesterase inhibition. 
    No target organ effect was seen upon histopathological examination. 
    An LD50 of approximately 8 mg/kg was obtained when methomyl was
    injected intraperitoneally in rats (Dashiell, 1972).

         The acute oral toxicity of methomyl formulations is in proportion
    to the amount of a.i. present and, therefore, they are less toxic than
    methomyl itself (Table 5). The same pattern is seen with the results
    of acute inhalation studies.  The signs of toxicity in the oral and
    inhalation studies are those shown by the active ingredient.  The
    dermal toxicity of the formulations is very low.

         Ocular toxicity was shown by a solid formulation containing 92.4%
    methomyl when 10 mg was introduced into rabbits' eyes.  Typical
    anticholinesterase effects were seen up to 20 min after treatment,
    including pupillary constriction of the treated eyes, incoordination,
    tremors and profuse salivation.  All of the effects had disappeared by
    the next day (Sarver, 1991g).

    7.2  Short-term exposure

         Six male rats were given methomyl in peanut oil by gavage at a
    dose of 5.1 mg/kg body weight per day, 5 times per week for 2 weeks. 
    The signs of toxicity were the same as those exhibited in acute oral
    studies (section 7.1) but they regressed during the second week of
    dosing.  All animals survived, and there were no compound-related
    histopathological changes (Kaplan & Sherman, 1977).


        Table 4.  Acute toxicity of technical grade methomyl
                                                                                                                                      

    Species       Sex       Route           Vehicle              Testa                   Result                  Reference
                                                                                                                                      

    Rat           M         oral            peanut oil           LD50                    17 mg/kg              Sherman (1966)

    Rat           F         oral            peanut oil           LD50                    23.5 mg/kg            Sherman (1968a)

    Rat           M         oral            water                LD50                    45 mg/kg              Trivits (1979)

    Rat           M         oral            water                LD50                    34 mg/kg              Sarver (1991a)

    Rat           F         oral            water                LD50                    30 mg/kg              Sarver (1991a)

    Rat           M         dermal          water                LD50 abraded skin       > 1000 mg/kg          Morrow (1972)

    Rat           M         inhalation      aerosol              4-h ALC                 0.30 mg/litre         Foster (1966a)

    Rat           M         inhalation      vapour               4-h ALC                 0.04 mg/litre         Foster (1966b)

    Rat           M         inhalation      spray                4-h LC50                0.45 mg/litre         Hornberger
                                                                                                               (1967)

    Rat           M/F       inhalation      aerosol              4-h LC50                0.258 mg/litre        Panepinto
                                                                                                               (1991a)

    Rabbit        M         oral            acetone/             ALD                     30 mg/kg              Sherman (1968c)
                                            peanut oil
                                                                                                                                      

    Table 4. (cont'd).
                                                                                                                                                

    Species       Sex       Route           Vehicle              Testa                   Result                  Reference
                                                                                                                                                

    Rabbit        M/F       dermal          water                LD50 intact skin        > 2000 mg/kg          Sarver (1991b)

    Dog           M         oral            capsule              ALD                     20 mg/kg              Sherman (1968d)

    Guinea-pig    M         oral            acetone/             ALD                     15 mg/kg              Kaplan &
                                            peanut oil                                                         Sherman (1977)

    Monkey        M/F       oral            water                ALD                     40 mg/kg              Kaplan &
                                                                                                               Sherman (1977)
                                                                                                                                                

    a  ALC = approximate lethal concentration;  ALD = approximate lethal dose

    Table 5.  Acute toxicity of some methomyl formulations
                                                                                                                                                

    Formulation       Species    Route                   Vehicle       LD50 (mg/kg) or LC50    Reference
    (% a.i.)                                                           (mg/litre)a
                                                                                                                                                

    Lannate 40 SP     rat        oral                    water         61 (male)               Sarver (1992a)
    (41.6%)                                                            73 (female)

    Lannate 20 L      rat        oral                    methanol      129                     Lheritier (1991a)
    (21.5%)

    Lannate 12.5 L    rat        oral                    water         208                     Sarver (1991c)
    (12.7%)

    Lannate 40 SP     rabbit     dermal (intact skin)    water         > 2000                  Sarver (1992b)
    (41.6%)

    Lannate 20 L      rat        dermal (intact skin)    methanol      > 4000                  Lheritier (1991b)
    (21.5%)

    Lannate 40 SP     rat        inhalation (4 h)        aerosol       0.66                    Kelly (1992)

    Lannate 20 L      rat        inhalation (4 h)        aerosol       1.3                     Jackson et al. (1991)
    (21.5%)

    Lannate 12.5 L    rat        inhalation (4 h)        aerosol       3.7                     Panepinto (1991b)
    (12.7%)
                                                                                                                                                

    a   Results are for both sexes, unless stated otherwise
    

         Groups of 10 male and 10 female rats were fed diets containing 0,
    10, 50, 125/500 (125 mg/kg for 6 weeks, 500 mg/kg for remaining
    period) or 250 mg methomyl/kg for 13 weeks. Assessments included
    haematological, biochemical and histopathological examinations.  There
    were no mortalities nor clinical signs due to treatment in any group. 
    A slight decrease in body weight was seen in males at the two higher
    dose levels and in females at 125/500 mg/kg. This was accompanied by
    lower food consumption.  The only change attributed to methomyl on
    histopathological examination was moderate erythroid hyperplasia in
    the bone marrow of males fed 250 mg/kg. Lower haemoglobin values in
    the males of this group at two months could be linked to this effect. 
    Histopathological examination of animals in the 125/500 mg/kg group
    did not reveal any changes due to treatment.  The noobserved-effect
    level based upon body weight change was considered to be 50 mg/kg
    diet, equivalent to 3.56 mg methomyl/kg body weight per day (Paynter,
    1966; Busey, 1966).

         When groups of four male and four female one-year-old dogs were
    fed diets containing 0, 50, 100 or 400 mg methomyl/kg for 3 months, no
    effects were seen in a range of clinical, haematological, biochemical
    and histopathological assessments (Kaplan & Sherman, 1977).

         A dose of 200 mg methomyl/kg body weight was applied as a 5%
    aqueous solution once a day 5 times per week for 3 weeks to the intact
    or abraded skin of five male, five female rabbits.  Each dose was
    occluded for 6 h and then the site washed with water.  There were no
    mortalities in animals with intact skin; clinical signs included nasal
    discharge, wheezing and diarrhoea.  With abraded skin, signs of
    toxicity, including laboured respiration, salivation and tremors,
    appeared within one hour of dosing, and three animals died, one after
    the first application and the other after the eighth application.  No
    treatment-related changes were seen upon histopathological examination
    (Kaplan & Sherman, 1977).

         Groups of rabbits were treated dermally (intact clipped skin)
    with doses of 0 (10 males, 10 females), 5, 50 (5 males 5 females) or
    500 (10 males, 10 females) mg methomyl/kg body weight per day for 21
    days.  The doses were applied in water each day and occluded for 6 h. 
    Half the males and females in the control and highest dose groups were
    killed at the end of the dosing regime, together with all animals in
    the other groups.  The remaining animals in the control and highest
    dose groups were allowed to recover over a 14-day period and then
    killed.  The only change noted clinically was a greater incidence of
    hyperactivity at 500 mg/kg.  There were no effects on body weight
    gain, haematology, blood biochemistry, organ weights or organ
    histopathology.  Plasma cholinesterase activity was depressed to 36%
    and 55% of normal at day 21 in highest dose males and females,

    respectively.  Brain cholinesterase activity was depressed to 48% and
    68%, respectively, in males and females at this dose, but red cell
    cholinesterase activity, although slightly decreased, was considered
    to be biologically insignificantly affected.  In males, at 50 mg/kg,
    the plasma cholinesterase activity was depressed to 77% and there was
    no inhibition of red blood cell cholinesterase activity of either sex. 
    All the depressed cholinesterase activities had returned to control
    values at the end of the 14-day recovery period.  The
    no-observed-effect level, based upon changes in plasma cholinesterase
    activity, was 5 mg/kg body weight per day in males and 50 mg/kg in
    female rabbits (Brock, 1989).

         Formulations of methomyl have also been tested by repeated dermal
    application to rabbits at doses equivalent to 50 or 100 mg
    methomyl/kg.  No effects were seen after ten daily doses of Lannate L
    (25.5% methomyl). Ten daily doses of Lannate LV (30% methomyl)
    produced mild skin irritation at the higher dose level.  Plasma
    cholinesterase activity was somewhat depressed at both dose levels but
    returned to normal over a 14-day recovery period (McAlack, 1973,
    Edwards, 1980).

         A Lannate dust containing 45% methomyl was the subject of a
    3-month inhalation study in male rats.  Exposure was at 14.8 mg/m3
    for 4 h/day, 5 days/week; the mass median dynamic diameter of the dust
    was 4.4 µm.  There were no effects on body weight, organ weight,
    histopathology or red cell cholinesterase activity.  Plasma
    cholinesterase activity was depressed to about 29% of the
    pre-treatment activity in samples taken 4 h after the last exposure
    (Ta'Naka et al., 1987).

    7.3  Long-term exposure

         Groups of 35 male and 35 female rats were fed diets containing
    methomyl at 0 (2 groups), 50, 100, 200 or 400 mg/kg for 22 months. 
    Five males and 5 females per group were killed at 12 months for gross
    and histopathological examination.  Assessments were made throughout
    the study for clinical condition, body weight, food consumption,
    haematology, blood and urine biochemistry, organ weight and
    histopathology. Growth of males at the highest dose was significantly
    lower than that of controls over the first year.  Growth of males at
    200 mg/kg and females at 400 mg/kg was also lower at this time, but
    not significantly.  Food consumption over the first 26 weeks was
    significantly lower than that of controls for the males fed  200 and
    400 mg/kg.  At 18 and 22 months there was a trend towards lower
    haemoglobin values in treated female groups. Compound-related
    increases in the incidence and severity of extra medullary
    haematopoiesis were observed in the spleen of females fed 200 or
    400 mg/kg. Compound-related changes were also seen in the kidneys of

    both sexes at 400 mg/kg, characterized by vacuolization of epithelial
    cells and hypertrophy of the proximal convoluted tubules.  On the
    basis of the body weight and haematopoietic findings in this study,
    the long-term no-observed-effect level for methomyl in rats was
    considered to be 100 mg/kg diet (Kaplan & Sherman, 1977).

         In a 2-year study on rats, methomyl was fed in the diet to groups
    of 80 males and 80 females at levels of 0, 50, 100 or 400 mg/kg.  The
    animals were observed and weighed regularly, and haematological and
    blood and urine biochemical measurements were made at 3, 6, 12, 18 and
    24 months.  Red cell cholinesterase activity was assayed in additional
    groups at 1, 2 and 4 weeks and  3, 6, 12 and 20 months.  Brain
    cholinesterase activity was assayed at 12 and 20 months.  Extensive
    histopathological examination was performed on animals killed at
    scheduled intervals, on animals dying and on animals killed at the end
    of the study.

         There was a significant reduction in body weight gain in both
    sexes at 400 mg/kg over the first 12 months but not during the
    subsequent 12 months.  There were no clinical signs attributable to
    treatment.  Survival rate was the same among the groups and there was
    an acceptable number of animals at termination (40-50%).  Erythrocyte
    counts, haemoglobin values and haematocrits were significantly lower
    in females at 400 mg/kg.  There were no compound-related changes for
    red cell or brain cholinesterase activity nor for other biochemical
    parameters.  Organ weights were unaffected by treatment. The incidence
    of bone marrow hyperplasia, focal hyperplasia in the adrenal medulla
    and focal degeneration in the adrenal cortex was slightly increased in
    males at 400 mg/kg.  The no-observed-effect level in the rat was
    there-fore confirmed as 100 mg methomyl/kg diet, equivalent to about
    5 mg/kg body weight per day (Kaplan, 1981).

         A comprehensive long-term (2 years) study on the mouse was
    initiated with 80 males and 80 females per group at levels of 0, 50,
    100 and 800 mg methomyl/kg diet.  Because of early high mortality, the
    level of the highest dose group was reduced to 400 mg/kg at week 28
    and then to 200 mg/kg at week 39.  The level of the mid-dose group was
    also reduced to 75 mg/kg at week 39.  Regular clinical observations
    and body weight and food consumption measurements were undertaken.
    Haematological analysis was carried out at 4, 13, 26, 52, 78 and 104
    weeks.  Organ weights were measured and an extensive histopathological
    examination carried out on all animals dying or killed.  The mortality
    rate was higher than that of controls at the highest and medium dose
    levels throughout the study, and was slightly higher, in male mice
    only, at the low dose level in the latter stage of the study. There
    were no clinical findings due to treatment and no effects on body
    weight gain or food consumption.  Some effects were noted on red cell
    parameters such as haemoglobin values and red cell counts during the

    first 26 weeks at the medium and highest dose levels.  However, these
    were not apparent during the remainder of the study, after these dose
    levels had been decreased.  No effects were observed on organ weights
    or microscopic findings.  The no-observed-effect level was considered
    to be 50 mg/kg in diet, equivalent to approximately 10 mg/kg body
    weight per day (Serota et al, 1981).

         A 2-year dog study was initiated with dietary levels of methomyl
    of 0, 50, 100, 400 and 1000 mg/kg with four males and four females per
    group.  After one year, one male and one female from each group was
    killed for interim examination.  Clinical condition was regularly
    observed and routine measurements made on body weight, food
    consumption, and haematological and bio-chemical parameters.  After 2
    years the surviving animals were killed, organs were weighed and a
    histopathological examination was undertaken.

         No clinical signs due to treatment were seen in animals at 50,
    100 and 400 mg/kg.  One highest dose female died after 8 weeks and its
    replacement also died within 18 days after showing compound-related
    toxic signs.  Two males at this dose level exhibited tremors,
    salivation and incoordination during week 13.  Slight to moderate
    anaemia was noted in the highest dose animals at 13 weeks and this
    persisted in one of the males.  No effects were seen on body weight or
    biochemical parameters.  Histopathological effects were noted in the
    kidneys and spleens of animals at 400 and 1000 mg/kg.  Changes in
    kidneys were characterized by increased pigmentation and epithelial
    swelling, and in the spleen as extra-medullary haematopoiesis and
    increased pigmentation.  A minimal to slight increase in bile duct
    proliferation was seen in livers of dogs at 1000 mg/kg, and bone
    marrow activity was also slightly increased in animals at this dose
    level.  The no-observed-effect level was therefore 100 mg/kg diet,
    equivalent to about 3 mg methomyl/kg body weight per day (Kaplan &
    Sherman, 1977).

    7.4  Skin and eye irritation; sensitization

    7.4.1  Skin irritation

         The skin irritation potential of methomyl was evaluated in six
    male rabbits with 0.5 g of the test material, moistened with deionized
    water, applied to the back of each animal.  Each site was covered with
    a semi-occlusive dressing and exposure continued for 4 h.  The skin
    was examined and evaluated 1, 24, 48 and 72 h after the end of the
    exposure period.  No dermal irritation was seen in any of the animals
    during the study and, therefore, methomyl is classified as
    non-irritant to skin (Sarver, 1991d).

         Methomyl formulations were also evaluated for skin irritation
    potential using the same test method as described above.  The
    substances tested were a solid formulation containing 92.4% methomyl
    (Sarver, 1991e) and two liquid formulations containing approximately
    20% and 12.7% methomyl (Clement, 1987a; Sarver, 1991f).  None of the
    formulations irritated rabbit skin.

         In a test on 10 guinea-pigs, methomyl was applied as a 60% paste
    in propylene glycol or as a 26% solution in Cellosolve and the 24-h
    reaction was noted as being mildly irritating (Kaplan & Sherman,
    1977).

    7.4.2  Eye irritation

         Methomyl, either as 10 mg dry powder or 0.1 ml of a 10% solution
    in propylene glycol, was tested in rabbits' eyes (2 per group).  One
    of each pair was washed after 20 sec and examination of each eye made
    at 1, 2, 3, 4 and 6 h after treatment and for up to 6 days thereafter. 
    Only mild conjunctivitis was seen on the day of treatment but no
    corneal injury was noted (Kaplan & Sherman, 1977).

         A solid formulation containing 92.4% methomyl was tested in the
    eyes of six male rabbits.  A quantity of 10 mg was introduced into one
    eye of each rabbit and evaluations of the reaction were undertaken
    after 1, 24, 48 and 72 h.  Pupillary constriction was evident after
    one hour but was not present the next day (see also section 7.1). 
    Only very mild conjunctival chemosis and redness was seen at 24 h
    after treatment and the formulation was considered to be non-irritant
    (Sarver, 1991g).

         Two liquid formulations, containing approximately 20% and 12.7%
    methomyl, respectively, were tested for eye irritancy using the method
    described in the previous paragraph.  In both cases, the formulation
    produced ocular irritation in the form of conjunctival redness and
    chemosis, iritis and corneal opacity within one hour and were
    classified as irritant.  These effects had disappeared after 21 days.
    (Clement, 1987b;  Sarver, 1991h).

    7.4.3  Skin sensitization

         In a test to evaluate the skin sensitization potential of
    methomyl, the material was applied as a paste to the abraded skin of
    five guinea-pigs 3 times a week for 3 weeks; five other guinea-pigs
    received four intradermal injections of 0.1 ml of a 1% solution.  The
    animals were then challenged after a 2-week rest period.  Methomyl was
    shown not to be a skin sensitizer in this test (Kaplan & Sherman,
    1977).

         A closed-patch repeated insult dermal sensitization evaluation
    (Beuhler test) was undertaken in guinea-pigs with technical methomyl. 
    The test compound (300 mg), moistened with water, was applied to the
    intact skin of each of 10 males and 10 females for 6 h once a week for
    3 weeks.  Two weeks after the last induction treatment, the animals
    were challenged with another 300 mg methomyl for 6 h.  No erythema was
    observed in either the induction or challenge phases, and therefore
    methomyl did not produce delayed contact sensitivity in the
    guinea-pig.  Positive control animals treated with DNCB produced the
    expected sensitization responses (Armondi, 1991a).

         A solid formulation containing 94.2% methomyl, subjected to the
    evaluation described in the previous paragraph, also failed to produce
    delayed contact hypersensitivity in guinea-pigs (Armondi, 1991b).  The
    same result was obtained with a liquid formulation containing 21.5%
    methomyl when given at 0.5 ml per application (Mercier, 1991). 
    Another liquid formulation containing 12.7% methomyl was tested in the
    Magnusson-Kligman guinea-pig sensitization maximization procedure and
    was found to be a moderate skin sensitizer under the conditions of the
    test (Armondi, 1992).

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

    7.5.1  Embryotoxicity and teratogenicity

         Teratogenicity studies have been undertaken in the rat and
    rabbit.

         Pregnant rats (25 per group) were fed 0, 50, 100 or 400 mg
    methomyl/kg diet during days 6-15 of gestation.  The dams were
    observed and weighed regularly and then killed on day 21 of gestation. 
    At that time the uterus was removed, and the number of corpora lutea,
    implantation sites, live and dead fetuses, resorptions and weight of
    live fetuses were recorded.  About one half of the fetuses from each
    litter were taken for skeletal examination and the remainder for soft
    tissue examination.  The pregnant rats at 400 mg/kg had significantly
    lower body weight and ate less food than those in the control group. 
    There were no clinical signs of toxicity and all rats survived the
    test period.  Parameters of pregnancy and fetal development, such as
    the number of litters with partial or total resorptions and fetal
    weight, were not affected in the test groups compared to controls. 
    There were no treatment-related abnormalities in the fetuses. 
    Methomyl was therefore not embryotoxic or teratogenic in the rat at
    levels up to 400 mg/kg diet, equivalent to 34 mg/kg body weight per
    day (Rogers et al., 1978).

         Groups of 20 pregnant rabbits were given 0, 2, 6 or 16 mg
    methomyl/kg body weight per day by gavage on days 7-19 of gestation. 
    The animals were observed and weighed regularly and killed on day 29. 
    The uteruses were then examined for pregnancy, number of
    implantations, early and late resorptions and live or dead fetuses. 

    Delivered pups were weighed and examined for visceral or skeletal
    abnormality.  One pregnant rabbit at 6 mg/kg died, probably due to
    gavage error.  At 16 mg/kg there were seven deaths during the test
    period due to the compound.  Clinical signs at the highest dose level
    included tremors, hyperactivity, excessive salivation, aggression and
    convulsions.  The no-observed-effect level for maternal toxicity was
    therefore 6 mg/kg body weight per day.  There was no effect on
    pregnancy rate or on the average numbers of corpora lutea,
    implantations, resorptions or live fetuses per dam in treated groups
    compared to controls.  There were no gross external visceral or
    skeletal variations due to treatment.  Methomyl is therefore not
    embryotoxic or teratogenic to the rabbit at doses up to 16 mg/kg, at
    which dose maternal toxicity occurred (Christian et al., 1983).

         In another study, pregnant rabbits (12 per group) were fed diets
    containing up to 100 mg methomyl/kg.  The pregnancy rate was low in
    all groups, including controls.  No effects were noted on a range of
    parameters including reproductive indices, fetal body weight or
    visceral and skeletal abnormalities.  However, due to experimental
    inadequacies the results are difficult to assess (FAO/WHO, 1987).

    7.5.2  Reproduction studies

         A three-generation (two litters per generation) rat study was
    undertaken to test the potential reproductive effects of methomyl (Lu,
    1983). The compound was fed at levels of 0, 50 or 100 mg/kg diet to 10
    males and 20 females for approximately 90 days post weaning prior to
    first mating to produce the F1a litter.  Test diets were fed through
    to subsequent re-mating to produce the F1b litter.  Ten males and 20
    females per group were then selected from the F1b litter and
    continued on their respective diets for approximately 90 days to
    produce F2a and then F2b litters.  The same procedure was used to
    produce subsequent litters of the next generation.  Records were kept
    of all matings, number of pregnancies, number of young in each litter
    born alive or dead, the body weight of offspring at weaning, and the
    respective reproduction and lactation indices.  Ten males and 10
    female offspring were selected from each group of the F3b litter for
    histopathological examination.  Methomyl did not affect the
    reproductive performance of rats in this study.  There were no effects
    on fertility, gestation or lactation and no compound-related
    abnormalities on gross examination.  No treatment related changes were
    seen upon histopathological examination of tissues from the offspring
    in the F3b litter (Kaplan & Sherman, 1977).

         A two-generation rat study was also carried out using high
    dietary levels of methomyl (600 and 1200 mg/kg) as well as a lower
    level of 75 mg/kg.  The F0 parents (13 males, 26 females) were mated
    after 100 days treatment and the F1 parents (20 males, 40 females)
    after a minimum of 120 days.  Spermatogenesis (based on sperm count)
    was measured on adult males in both generations after breeding, in
    addition to the standard assessments of reproductive performance. 
    Histopathological examination was undertaken on a selection of tissues
    from parents and pups in both generations.  Body weight depression in
    parents, seen at all or some stages during treatment at 600 and
    1200 mg/kg in both generations and at 75 mg/kg in the F1 generation,
    was probably related to lower food intake.  Reduced red blood cell
    counts were seen in females at the highest dose level, together with a
    small (15-25%) depression in plasma cholinesterase activity in both
    sexes at this level.  Decreases in litter size and live births were
    shown for the highest dose F0 group and for all F1 groups for
    which a clear no-observed-effect level was not established.  Survival
    during lactation in F1 pups (from F0 parents) was reduced at the
    highest dose level, as was survival in highest dose F2 pups during
    early lactation up to day 4.  Pup body weight was slightly reduced at
    75 mg/kg, significantly reduced at the two higher levels in the F1
    generations and reduced at the 600 and 1200 mg/kg levels in the F2
    generation.  No histopathological changes due to treatment were seen
    in any of the tissues examined in parents or offspring.  No effects on
    the reproductive parameters of fertility indices, gestation length or
    male sperm counts were seen at dose levels up to and including 1200 mg
    methomyl/kg in diet (Lu, 1983).

    7.6  Mutagenicity

         Numerous  in vitro mutagenicity assays, to various end-points,
    have been carried out on methomyl by several investigators (Table 6). 
    Methomyl did not show mutagenicity or cause primary DNA damage in
    bacterial or mammalian cells  in vitro.  It showed cytogenetic
    potential in human lymphocytes  in vitro as indicated by an increase
    in micronuclei and chromosomal aberrations.

         In an  in vivo study, the clastogenic potential of methomyl was
    assessed by its ability to cause numerical and structural chromosomal
    aberrations in rat bone marrow cells.  Single doses of methomyl were
    given by gavage to groups of 15 male and 15 female rats at doses of 2,
    6 or 20 mg/kg body weight; five males and five females were killed at
    6, 24 and 48 h after dosing and the bone marrow cells harvested. These
    were examined for chromatid and chromosome breaks and for gaps and
    other aberrations.  The results showed that there was no significant
    increase in the frequency of chromosomal aberrations and no
    significant differences between the chromosome numbers and the mitotic
    indices of the dosed groups and the controls (Farrow et al, 1984).


        Table 6.  Summary of results of in vitro mutagenicity assays and related end-point studies on methomyl
                                                                                                                                                

    Test                   Organism                     Activation +    Dose range             Mutagenic        Reference
                                                        and/or -c                              potential
                                                                                                                                                

    Prokaryotes

    Point mutation       Salmonella typhimurium         -               50 nM                  negative      Blevins et al. (1977a)
                         (5 strains)a

    Point mutation       S. typhimurium (5 strains)     + and -         up to 5000 µg/plate    negative      Moriya et al. (1983)
                         Escherichia coli (WP2hcr)      + and -                                negative

    Point mutation       S. typhimurium (5 strains)     + and -         up to 1 mg/plate       negative      Waters et al. 1982

    Point mutation       E. coli, WP2uvr A              + and -         up to 1 mg/plate       negative      Waters et al. 1982

    DNA damage           E. coli pol A                  -               1 mg/disc              negative      Waters et al. 1982
                         W3100, p 3478

    DNA damage           Bacillus subtil recM45         -               1 mg/disc              negative      Waters et al. 1982

    Yeast

    DNA damage           Saccharomyces cerevisiae       + and -         1-3.5%                 negative      Waters et al. 1982
                         D3

    Mammalian cells

    DNA damage           Human lung fibroblast WI-38    + and -         10-7-10-3M             negative      Waters et al. 1982

    DNA damage           Rat hepatocytes (UDS)          -               1 µM-75 mM             negative      Vincent (1985)
                                                                                                                                                

    Table 6 (cont'd).
                                                                                                                                                

    Test                   Organism                     Activation +    Dose range             Mutagenic        Reference
                                                        and/or -c                              potential
                                                                                                                                                

    DNA damage           Human skin cell DNA            -               10-5M                  negative      Blevins et al. (1977b)

    Gene mutation        Chinese hamster V79 cells      + and -         1-10 mM                negative      Wojciechowski et al. (1982)

    Gene mutation        Chinese hamster ovary          -               10-55 mM               negative      McCooey et al. (1984)
                         (CHO) cells, HGPRT             +               100-350 mM

    Chromosome           Human lymphocytesb             NA              0.02-0.54 mM           positive      Bonatti et al. (1994)
    aberrations          (whole blood culture)

    Sister-chromatid     Human lymphocytesb             NA              0.02-0.54 mM           negative      Bonatti et al. (1994)
    exchange             (whole blood culture)

    Micronuclei          Human lymphocytesb             NA              0.01-0.09 mM           positive      Bonatti et al. (1994)
                         (whole blood culture)

    DNA single strand    Human lymphocytesb             NA              0.06-2 mM              negative      Bonatti et al. (1994)
    breaks               (whole blood culture)

    DNA oxidative        Human lymphocytesb             NA              0.25 - 1 mM            negative      Bonatti et al (1994)
    damage               (whole blood culture)
                                                                                                                                                

    a   Plate incorporation and spot tests
    b   The metabolic activity of the cell cultures was demonstrated by the positive control response
    c   NA = not applicable
    
         Methomyl was tested in the sex-linked recessive lethal assay with
     Drosophila melanogaster at concentrations of 4 and 10 mg per litre
    in the test medium.  No increase in mutation rate was observed in this
    assay (Waters et al., 1982).

          A formulation (Lannate 20) containing 20% methomyl, but of
    otherwise unstated composition, caused an increase in the number of
    sex-linked recessive lethals, but with no observed translocations. 
    The same formulation increased the incidence of abnormal sperm and
    frequency of chromosomal aberrations in mice (Hemavathy &
    Krishnamurthy, 1987a,b).

    7.7  Carcinogenicity

         The carcinogenic potential of methomyl was assessed in the
    long-term rat and mouse studies already described in section 7.3.

         In the earliest study, groups of 35 male and 35 female rats were
    fed 0 (2 groups), 50, 100, 200 or 400 mg methomyl/kg diet for 22
    months.  No differences were seen in the incidence of neoplastic
    lesions between control and treated groups (Kaplan & Sherman, 1977).

         In the more recent rat study, groups of 80 males and 80 females
    were fed 0, 50, 100 or 400 mg methomyl/kg diet for 2 years.  The
    mortality rates were similar in all groups and there was an overall
    survival of 40-50% by the end of the study. More than 30 tissues/rat
    were examined microscopically from animals killed or dying during the
    study and at interim and terminal sacrifice.  There was no indication
    of any differences between groups in the appearance of any individual
    tumour nor were there any differences between groups for the number of
    tumour-bearing rats or those with benign or malignant tumours (Kaplan,
    1981).

         The 2-year mouse study was initiated at dietary levels of 0, 50,
    100 and 800 mg/kg with groups of 80 males and 80 females.  By week 39
    the highest dose level had been reduced to 200 mg/kg and the 100 mg/kg
    level to 75 mg/kg (see section 7.3 for details).  Mortality was higher
    in the highest dose male and female groups than in controls throughout
    the study and was also somewhat higher in the mid-dose group. 
    Adequate numbers of mice survived to the termination of the study
    (30-50% for female groups and 38-68% for male groups). 
    Histopathological examination on more than 30 tissues per mouse was
    undertaken on animals killed or dying during the study and at terminal
    sacrifice.  There were no differences between groups for the numbers
    of tumour-bearing mice or those with benign or malignant tumours
    (Serota et al., 1981).

         Methomyl did not transform hamster embryo cells in a
    trans-placental host-mediated assay, nor did the cultured cells from
    this assay induce tumours when injected subcutaneously into young
    adult nude mice (Quarles et al., 1979).

    7.8  Other special studies

    7.8.1  Cholinesterase studies in vivo and in vitro

         Due attention must be given to the measurement of cholinesterase
    activity in blood and brain samples because of the fast spontaneous
    reactivation of the methomyl-inhibited enzyme.  It is important to
    analyse samples in the minimum possible time after sampling and to use
    an analytical method which requires the minimum of sample dilution and
    shortest assay time.  If these criteria are not followed then
    cholinesterase inhibition due to methomyl can be misinterpreted.

         In groups of rats fed 0, 50, 100, 200, 400 or 800 mg methomyl per
    kg diet for 79 days, only those fed the highest dose showed blood
    acetylcholinesterase activity inhibition as assayed by the Ellman
    method.  Males showed blood cholinesterase activity inhibition of
    25-40% early in the study (by 11 days) while females showed this
    inhibition towards the end of the study period (Singles, 1970a).  In
    an extension of this study, the blood acetyl-cholinesterase activity
    of rats fed 400 or 800 mg/kg was assayed by the Ellman method and a pH
    stat method after 5 months of feeding.  In neither group was there an
    effect on blood acetyl-cholinesterase activity (Singles, 1970b).

         Methomyl was fed to groups of rats in the diet at levels of 0,
    100, 400 or 800 mg/kg, and blood was taken for red cell and plasma
    acetylcholinesterase activity assay at 1, 7, 14, 21 and 28 days. 
    Brain acetylcholinesterase activity was also measured on rats at 14
    and 29 days.  All assays were undertaken by the Ellman method.  There
    were small depressions of acetylcholinesterase activity (up to 20%) in
    red cells and plasma of males and females at 800 mg/kg.  Brain
    acetylcholinesterase activity was also slightly depressed (<17%) at
    this dose level.  There were no consistent findings of
    acetylcholinesterase inhibition at the two lower levels of 100 and
    400 mg/kg (Barnes, 1978).

         Lannate, containing 90% methomyl, was given to 14 male rats at
    41 mg/kg body weight by oral intubation each day for 8 successive
    days.  The animals were killed 24 h after the last dose and blood was
    taken for the assay of serum cholinesterase activity by a colorimetric
    method.  The activity was depressed by 40% compared to controls
    (Borady et al., 1983).

         Cholinesterase activity in plasma and red cells of rats was
    assayed after the dermal application of methomyl.  Four groups of rats
    were treated dermally with 200 mg methomyl per rat and blood samples
    were collected 2, 4, 6 and 24 h after treatment.  Plasma
    cholinesterase activity was markedly reduced at each time interval

    compared to controls (22-50% of control value) while red cell
    cholinesterase activity was less affected (80-91% of control value). 
    Groups of rats were also treated dermally with 25 or 100 mg per rat
    and blood was collected at 24 and 72 h after treatment.  Plasma
    cholinesterase activity was depressed at both levels and at both time
    intervals, but red cell acetylcholinesterase was unaffected (Henry,
    1981).

         Lannate powder, containing 45% methomyl, was the subject of
    inhalation studies using a single 4-h exposure to 9.9 mg/m3 or
    repeated exposures to 14.8 mg/m3 (see section 7.2 for details). 
    Plasma cholinesterase activity was markedly depressed (by 50%) for 4 h
    after the single exposure, but showed recovery almost to the control
    value within 20 h.  Red cell cholinesterase activity was not
    inhibited.  Plasma cholinesterase activity was less affected (29%
    depression) 4 h after the last of the repeat exposures than after the
    single exposure (Ta'Naka et al., 1987).

         The I50 value (the molar concentration of inhibitor giving 50%
    reduction in enzyme activity in given experimental conditions) for
    methomyl was determined  in vitro for human and rat red blood cell
    acetylcholinesterase activity using a modified Ellman method.  Human
    acetylcholinesterase was approximately six times more sensitive to
    methomyl's action than rat acetylcholinesterase (I50 values of
    0.265 × 10-5 mol/litre and 1.56 × 10-5 mol/litre, respect-ively). 
    Regeneration studies using a gel filtration method showed that
    methomyl-inhibited rat acetylcholinesterase regenerates at a faster
    rate than the human enzyme, with half-lives of 26.6 and 38.0 min,
    respectively (Carakostas, 1987).

    7.8.2  Neurotoxicity

         Hens given a single oral (LD50) dose of 28 mg methomyl/kg
    either died within 10 min or survived.  Survivors showed toxic signs
    of lacrimation and salivation, but no evidence of wing or leg
    paralysis.  After a 21-day recovery period, no abnormalities were
    observed upon histopathological examination of the sciatic nerve. 
    Doses much higher than the oral LD50 (up to 200 mg/kg) were given to
    hens without causing mortality after they had been pre-treated with
    atropine sulfate subcutaneously at 10 mg/kg.  Wing or leg paralysis
    was not observed and there were no histopathological abnormalities in
    the sciatic nerve after a 21-day recovery period.  Birds treated with
    tri- o-cresyl phosphate (TOCP) at 500 mg/kg showed the leg paralysis
    and sciatic nerve degeneration expected of a positive control
    substance (Krauss & Stula, 1967).

    7.8.3  Potentiation studies

         Potentiating properties were determined by administering one-half
    the oral LD50 of methomyl to rats, followed immediately by one-half
    the LD50 of another anticholinesterase pesticide, and then recording
    the resultant mortality over 14 days.  Out of 18 pesticides tested,
    only Sevin and Ronnel showed the ability to increase mortality
    indicative of a potentiation effect (Sherman, 1967). In another study,
    the inhibition of cholinesterase activity in rat blood after the oral
    administration of methomyl alone or in combination with another
    anticholinesterase pesticide was used to measure potentiating effects. 
    Methomyl in combination with methyl parathion or phosdrin was shown to
    be potentiating, while antagonism occurred when it was combined with
    dimethoate (Henry, 1975).

         Rats (10 per sex and per group) were given methomyl at 200 mg/kg
    diet and ethanol as a 10% aqueous solution, either separately or
    together, for a period of 12 weeks.  There was some evidence of
    increased effects as a result of the combined administration resulting
    in decreased body weights from weeks 2 (females) and 4 (males) and
    increased relative organ weights for adrenals (males) and kidneys
    (females).  In male rats, the combination of the two compounds
    increased hepatic triglycerides and free fatty acids and decreased
    brain acetylcholinesterase activity more than that expected from
    either compound alone (Antal et al., 1979).  Ethanol administered in
    the diet to rats, at a level equivalent to 25% of the calorie intake,
    did not potentiate erythrocyte acetylcholinesterase inhibition by
    methomyl coadministration at 200 mg/kg in the diet (Bracy et al.,
    1979).

         In female rats only, the combination of methomyl and caffeine
    retarded growth, increased the relative weight of kidneys, spleen,
    adrenals, liver and heart, depressed glucose-6-phosphate dehydrogenase
    activity, and increased aniline hydroxylase and glucose-6-phosphatase
    activity (Bedö & Cieleszky, 1980).

    7.8.4  Antidote studies

         The antidotal properties of several agents against the toxicity
    of methomyl have been examined in a number of species.

         Potential antidotes were administered within one minute after
    oral lethal doses of methomyl (30 or 60 mg/kg) were given to rats.  Of
    the agents used, atropine sulfate given intraperitoneally as a single
    dose of 50 mg/kg proved to be the most effective antidote.  Other
    agents used which were less effective or ineffective were
    pyridine-2-aldoxime methiodide (PAM) and tetra-ethylammonium chloride
    (TEAC) (Sherman, 1968a).  Rats were also used in a study of the
    effectiveness of obidoxime or  N-methyl-pyridinium-2-aldoxime

    methane-sulfonate (P2S) as antidotes alone or in combination with
    atropine sulfate.  Methomyl was injected subcutaneously as solutions
    of logarithmically graded concentrations (1 ml/kg body weight), and at
    the onset of signs of toxicity atropine sulfate (17.4 mg/kg), P2S
    (50 mg/kg) and obidoxime (90 mg/kg) were injected subcutaneously
    either alone or in a combination.  Lethality was reduced by atropine
    sulfate or P2S but obidoxime was ineffective.  Atropine sulfate in
    combination with P2S also was effective (Natoff & Reiff, 1973).

         Mice fed a lethal dose of 100 mg methomyl/kg in pellets and then
    given TEAC by injection 10 min later survived, and resumed normal
    activity within another 10 min (Andrews & Miskus, 1968).  Atropine
    sulfate (50 mg/kg intraperitoneal) was shown to have antidotal
    activity in guinea-pigs given methomyl orally at lethal single doses
    of 15-60 mg/kg (Sherman, 1968b).  Dogs given a single oral dose of 10
    or 20 mg methomyl/kg by capsule were protected against the toxic
    effects if atropine sulfate was given very quickly, i.e. within a few
    minutes.  The antidote was more effective when given intravenously
    than when given intramuscularly or orally (Sherman, 1968c).

         The antidotal effectiveness of atropine administered
    intravenously or orally at 1 or 10 mg/kg and hexamethonium or TEAC
    given intravenously at 10 mg/kg was evaluated in rhesus monkeys dosed
    with 20 or 40 mg methomyl/kg orally. Atropine at 1 mg/kg, given
    intravenously or orally, was effective as an antidote for the
    sublethal dose of 20 mg methomyl/kg.  Atropine at 10 mg/kg orally,
    administered immediately after the appearance of toxic signs, was an
    effective antidote for the lethal dose of 40 mg methomyl/kg.  Recovery
    occurred within 2-5 h of the methomyl dose.  TEAC at 10 mg/kg
    (intravenous) also prevented the death of one monkey after a lethal
    dose of methomyl, although recovery took longer than after atropine. 
    Hexamethonium did not appear to be very effective (Teeters, 1968).

    7.8.5  Other studies

         Lannate (90% methomyl) was given to 14 male rats at the high dose
    level of 41 mg/kg by intubation each day for 8 days and the animals
    were killed 24 h after the last dose for hepatic and serum assays. 
    Liver weight was not increased, nor was there histopathological
    evidence of fatty deposit, but total lipids including cholesterol and
    phospholipids were increased.  The treatment also increased the level
    of serum triglycerides, phospholipids and free fatty acids and
    increased the activity of GOT, GPT and alkaline phosphatase enzymes
    (Borady et al., 1983).  Lung triglyceride, cholesterol and
    phospholipid contents were not affected when rats were exposed to
    Lannate (45% methomyl) dust at 14.8 mg/m3 by inhalation for 4 h/day,
    5 days/week for 3 months (Ta'Naka et al, 1987).

         Single oral doses of 2 or 10 mg methomyl/kg increased pancreatic
    chymotrypsin, lipase and amylase activities in male and female rats. 
    Rats fed 100, 400 or 800 mg/kg diet for 10 days showed elevated serum
    cholesterol in females only.  Hepatic aminopyrine demethylase and
    aniline hydroxylase activities were increased in female rats at 400
    and 800 mg/kg.  When rats were given 100 or 200 mg/kg diet, females
    fed 200 mg/kg showed elevation of total serum lipids and cholesterol. 
    The females also showed decreased hepatic glucose-6-phosphatase
    activity and vitamin A at this level (Bedö & Cieleszky, 1980).

         The effect of methomyl on a number of serum constituents was
    studied in rats given oral doses of 6.8 mg/kg per day, 6 days/week for
    4 weeks.  Increases were seen over the 4-week period for serum
    glucose, cholesterol, GOT and GPT, while decreases were seen for serum
    total protein albumin, globulin and cholinesterase activity. However,
    since control values did not seem to be available for the 4-week
    period, it was difficult to evaluate the significance of the results
    for methomyl (Saleh, 1990a,b,c).

    7.9  Factors modifying toxicity

         It has been shown that synthesized nitrosomethomyl is mutagenic
     in vitro and is capable of producing stomach tumours in rats
    (Blevins et al., 1977a,b; Lijinsky & Schmahl, 1978).  However, when
    methomyl is incubated with nitrite and macerated meat under simulated
    stomach conditions, there is no evidence that nitrosomethomyl is
    formed (see section 4.3).

    7.10  Mechanisms of toxicity - mode of action

          As a member of the carbamate class of compounds, methomyl has a
    well-known mode of action via inhibition of the enzyme
    acetylcholinesterase at nerve junctions.  A detailed description of
    the mechanism of action of carbamates on cholinesterases is given in
    Environmental Health Criteria 64: Carbamate pesticides: a general
    introduction (IPCS, 1986).  Studies with methomyl show that the onset
    of toxic action is rapid and that, in common with many other
    carbamates, the toxic effect is rapidly reversible.  Because of this,
    it is important to use appropriate assay methods when measuring
    cholinesterase activities during toxicity studies.  Failure to allow
    for the rapid reversibility of the action can lead to underestimation
    of enzyme inhibition.

         The acute toxic action of methomyl is characterized by signs of
    poisoning typical of anticholinesterase action, i.e. lacrimation,
    profuse salivation, tremor and pupil constriction.  Surviving animals
    quickly show signs of recovery, often within hours.  The toxic action
    can be countered by the anticholinergic antidote atropine sulfate. 
    The potency of methomyl is greatest when given by the oral or
    inhalation routes of administration.  It has very low acute toxicity
    when given dermally, presumably because during the slower absorption
    phase there is time for recovery from toxic action and thus the effect
    is never fully exerted.

    8.  EFFECTS ON HUMANS

    8.1  General population

    8.1.1  Accidental and suicidal poisoning

         Five Jamaican fishermen prepared a meal to which they
    accidentally added methomyl instead of salt.  Within minutes of eating
    the meal, three of the men were badly affected, twitching, trembling
    and frothing at the mouth, and died within 3 h.  One of the other two
    also showed toxic symptoms, while the other was unaffected.  Both
    survivors were given atropine and the symptomatic patient recovered
    within 2 h after treatment.  Postmortem examination of the dead men
    revealed highly congested stomach lining, lungs, trachea and bronchi. 
    Analysis showed that part of the meal (roti) contained about 1%
    methomyl.  It was estimated that the victims had consumed about
    12-15 mg methomyl/kg (Liddle et al., 1979).

         A 31-year-old woman committed suicide, using a methomyl
    preparation, together with her three children, one of whom (a
    9-year-old son) survived.  Postmortem examination showed congestion of
    the stomach mucous membranes and the lungs.  Analysis of organs of the
    mother and a 6-year-old son showed highest methomyl concentrations in
    the liver (15.4 and 56.5 mg/kg, respectively).  Large amounts of
    methomyl were present in the stomach contents and it was estimated
    that the doses were 55 mg/kg for the mother and 13 mg/kg for the son
    (Araki et al., 1982).

         A woman attempted suicide by ingesting about 2.25 g methomyl. 
    After 6 h, methomyl was present in the blood at a concentration of
    1.61 mg/kg and in the urine at 10.9 mg/litre; at 15 h the levels were
    0.04 mg/kg and 0.25 mg/litre, respectively, and at 22 h methomyl could
    not be detected (Noda, 1984).

         Symptoms and treatment were described for 11 patients who had
    suffered methomyl poisoning in Spain over a 5-year period. 
    Intoxication was accidental in six cases and suicidal in the other
    five.  The time interval between exposure and admission for treatment
    averaged 2.8 h.  All of the subjects showed cholinergic symptoms;
    plasma cholinesterase activity was normal in four cases and moderately
    reduced in the others. Treatments applied included gastric lavage,
    washing the skin, administration of activated charcoal and small doses
    of atropine, according to the symptoms involved.  All the patients
    recovered within 24-48 h (Martinez-Chuecos et al., 1990).

         A blood level of 0.57 mg methomyl/litre was measured in a pilot
    who had died as a result of a crash while spraying a solution of
    methomyl and chlorothalonil in methanol.  Analysis was not undertaken
    for chlorothalonil and methanol (Driskell et al., 1991).

         A 79-year-old man and his 73-year-old wife attempted suicide by
    ingesting methomyl powder.  The woman died within 19 h but the husband
    survived after treatment by gastrolavage, followed by administration
    of atropine sulfate.  The serum methomyl concentration in the woman
    was 44 mg/kg 1 h after ingestion and 0.2 mg/kg in the blood at
    autopsy.  The methomyl blood concentration of the man was
    0.01-0.1 mg/kg 28 h after ingestion (Miyazaki et al., 1989).

    8.2  Adverse effects of occupational exposure

         Pesticide operators were reported to be affected after handling
    powder formulations of methomyl.  In one case, an operator mixed a
    powder formulation and sprayed vegetables without taking any special
    precautions.  He displayed poisoning symptoms within 1 h.  His blood
    cholinesterase activity had decreased to 40% of normal after 12 h but
    had recovered to within 80% of normal after 36 h.  Other operators, a
    mixer-loader, pilot and markers, using recommended safety precautions,
    did not show any effects on their red cell or plasma cholinesterase
    activities after handling liquid formulations and subsequent aerial
    application of methomyl (Simpson & Bermingham, 1977).

         In a survey of agricultural applicators in California, USA, in
    1982-1989, methomyl was reported to be involved in 129 out of 5371
    exposure-related illnesses due to pesticides.  For the period
    1982-1985 and for the same area, methomyl was considered responsible
    for 47 illnesses out of 238 reported cases. Exposure was described as
    either short term (< 3 days), longer term (> 3 days) or accidental
    (Brown et al., 1989).  In 1986, in a summary of reported
    pesticide-related illnesses and injuries in California, methomyl was
    identified as the probable causative agent in 7 out of 1065 confirmed
    occupational cases.  These cases were described as "..having some
    likelihood of being pesticide related" (Edmiston & Maddy, 1987).

         An investigation of workers in a pesticide formulation plant
    revealed that 11 out of 102 workers had been hospitalized due to
    work-related illness.  Most frequent were symptoms of exposure to
    methomyl and methaemoglobinaemia due to 3,4-dichloroaniline (Morse et
    al., 1979).

         Significant T-wave changes (decreased height, inversion, and
    leftward deviation of T-wave axis) were shown in 10 out of 22 spraymen
    applying methomyl for five days under field conditions.  These changes
    reverted to pre-exposure levels within one week.  Sufficient
    information was not available to evaluate the significance of these
    findings for operator exposure, and further studies are required to
    fully understand their significance (Saiyed et al., 1992).

         Two case reports of allergic contact dermatitis with exposure to
    methomyl have been described.  In the first case, a 26-year-old woman
    had gradually worsening itchy hand eczema for six months when working
    in a plant nursery, pollinating, pricking out and potting plants
    sprayed with methomyl (Lannate) solution.  After she avoided touching
    the sprayed plants or used polyvinyl gloves she became free of eczema. 
    She also reacted positively to a 1% aqueous Lannate solution,
    indicating that Lannate was a cause of the hand eczema.  The second
    patient had already had hand eczema for 14 years with recent
    worsening.  As soon as she changed her job and no longer had contact
    with Lannate her eczema disappeared (Bruynzeel, 1991).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Microorganisms

         The effect of methomyl on sewage microorganisms was assessed
    indirectly by monitoring total oxygen demand (TOD) over a 24-h period. 
    A mixture of activated sludge, phosphate buffer and a simulated waste
    consisting of Bactopeptone and meat extract was incubated with
    methomyl at concentrations of 0, 1, 5, 10, 50 and 90 mg/litre.  Only
    at 90 mg/litre was there a slight effect on TOD (<10%), indicative of
    a minor effect on microorganism activity (Belasco, 1972a).

         A fine sand and two silt loam soils were treated with 18 mg
    methomyl/kg, and the soil fungi and bacteria populations counted after
    11 days.  The effect on total microbial activity was determined by
    measuring the CO2 evolved periodically over 56 days. Neither soil
    microorganism populations nor CO2 production was affected by the
    high level of methomyl in the soils, when compared to controls
    (Peeples, 1977).

         When methomyl was incorporated into a silt loam sand at 0.5 mg/kg
    together with ammonium sulfate, no effect on nitrification occurred
    over a 6-week period.  This level of incorporation represented the
    recommended field treatment of 0.56 kg/ha.  At ten times this level of
    incorporation there was some delay (8-9 days) in reaching the 50%
    nitrification level, but by 4 weeks the level was the same as that in
    the control soil (Han, 1972).

         Methomyl, in the form of Lannate 20L (20% a.i.), was incorporated
    into a sandy and a loamy soil at rates of 1.87 and 18.7 mg a.i./kg and
    incubated at 20°C for 28 days.  Dehydrogenase activity, measured at 14
    and 28 days, was unaffected by either rate of incorporation in both
    soils.  Ammonia nitrogen and nitrate nitrogen declined by about the
    same extent in both soils over the 28-day period.  This could have
    been due to stimulation of nitrogen assimilation by the product
    (Danneberg, 1991).

    9.2  Aquatic organisms

    9.2.1  Algae

         The effect of methomyl on algal growth was assessed using
    Selenastrum capricornutum as test species.  The organism was cultured
    under continuous illumination at 24°C with methomyl at concentrations
    of 6.25-100 mg/litre for 120 h.  Algal growth was monitored at
    intervals over the exposure period by measuring the absorbency of

    light at 665 nm.  The EbC50, (median effective concentration for
    inhibition of growth based on a comparison of areas under the growth
    curves after "b" hours) after 72 and 120 h was 60 mg/litre.  The
    ErC50  (median effective concentration for growth inhibition based
    on a comparison of maximum growth rates from "x" to "y" hours) from
    24-48 h was 140 mg/litre (extrapolated value).  The no-observed-effect
    concentration was 6.25 mg/litre (Douglas & Handley, 1988).

         A similar study was carried out using Lannate 20L (20% methomyl)
    as test substance at concentrations of 6.25-200 mg/litre.  The EbC50
    (72 h) was 68 mg/litre, EbC50 (120 h) was 116 mg/litre and the ErC50
    (0-24 h) was 67 mg/litre.  A no-observed-effect concentration of
    6.25 mg/litre was established (Douglas & Halls, 1991).

    9.2.2  Fish

         The acute toxicities (96-h LC50, etc.) for several species of
    fish are shown in Table 7.  The 96-h LC50 values lie mostly within
    the range of 0.5-2 mg/litre.  The most resistant species tested were
    the cutthroat trout with a 96-h LC50 of 4-7 mg/litre.  Generally,
    within a species, the higher the water temperature the higher the
    acute toxicity.  Results for some methomyl formulations are shown in
    Table 8.  These show lower acute toxicity, corresponding to the lower
    methomyl content.  There are few descriptions of toxic signs in
    affected fish.  In an acute study with carp and tilapia, the fish sank
    to the bottom of the tank and moved sluggishly, then became highly
    excited 10 min before death (El-Refai et al., 1976).  Shrimps became
    lethargic before dying (Bentley, 1973;  Sleight, 1973).

         Two longer-term studies have been undertaken with methomyl and a
    formulation.  This included a 21-day flow-through study on fingerling
    rainbow trout with Lannate 20L (21.5% methomyl) at 13°C.  The
    concentrations tested were 0.63, 1.3, 2.5, 5.0, 10 and 20 mg/litre,
    equivalent to 0.14-4.3 mg methomyl/litre.  No effects on fish length
    or weight were noted throughout the study.  Some increase in mortality
    occurred, from day 12 onwards, in the 5 mg/litre group, and greater
    dose-related increases were seen at the two higher concentrations
    throughout most of the study.  Surviving fish at these concentrations
    showed increasing incidence of one or more of the signs of
    discoloration, lying on the tank bottom, gasping, bloated stomach,
    loss of equilibrium.  The 21-day LC50 was calculated to be
    6.1 mg/litre formulation (equiv. 1.3 mg methomyl/litre) and the
    no-observed-effect concentration was 2.5 mg/litre formulation (Baer,
    1991c).


        Table 7.  The acute toxicity of methomyl to fish (static test)
                                                                                                                                                

                                                                           LC50 (mg/litre)
    Species                                     Temperature (°C)    96 h        48 h       24 h        Reference
                                                                                                                                                

    Atlantic salmon (Salmo salar)                   12              1.12                               USDI (1978)
    (0.48 g)                                        17              0.56                               USDI (1978)

    Bluegill sunfish (Lepomis macrochirus)          12              2.00                               USDI (1978)
                                                    22              0.86                               USDI (1978)
                                                    23              2.00                               Carter & Graves (1973)
                                                    22              1.00                               USDI (1975)

    Brook trout (Salvelinus fontinalis)             12              1.50                               USDI (1978)

    Carp (Cyprinus carpio) (5 cm)                   25                          2.8                    Yoshida & Nishiuchi (1972)

    Channel catfish (Ictalurus punctatus)           22              0.53                               USDI (1978)
    (1.8 g)                                         26                                     0.92        Carter & Graves (1973)

    Cutthroat trout (Salmo clarkie)                 10              6.8                                USDI (1978)
                                                    10              4.05                               USDI (1975)

    Fathead minow (Pimephales promelas)              -              2.8                                Mayer & Ellersieck (1986)
    (0.75 g)

    Japanese goldfish (Carassius auratus)           25                          2.7                    Yoshida & Nishiuchi
    (4 cm)                                                                                             (1972)

    Killifish (Oryzias latipes) (2.5 cm)            25                          0.87                   Yoshida & Nishiuchi (1972)
                                                                                                                                                

    Table 7. (cont'd).
                                                                                                                                                

                                                                           LC50 (mg/litre)
    Species                                     Temperature (°C)    96 h        48 h       24 h        Reference
                                                                                                                                                

    Largemouth bass (Micropterus                    22              1.25                               USDI (1978)
    salmoides) (3 g)

    Loach (10 cm)                                   25                          1.5                    Yoshida & Nishiuchi (1972)

    Rainbow trout (Salmo gairdneri)                  7              2.00                               USDI (1978)
                                                    12              1.60                               USDI (1978)
                                                    17              0.86                               Mayer & Ellersieck (1986)

    Sheepshead minnow (Cyprinodon                   21.6            1.16                               Boeri & Ward (1989)
    variegatus)
                                                                                                                                                

    Table 8.  The acute toxicity of some methomyl formulations to fish (static test)
                                                                                                                                                

                                                                                        LC50 (mg/litre)
                                                                                                      
    Species                                      Formulation       Temperature (°C)     96 h     48 h      Reference
                                                                                                                                                

    Bluegill sunfish (Lepomis macrochirus)       24% kg a.i.           -                0.7                USDI (1978)

    Bluegill sunfish (Lepomis macrochirus)       Lannate 20 L          21.5             5.1                Baer (1991a)

    Bluegill sunfish (Lepomis macrochirus)       Lannate 90% WDP       -                2.1                USDI (1978)

    Carp (Cyprinus carpio)                       Lannate 25 WP         22               4.7 -              Ökolimna (1980)
                                                                                        12.5

    Carp (Cyprinus carpio) (1.75 g)              Lannate 24 EC         22-25                     2.96      El-Refai et al. (1976)

    Carp (Cyprinus carpio) (31.5 g)              Lannate 24 EC                                   1.21      El-Refai et al. (1976) 

    Rainbow trout (Salmo gairdneri)              Lannate 20 L          12.6             18                 Baer (1991b)
                                                 Lannate 90% WDP       13               3.4                McCain (1971)

    Tilapia (Tilapia nilocita) (1.5 g)           Lannate 24EC          22-25            0.92               El-Refai et al. (1976)

    Tilapia (Tilapia nilocita) (13.8 g)                                                 0.88

    Channel catfish (Ictaurus punctalus)         24% liquid form       -                0.3                USDI (1978)

    Channel catfish (Ictaurus punctalus)         29% liquid form                        0.3                USDI (1978)

    Brook trout (Salvelinus fontinalis)          24% liquid form       -                2.2                USDI (1978)
                                                                                                                                                

    Table 8 (cont'd).
                                                                                                                                                

                                                                                        LC50 (mg/litre)
                                                                                                      
    Species                                      Formulation       Temperature (°C)     96 h     48 h      Reference
                                                                                                                                                

    Killifish (Oryzias latipes) (2.5 cm)                               25                        0.87      Yoshida & Nishiuchi
                                                                                                           (1972)

    Largemouth bass (Micropterus                                       22               1.25               USDI (1978)
    salmoides) (3 g)

    Loach (10 cm)                                                      25                        1.5       Yoshida & Nishiuchi
                                                                                                           (1972)

    Rainbow trout (Salmo gairdneri)                                    7                2.00               USDI (1978)
                                                                       12               1.60               USDI (1978)
                                                                       17               0.86               Mayer & Ellersieck (1986)

    Sheepshead minnow (Cyprinodon                                      21.6             1.16               Boeri & Ward (1989)
    variegatus)
                                                                                                                                                
    

         In an early life-stage toxicity study, fathead minnow embryos and
    larvae were exposed for 28 days to methomyl at concentrations of
    27-491 µg/litre.  The water was changed at the rate of 10 aquarium
    volumes each 24 h and was maintained at a temperature of 25°C.  Embryo
    hatch and larval survival and growth was evaluated.  The percentage
    embryo hatch was not affected at any concentration.  Larval survival
    was significantly reduced at concentrations down to 117 µg/litre and
    growth reduced at 243 and 491 µg/litre.  The maximum acceptable
    toxicant concentration was estimated to be >57 µg/litre and
    <117 µg/litre (Driscoll & Muska, 1982).

    9.2.3  Other aquatic organisms

         The acute toxicity results for a variety of other aquatic
    organisms are shown in Table 9.   Daphnia magna appears to be one of
    the most susceptible species to the acute toxic action of methomyl,
    and the Eastern oyster the least susceptible.  This difference was
    further emphasized in two other studies.  The 48-h EC50 for the
    Lannate 20L formulation (21.5% methomyl) was 0.033 mg/litre
    (equiv.0.007 mg methomyl/litre) for Daphnia magna neonates (Baer,
    1991d).  The 96-h EC50 for the Eastern oyster was > 140 mg/litre,
    as measured by the effect of methomyl on shell deposition in a
    flow-through test at 21.2 to 23.7°C (Ward & Boeri, 1991).

         The effect of methomyl or its formulation on Daphnia magna was
    studied in longer-term tests on survival, growth and reproductive
    capacity.  A study was initiated with < 24-h-old daphnids exposed to
    measured methomyl concentrations of 0.7, 1.0, 1.6, 3.5, 7.5 or
    13.8 µg/litre.  The test was conducted over a 21-day period at  20°C 
    under semi-static conditions with  2-day renewal of the test
    solutions. Methomyl was found to be stable in these solutions for up
    to 72 h.  Daphnid survival and growth were not affected at any
    concentration.  The number of young produced and number of young per
    adult were reduced at 3.5, 7.5 and 13.8 µg/litre.  There was some
    delay in the first day of reproduction at all levels, but this was
    considered to be biologically significant only at 3.5 µg/litre or
    more, where the number of young was affected.  The maximum acceptable
    toxicant concentration was estimated to be between 1.6 and
    3.5 µg/litre (Brittelli, 1982).

         In another 21-day study,  Daphnia magna were exposed to Lannate
    20 (21.5% methomyl) at nominal concentrations of 0.63, 1.5, 3.4, 8.
    18, 43, 100 or 232 µg/litre.  The test conditions and parameters
    measured were as described above.  At 232 µg/litre all daphnids died
    early in the study, but there was no effect on survival at the lower
    concentrations nor was growth affected.  The 21-day EC50, based upon
    adult survival, was estimated to be 160 µg/litre (equivalent to 26 µg
    methomyl/litre).  The total young produced and number of young per
    adult were decreased at 3.4 µg/litre but not at 8 µg/litre.  The
    21-day no-observed-effect concentration was therefore considered to be
    8 µg/litre, equivalent to 2.1 µg methomyl/litre (Baer, 1991e).

        Table 9.  The acute toxicity of methomyl to other aquatic organisms (static test)
                                                                                                                                                

                                                                                              LC50 (mg/litre)
                                                                                                                 
    Species                             Stage           Methomyl         Temperature (°C)   48 h            96 h      Reference
                                                        product
                                                                                                                                                

    Midge (Chironomus plumosus)         mature          95% technical       22             0.088 (EC50)               USDI (1978)
                                                        24% conc                           0.032                      USDI (1978)

    Eastern oyster (Crassostrea         embryo/         technical           20             4.0 (EC50)                 Ward & Boeri (1990)
    virginica)                          larvae

    Fiddler crab (Uca pugilator)        20 mm           Lannate L           21                              2.38      Bentley (1973)
                                                        (24%)

    Grass shrimp (Palaemonetes          18 mm           Lannate 90          21                              0.049     Sleight (1973)
    vulgaris
                                        18 mm           Lannate L           21                              0.130     Bentley (1973)
                                                        (24%)

    Gammarus pseudolimnaeus             mature          technical           17                              0.92      USDI (1978)

    Mud crab (Neopanope texana)         15 mm           Lannate 90          21                              0.41      Sleight (1973)

    Mysid shrimp (Mysidopsis bahia)     10 day          99% technical       21.5                            0.22      Ward & Boeri (1989)

    Pink shrimp (Panaeus duorarum)      55 mm           Lannate 90          21                              0.019     Sleight (1973)

    Stonefly (Pteronarcys dorsarta)     naiad           technical           7                               0.034     USDI (1975)
                                                                                                                                                

    Table 9. (cont'd).
                                                                                                                                                

                                                                                                 LC50 (mg/litre)
                                                                                                                
    Species                             Stage               Methomyl         Temperature (°C)    48 h      96 h      Reference
                                                            product
                                                                                                                                                

    Stonefly (Pheronarcella badia)      Year Class 1        99% technical                                  0.069     Mayer & Ellersieck (1986)

    Stonefly (Pheronarcella badia)      Year Class 1        24% a.i.                                       0.06      Mayer & Ellersieck (1986)

    Stonefly (Slewala sp.)              Year Class 1        95% technical                                  0.034     Mayer & Ellersieck (1986)

    Stonefly (Slewala sp.)              Year Class 1        24% a.i.                                       0.92      Mayer & Ellersieck (1986)

    Stonefly (Isogenus sp.)             Year Class 1        95% a.i.                                       0.343     Mayer & Ellersieck (1986)

    Stonefly (Isogenus sp.)             Year Class 1        24% a.i.                                       0.029     Mayer & Ellersieck (1986)

    Scud (Gammarus pseudolimneus)       adult               99% technical                                  0.92      Mayer & Ellersieck (1986)

    Scud (Gammarus pseudolimneus)       adult               24% a.i.                                       0.72      Mayer & Ellersieck (1986)

    Scud (Gammarus pseudolimneus)       adult               24% a.i.                                       1.05      Mayer & Ellersieck (1986)
                                                            (flowthrough)

    Water flea (Daphnia magna)          neonate             95% technical        18              0.032               Goodman (1978)
                                                                                                                                                

    Table 9. (cont'd).
                                                                                                                                                

                                                                                          LC50 (mg/litre)
                                                                                                             
    Species                         Stage           Methomyl           Temperature (°C)   48 h           96 h    Reference
                                                    product
                                                                                                                                                

    Water flea (Daphnia magna)      1st instar      95% technical           21            0.009 (EC50)           USDI (1978)

    Water flea (Daphnia magna)      -               24% conc                              0.0076                 USDI (1978)

    Water flea (Daphnia magna)      -               Lannate 20L             20.4          0.033                  Baer (1991e)
                                                    (21.5)

    Water flea (Daphnia magna)      1st instar      95% technical                         0.088                  Mayer & Ellersieck (1986)
                                                                                                                                                
    
    9.3  Terrestrial organisms

    9.3.1  Terrestrial invertebrates

         The acute toxicity of a liquid (Lannate 20L) and a solid (Lannate
    25WP) methomyl formulation to earthworms  (Eisenia foetida andrei) was
    determined over a 14-day period.  The formulations were mixed with
    artificial soil (70% industrial sand, 20% kaolite and 10% moss peat)
    at six concentrations of 0-500 mg/kg (Lannate 20L) and 0-1000 mg/kg
    (Lannate 25WP), with 40 earthworms per concentration.  The 7-day
    LC50 values were estimated to be 165 mg/kg and 147 mg/kg,
    respectively, and the 14-day LC50 values 102 mg/kg and 87 mg/kg,
    respectively (Armstrong et al., 1991; Caley et al., 1991).

         Laboratory tests were undertaken to determine the broadcast
    dosage of methomyl, as a 90% SP, required to kill 50% of earthworms
    (night crawlers,  Lumbricus terrestris L).  The test substance was
    mixed with moistened potting soil at six rates from 0 to 35 kg/ha with
    40 worms per rate.  The estimated rate causing 50% mortality was
    11.4 kg methomyl/ha (Ruppel & Laughlin, 1977).

         The biochemical changes in experimental snails,  Eubania
     vermiculata (Müller), were studied  after treatment with 0.2%
    methomyl in bran bait (w/w) for periods of 1, 3, 5, 7 and 10 days. 
    There was a significant reduction in total soluble proteins, lipids
    and glycogenic content, and significant increase of glutamic
    oxalocetic transaminase, glutamic pyruvic transaminase and
    catalase activities (El-Wakil & Radwan, 1991).

         A bran methomyl bait (0.5% w/w) was tested for its molluscicidal
    activity on the white garden snail  (Theba psiana) and compared with
    that of four other oxime carbamate pesticides (aldicarb, aldoxycarb,
    oxamyl and thiofanox).  Methomyl had the most potent molluscicidal
    activity.  The time for 50% mortality of snails (LT50) for methomyl,
    oxamyl, aldoxycarb, aldicarb and thiofanox was 2.31, 3.97, 4.69, 5.77
    and 6.67 days, respectively.  The activities of acetylcholine
    esterase, acid phosphatase and alkaline phosphatase were inhibited by
    the pesticides in line with their potency.  GOT and GPT activities
    were significantly increased by methomyl (Radwan et al., 1992).

         Juvenile (4-week-old) laboratory reared earthworms
     (Allolobophora caliginosa) were kept individually in soil treated
    with methomyl for 7 days.  Relative toxicity, i.e. concentration in
    soil (mg/kg) causing zero growth, compared to the standard,
    carbofuran, (0.10) was 0.54 (Martin, 1986).

         The acute toxicity of methomyl to bees has been reported by
    several investigators using different types of test.  In one such test
    groups of 20 bees were treated individually with a range of doses, the
    methomyl being applied to the thorax of each bee in a 1 µl acetone
    solution.  The mortality was determined after 48 h and the LD50 was

    calculated as 0.1 µg/bee (Meade, 1984).  The acute toxicity of
    methomyl by topical application to the honey-bee  (Apis mellifera) was
    compared to that of the Western Yellow jacket  (Vespula pensylvanica)
    after the pleural application of a 1 µl solution in acetone to each
    insect.  Methomyl was less toxic to the honey-bee, with a 48-h LD50
    of 12 µg/g, than to the Yellow jacket (0.9 µg/g) (Johansen & Davis,
    1972).  A contact LD50 of 1.29 µg per bee has been reported by
    Atkins et al., (1976) and an oral LD50 of 0.2 µg/bee by Clinch &
    Ross (1970).

         The speed of action of methomyl on honey-bees was assessed in a
    special laboratory trial.  A commercial formulation (90% DP) was
    diluted in 33% sucrose solution to give concentrations equal to 1.5, 2
    or 4 x LD90. These were fed to bees and the effects observed as two
    stages; the first was characterized by very fast and erratic movement
    and the second by the bees being unable to walk or fly.  The time
    intervals to reach each stage were recorded (20 bees), as were the
    times taken for 50% and 90% bees to be affected. Methomyl was the
    fastest acting of 10 pesticides tested, taking about 3-5 min to give a
    50% effect level.  It was suggested that this type of information was
    needed when interpreting the results of field trials (Clinch & Ross,
    1970).

         In a tent trial, a methomyl formulation (35% methomyl) was
    applied to Phacelia at a 0.3% concentration in the evening after bees
    had finished flying and then rewetted early next morning prior to the
    start of flight.  Observations were made later that day and during the
    following two days.  Fewer bees visited the trial tent during this day
    than visited the control tent.  Large numbers of bees were found dead
    in front of the hive and at the trial tent edges (about one order of
    magnitude higher) on the first day.  On the second day about three
    times the number of dead bees were found when compared to the control. 
    Fewer bees were found dead when the trial was repeated with the spray
    deposit left dry (Stute, 1983).

         Methomyl was among 400 pesticides assessed in honey-bee
    laboratory and field studies by the University of California over 20
    years.  The compound was placed in the highly toxic category, i.e.
    severe losses should be expected if the pesticide is used when bees
    are present at treatment or within a day thereafter.  It was shown
    that the contact LD50 of 1.29 µg/bee can be converted directly to
    1.29 kg/ha, this being the application rate expected to cause a 50%
    mortality among foraging bees in a treated field crop, at the time of
    application or shortly thereafter. Several recommendations were
    included to help minimize bee losses when spraying with insecticides,
    including early morning or night applications, since there is less
    risk to honey-bees at these times (Atkins et al., 1976).

    9.3.2  Birds

         The results for methomyl in acute oral and short-term dietary
    studies in birds are shown in Tables 10 and 11. In an acute toxicity
    study on the bobwhite quail, a dose of 5.62 mg/kg produced lethargy,
    reduced reaction to external stimuli, loss of coordination and lower
    limb weakness within 30 min of dosing. The birds recovered within 2 h. 
    The effects increased at higher doses and included salivation and wing
    droop, but recovery in survivors was rapid, within hours to one day. 
    There were no mortalities at 10 mg/kg or less (Beavers, 1983). 
    Chickens given methomyl by capsule at 25 or 50 mg/kg showed muscle
    tremor, ataxia, salivation, convulsions and death within 30 min
    (Palmer & Schlinke, 1978).

         In a one-generation study, 20-week-old bobwhite quail, 16 male
    and 16 female per group, were fed diets containing 0, 50, 150 or
    500 mg methomyl/kg for 20 weeks in their first breeding season. 
    Assessments included adult clinical health, weight gain and food
    consumption and the reproductive parameters for numbers of eggs laid,
    development of eggs, viability of embryos, percent hatchability,
    offspring survival and eggshell thickness.  There were no signs of
    toxicity in the adults or of treatment-related mortality.  There was a
    slight decrease in body weight gain in males at 500 mg/kg up to week
    8.  No effects on reproductive parameters were seen at the two lower
    dietary levels.  No treatment-related effects were observed for egg
    shell thickness at methomyl concentrations of 50, 150 or 500 mg/kg.
    Mean thicknesses of bobwhite quail eggs were 0.221 (± 0.02), 0.216
    (± 0.01) and 0.214 (± 0.01) mm, respectively.  Treatment groups did
    not differ significantly from the control (0.212 ± 0.02 mm). A small
    but biologically significant reduction in the numbers of eggs laid per
    hen and a subsequent reduction in the numbers of offspring were seen
    at 500 mg/kg.  A clear no-observed-effect concentration of 150 mg
    methomyl/kg diet was therefore determined (Beavers et al., 1991a).

         A one-generation study of similar design and the same dietary
    concentrations was undertaken with the mallard duck for a period of 18
    weeks.  There were no signs of toxicity or treatment-related
    mortalities in the adults.  No effect was seen on body weight at the
    two lower levels but a decrease in weight gain occurred in hens fed
    500 mg/kg over the last 10 weeks of the study.  Egg shell thickness
    was not affected by methomyl.  Mean shell thicknesses of eggs from
    exposed ducks were 0.378 (±0.03), 0.379 (±0.07) and 0.370 (±0.03) mm
    for 50, 150 and 500 mg/kg, respectively.  No significant differences
    from the control (0.378 ± 0.03 mm) were detected.  A slight reduction
    in the percentage of viable embryos was observed at 500 mg/kg.  A
    clear no-observed-effect concentration was therefore established at
    150 mg/kg (Beavers et al., 1991b).


        Table 10.  Acute toxicity studies on birds
                                                                                                                                                

    Species                                    Test                                     Acute oral LD50           Reference
                                                                                        (mg/kg)
                                                                                                                                                

    Bobwhite quail (Colinus virginianus)       intubation, suspended in corn oil        24.2                      Beavers (1983)

    Japanese quail (Coturnix japonica)         intubation, suspended in                 34                        Smith (1982)
                                               carboxymethylcellulose

    Chicken (White Leghorn-Cornish)            capsule                                  minimum toxic dose        Palmer & Schlinke (1978)
                                                                                        25

    Mallard duck (Anas platyrhynchos)                                                   15.9                      Tucker & Crabtree (1970)

    Pheasant (Phasianus colchicus)                                                      15.4                      Tucker & Crabtree (1970)

    Common pigeon (Columba livia)              in polyethylene glycol                   10.0                      Schafer (1975)a

    Common grackle (Quiscalus quiscala)        in polyethylene glycol                   13.3                      Schafer (1975)a

    Starling (Sturnus vulgaris)                in polyethylene glycol                   31.6                      Schafer (1975)a

    House sparrow (Passer domesticus)          in polyethylene glycol                   13.3                      Schafer (1975)a

    Starling (Sturnus vulgaris)                gavage in propylene glycol               42                        Schafer (1972)

    Redwing (Agelaius phoeniceus)              gavage in propylene glycol               10                        Schafer (1972)
                                                                                                                                                

    a  Schafer EW Jr (1975)  Avian toxicity tests - letter to Dr HJ Thome, April 28 1975 (unpublished report submitted to WHO by Du Pont)

    Table 11.  Dietary toxicity studies on birds
                                                                                                                                                

    Species                                     8-day Test                   Dietary LC50         Reference
                                                (5 days feeding, 3 days      (mg/kg)
                                                observation)
                                                                                                                                                

    Bobwhite quail (Colinus virginianus)        4 concentrations                1100           Heath et al. (1972)

    Japanese quail (Coturnix japonica)          6 concentrations                3124           Heath et al. (1972)

    Mallard duck (Anas platyrhynchas)           6 concentrations                2883           Heath et al. (1972)

    Bobwhite quail                              7 concentrations                3680           Busey (1967)

    Pekin duck                                  7 concentrations                1890           Busey (1967)
                                                                                                                                                
    
         Methomyl did not give any indication of a teratogenic effect in a
    chick embryo test when it was injected into the yolk (Proctor et al.,
    1976).

    9.4  Field studies

         Bobwhite quails, 6 males and 6 females, were exposed to sprays of
    Lannate formulations, equivalent to a field application of 1 kg
    methomyl/ha, once every 48 h for a total of four applications. The
    birds were killed 14 days after the last application.  There were no
    observable effects due to exposure and no treatment-related changes in
    tissues on gross examination (Aftosmis, 1973a,b).

         A simulated field trial was carried out on two groups of bobwhite
    quail (three males and three females per group).  One group was fed
    prior to treatment, the other group was fed 12 h after treatment.  The
    treatment consisted of spraying methomyl over the test area at the
    rate of 1.1 kg/ha.  In all, six sprayings were made, each 5 days
    apart, with a 15-day observation period after the last application. 
    Some weight loss occurred in the group fed prior to treatment;
    otherwise there were no observable effects on surviving  birds
    compared to controls and no changes due to treatment upon gross
    examination of tissues (Hinkle & Cameron, 1980).

         In 1978, 400 ha of Maine (USA) forest land was treated with the
    formulation Lannate LV at the rate of 0.28 kg methomyl/ha to control
    spruce budworm.  Monitoring of more than 30 species of songbirds was
    undertaken over 6-day census periods pre-spray, immediately post-spray
    and 2 weeks post-spray.  The census was carried out firstly by
    individual bird counts and then by territorial counts.  Searches were
    made for dead birds.  Spray deposit cards were used to ensure that the
    insecticide was present in the census plots.  A concurrent sampling
    and analytical programme determined the residue levels of methomyl in
    trees and other plants, leaf litter, soil and water.  The maximum
    level detected was 15 mg/kg in foliage from the top third of the
    trees.  Underbrush had initial residues of 6 mg/kg, low levels were
    found in leaf litter, negligible amounts in soil and none in water. 
    These levels dissipated rapidly apart from leaf litter where low
    levels lasted 34-61 days.  The study revealed no evidence of changes
    in the activity levels among songbirds.  No dead or intoxicated birds
    were found and there was no disruption of nesting birds (Brown, 1978). 

         A study of brain cholinesterase activity was undertaken on wild
    mice  (Mus musculus) trapped over a period of 3 days after a soya
    bean field had been sprayed with Lannate 1.8 L at 0.5 kg methomyl/ha. 
    Some inhibition of brain cholinesterase activity occurred at a level
    of about 10% over the study period indicating the possibility of a
    small effect (Montz et al., 1983).

         A census of birds was undertaken before and after spraying a
    field of hops in Kent, United Kingdom, with 0.56 kg methomyl per ha. 
    Records were made of birds seen, feeding in the hop field, singing and
    nesting.  Monitoring was carried out 1, 3 and 10 days after spraying. 
    Principal species observed feeding upon the sprayed area included
    blackbird, song thrush, various tits and finches, robin, wren and
    hedge sparrow.  There was no apparent difference in feeding habits
    before or after spraying and no unhealthy or dead birds were found
    over the total observation period (Orpin, 1971).

         Methomyl (90% SP), applied at 3.4 kg/ha pasture, produced
    decreases in population and biomass of three species of earthworms of
    28.5% and 14%, respectively.  The compound was considered to be the
    least active of the seven pesticides tested (Tomlin & Gore, 1974).

    10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1  Evaluation of human health risks

         Methomyl is a carbamate cholinesterase inhibitor with a
    well-known mechanism of toxic action.  It is particularly toxic by the
    acute oral and inhalation routes in animal studies, but it has low
    dermal toxicity.  Acute toxic signs in animals are typical of those of
    a cholinesterase inhibitor.  The reversibility of acute toxic action
    is rapid, with survivors showing quick recovery from toxic signs and
    reversal of cholinesterase inhibition in the blood and brain.  The
    quick recovery from toxic effects is due to the rapid reversibility of
    methomyl-inhibited cholinesterase, which is facilitated by the rapid
    clearance of the compound from the body.  Data from accidental and
    intentional human poisonings show that the level of acute methomyl
    toxicity in humans is similar to that found in laboratory animals.

         Because of the rapid reversibility of the action of methomyl
    during periods of feeding, acute toxic signs and blood cholinesterase
    inhibition were rarely seen in dietary studies.  The most consistent
    findings in longer-term studies at the higher dietary levels were
    decreases in body weight gain in rodents and reduced red blood cell
    indices in rodents and dogs.  There was no evidence for carcinogenic
    potential from three long-term studies in rodents.  The compound was
    negative in  in vitro genotoxicity tests that investigated several
    end-points, but methomyl showed cytogenetic potential in human
    lymphocytes.  It was negative in an  in vivo rat bone marrow
    chromosomal study.

         NOELs were identified in each of the long-term animal studies,
    based upon depression of body weight gain and red blood cell indices. 
    These were 5 mg/kg body weight per day in rats, 8.7 mg/kg body weight
    per day in mice and 3 mg/kg body weight per day in dogs.  In the
    absence of any marked species differences in toxic effect in these
    studies, the NOEL in the dog of 3 mg/kg body weight per day should be
    used for the purpose of human risk estimation.

         The proposed toxicological criteria for setting guidance values
    are presented in Table 12.

    10.2  Evaluation of effects on the environment

         Adsorption of methomyl to soil is low to moderate with hardly any
    desorption.  Aerobic degradation in soil (with a half-life of around
    one week) is about twice as fast as anaerobic degradation.  A relative
    increase in soil organic matter delays degradation.


        Table 12.  Proposed toxicological criteria for setting guidance values
                                                                                                                                                

    Exposure scenario     Relevant route/effect                              Result/remarks
                                                                                                                                                

    Short-term            oral, acute, several species including human       highly toxic; rat LD50 = 17 mg/kg body weight;
    (1-7 days)                                                               LOELa= 5 mg/kg body weight

                          eye, irritation, rabbit                            mild irritant

                          inhalation, acute, rat                             highly toxic; LC50 = 0.26 mg/litre (4-h aerosol);
                                                                             NOELb = 0.14 mg/litre

                          dermal, acute, rat and rabbit                      low toxicity; intact skin - LD50 > 2000 mg/kg body weight;
                                                                             NOELc = 2000 mg/kg body weight in the rabbit

    Medium-term           repeat dermal, rabbit                              21-day study; no toxicologically significant effects at
    (1-26 weeks)                                                             50 mg/kg body weight per day

                          repeat oral, rat                                   13-week study; NOEL = 3.6 mg/kg body weight per day

                          maternal oral, rabbit                              teratology study; NOEL = 6 mg/kg body weight per day

    Long-term             repeat oral, dog                                   2-year study; NOEL = 3 mg/kg body weight per day
                                                                                                                                                

    a   mild cholinergic signs of toxicity in guinea-pig
    b   no-observed-effect level for clinical signs and death
    c   no clinical symptoms noted except signs of skin irritation
    
         Despite the above adsorption characteristics, leaching of
    methomyl in soil to levels deeper than 20 to 30 cm has not been
    observed.  The concentrations of methomyl in both surface and well
    water are below the limit of detection.  Methomyl is degraded rapidly
    with a half-life of about one week in water and sediment.  In sterile
    water, methomyl is stable for at least 30 days at normal environmental
    pH.

         Application of methomyl to plant leaves results in rapid
    absorption of about half the amount applied (the other half being
    adsorbed), and there is no indication of translocation.  In contrast,
    when applied to soil, uptake through the roots occurs readily with
    rapid translocation to the leaves.  Adsorbed foliar residues degrade
    with a half-life in the order of 4 days.  Absorbed methomyl
    concentrations in food crops decline rapidly to about 5% within one
    week; this may be due to growth dilution.

         Bioaccumulation by rainbow trout did not occur in a flow-through
    study.  Depuration occurred within one day of transfer to clean water. 
    Trout were discoloured when exposed to levels between 0.075 and
    0.75 mg/litre, an effect that disappeared within 5 days, the time
    depending on original exposure concentration.

         At recommended application rates, methomyl does not adversely
    affect microbial activity in temperate soil; nitrification can be
    delayed at applications 10 times higher.  An aquatic green alga showed
    a NOEC for growth of 6.25 mg/litre.

         Several aquatic invertebrates, and particularly daphnids, are
    very sensitive to methomyl, the LC50s being of the order of 10 to
    100 µg/litre. MATC values from two 21-day  Daphnia studies were
    estimated to be around 2 µg/litre. Kills of aquatic invertebrates are
    expected following overspray.

         Fish, both freshwater and estuarine, are less sensitive, the
    LC50s ranging from 0.5 to 7 mg/litre.  Two longer-term studies gave
    an NOEC of 0.5 mg/litre for lethality of fingerling rainbow trout and
    an MATC of > 0.06 and > 0.12 mg litre for survival of embryo larval
    stages of fathead minnow. Given the low persistence of methomyl and
    its relatively low acute toxicity to fish, the risk is expected to be
    low.

         Laboratory tests in artificial soil with methomyl formulations
    (25% WP) established a 14-day LC50 of 90-100 mg formulation/kg for
    earthworms.  It was estimated that 11 kg a.i./ha of methomyl would
    kill 50% of earthworms.  A field application of 3 kg a.i./ha caused
    reduced earthworm population (28%) and biomass (14%).  The TER for
    earthworms is around 40 indicating low risk.

         Methomyl is classified as highly toxic to honey-bees, the topical
    LD50 being approximately 0.1 µg/bee.  Field (tent) trials showed
    dead bees both at the treatment tent and hive when residues from
    spraying the previous day were wetted.  Less effect was seen with dry
    residues.  Methomyl has not been implicated in bee incidents in the
    field; this probably reflects advice to restrict spraying times to
    protect bees.

         Acute oral LD50s for various bird species range between 10 and
    40 mg/kg body weight. Dietary LC50s (5 days) range from 1100 to
    3700 mg/kg diet.  Methomyl poses an acute oral risk to birds,
    particularly from granules;  dietary intake from contaminated food is
    not expected to kill birds.  An example of a toxicity exposure ratio
    for birds and fish is shown in Table 13.

         The NOEC for reproduction was established at 150 mg/kg diet for
    both the bobwhite quail and mallard duck. Field studies following
    spraying of methomyl formulations in forests showed no mortality of
    songbirds and no changes in feeding behaviour or general activity.
    Reduced fat deposits of songbirds reflect reduced insect prey.  It was
    not considered that methomyl poses a threat to birds after recommended
    applications.

         The high acute toxicity of methomyl to laboratory mammals
    indicates a similar hazard to wild mammals.


        Table 13.  Toxicity exposure ratios for birds, fish and aquatic invertebrates based on application rates of 2.5 kg a.i./ha
               methomyl to soybeans (worst case)
                                                                                                                                                

    Risk category                 LC50 (mg/litre or mg/kg diet)         Estimated exposure         Toxicity/exposure ratio (TER)c
                                                                    (mg/litre or mg/kg diet)a,b
                                                                                                                                                

    Acute bird                            10                               50-364                              02-0.027

    Acute fish (stream)                   0.5                              0.2                                 2.5

    Acute fish (pond)                     0.5                              0.04                                12.3

    Acute aquatic invertebrate            0.009                            0.2                                 0.045
    (stream)

    Acute aquatic invertebrate            0.009                            0.04                                0.225
    (pond)
                                                                                                                                                

    a   Estimated environmental concentration in the terrestrial environment (for bird exposure) is based on the stated application rate
        and the assumption of deposition on short grass using the US EPA monogram
    b   Aquatic exposure concentrations were taken from the STREAM model based on a single application and estimated run-off into water;
        no direct overspray is included
    c   TER is the toxicity (as LC50) divided by the exposure; values at or below 1.0 indicate likely exposure to toxic concentrations
        by organisms in the different risk categories
    
    11.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH

         Considering the toxicological characteristics of methomyl, both
    qualitatively and quantitatively, it is concluded, on the basis of the
    no-observed-effect level of 3 mg/kg body weight per day in the 2-year
    toxicity study on dogs and applying a 100-fold uncertainty factor,
    that 0.03 mg/kg body weight per day will probably not cause adverse
    effects in humans by any route of exposure.

    12.  FURTHER RESEARCH

         No further studies were thought to be necessary.

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The Joint FAO/WHO Meeting on Pesticide Residues has discussed and
    evaluated methomyl on several occasions since 1975.  Residue aspects
    were discussed in 1975, 1976, 1977, 1978, 1986, 1987, 1988, 1989, 1990
    and 1991 (FAO/WHO, 1976, 1977, 1978, 1979, 1986, 1987, 1988a,b,
    1990a,b,c, 1991).  Toxicological evaluations took place in 1978, 1986
    and 1989, when an Acceptable Daily Intake (ADI) of 0-0.03 mg/kg body
    weight was established (FAO/WHO, 1979, 1987, 1990a,b).

         The Joint FAO/WHO Codex Alimentarius Commission has established
    maximum residue limits (MRLs) for methomyl in various commodities
    (FAO/WHO, 1993).

         It should be noted that the 1992 CCPR meeting decided to combine
    MRLs for thiodicarb and methomyl into a single list.  In the cases of
    different MRLs the higher limit would prevail.

         Methomyl is listed in Class IB ("Highly Hazardous") in the WHO
    Recommended Classification of Pesticides by Hazard and
    Guidelines to Classification (1994-1995) on the basis of its rat acute
    oral LD50 value of 17 mg/kg body weight (IPCS, 1994).

         The time-weighted average (TWA) adopted by the American
    Conference of Governmental Industrial Chemists (ACGIH) is 2.5 mg/m3
    (ACGIH, 1994-1995).

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    methomyl insecticide). Newark, Delaware, E.I. Du Pont de Nemours and
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    Aftosmis JG (1973b) Carbamic acid, methyl ester with oxime function of
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    Araki M, Yonemitsu K, Kambe T, Idaka D, Tsunenari S, Kanda M, &
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    Armondi S (1991b) Closed-patch repeated insult dermal sensitization
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    Armondi S (1992) Closed-patch repeated insult dermal sensitization
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    Baer KN (1991a) Static, acute, 96-hour LC50 of DPX-X1179-423 to
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    RESUME

    1.  Identité, propriétés physiques et chimiques, et méthodes d'analyse

         Le méthomyl est un solide cristallin blanc dont le point de
    fusion est de 77°C et la tension de vapeur de 0,72 mPa à 25°C.  Sa
    solubilité dans l'eau est de 54,7 g/litre et son coefficient de
    partage octanol/eau (Kow) est de 1,24.  Il est stable dans l'eau
    stérile à pH 7 mais il se décompose à pH plus élevé, sa demi-vie étant
    de 30 jours à pH 9 et 25°C.

         Le dosage du méthomyl dans divers échantillons consiste en une
    extraction suivie d'une purification, l'analyse finale s'effectuant
    par chromatographie en phase liquide à haute performance ou
    chromatographie gaz/liquide.  Dans certains cas, avant le dosage
    proprement dit, on transforme le méthomyl en oxime ou en fluorophore
    (post-colonne).

    2.  Sources d'exposition humaine et environnementale

         Le méthomyl est préparé en faisant réagir le
     N-hydroxythioacétimidate de  S-méthyle (MHTA) en solution dans le
    chlorure de méthylène, sur l'isocyanate de méthyle gazeux à 30-50°C. 
    Il s'agit d'un carbamate à propriété insecticide que l'on utilise
    partout dans le monde sur toutes sortes de cultures.  Il sert
    notamment à protéger les fruits, les vignes, le houblon, les légumes,
    les céréales, le soja, le coton et les plantes ornementales.  A
    l'intérieur des bâtiments, on l'utilise aussi pour détruire les
    mouches dans les animaleries et les laiteries.

         Il est principalement présenté sous forme de poudre hydro-soluble
    ou encore de liquide miscible à l'eau que l'on dilue pour le
    traitement des cultures au sol ou en pulvérisations aériennes.  Les
    doses d'emploi vont habituellement de 0,15 à 1,0 kg de matière active
    par hectare.  C'est essentiellement au cours de la préparation et de
    l'épandage de ces produits ou par suite de l'ingestion de résidus
    subsistant sur des cultures vivrières qu'il peut y avoir exposition
    humaine (voir section 5.3.1.4).

    3.  Transport, distribution et transformation dans l'environnement

         Les études de laboratoire montrent que le méthomyl est faiblement
    adsorbé aux particules du sol.  On a ainsi montré que l'adsorption
    était faible sur les minéraux argileux en particulier l'illite;  sur
    les matières organiques du sol, elle est multipliée par 50 tout en
    restant encore relativement faible.  Une fois adsorbés, les résidus ne
    se désorbent pratiquement pas.  Du fait de ses propriétés, on peut
    penser que le méthomyl doit être doté d'une certaine mobilité dans le
    sol.

         Dans l'environnement naturel, la décomposition abiotique du
    méthomyl par hydrolyse ou photolyse est lente ou nulle.

         Dans le sol, la décomposition aérobie est environ deux fois plus
    rapide que la décomposition anaérobie.  On a fait état de valeurs de
    la demi-vie dans le sol qui vont de quelques jours à plus de 50 jours; 
    la sécheresse retarde la décomposition.  Dans la pratique, on peut
    considérer que dans la plupart des cas, on aura après épandage, une
    demi-vie d'environ une semaine.

         Dans les conditions de plein champ, le méthomyl ne pénètre pas
    dans le sol, par lessivage, à une profondeur de plus de 20-30 cm et il
    n'y a pas de contamination des eaux souterraines.

         Lorsqu'on épand du méthomyl marqué au 14C sur les feuilles de
    végétaux, il y absorption, mais le produit n'est pas transporté dans
    d'autres parties de la plante.  Lorsqu'on l'applique sur le système
    radiculaire, le composé est fixé par la plante, le principal résidu
    étant le méthomyl lui-même. Les produits de décomposition volatils du
    méthomyl sont le CO2 et l'acétonitrile.  Le reste de la fraction
    radioactive se retrouve dans les constituants naturels de la plante
    tels que les lipides ainsi que les acides et les sucres du cycle de
    Krebs.  Dans le feuillage, la demi-vie du méthomyl est de l'ordre de
    quelques jours.

         Après exposition de truites arc-en-ciel à ce composé pendant 28
    jours dans un système à courant d'eau, on n'a trouvé aucun signe
    d'accumulation.

    4.  Concentrations dans l'environnement et exposition humaine

         Si l'on en croit les analyses effectuées sur diverses sources
    d'eau après épandage du composé aux doses recommandées, il est
    probable que les concentrations de méthomyl dans les eaux souterraines
    sont soit très faibles, soit inférieures à la limite de détection
    (< 0,02 mg/litre).

         De faibles résidus de méthomyl se retrouvent sur les cultures,
    notamment vivrières, lors de la récolte, les quantités dépendant de
    facteurs tels que la dose d'emploi, le laps de temps écoulé depuis le
    dernier épandage et le type de culture.  Ces résidus sont
    essentiellement constitués du produit initial.

         Dans les produits laitiers, les résidus de méthomyl sont soit
    inférieurs à la limite de détection, soit très faibles.  Après
    administration de méthomyl à des vaches laitières sous forme de
    capsules, pendant 28 jours à une dose équivalant à 80 mg/kg de

    nourriture, on n'a pas retrouvé de résidus décelables de ce composé ou
    de son métabolite (le MHTA) dans la lait ou les tissus de ces animaux
    (< 0,02 mg/kg).  Aucune trace de méthomyl n'a été non plus décelée
    dans les oeufs ou dans les tissus de poules pondeuses qui en avaient
    reçu 1 ou 10 mg/kg dans leur nourriture pendant quatre semaines.

         Des analyses effectuées par sondage aux Etats-Unis sur la ration
    totale ou sur certains types d'aliments, ont montré que la
    concentration de méthomyl était soit très faible, soit inférieure à la
    limite de détection.  Par ailleurs, un certain nombre d'opérations
    tels que le lavage, l'épluchage ou la cuisson, réduisent encore la
    teneur en résidus.

         Des études effectuées lors du retour des ouvriers agricoles sur
    les vignobles après épandage, notamment dans les conditions du désert
    de Californie, ont montré que pour un résidu foliaire mobile tombé à
    0,1 µg/cm2, l'exposition était maximale au niveau du torse et de la
    tête lorsque les ouvriers agricoles pratiquaient l'incision annulaire,
    le torse et les mains étant les plus touchés lors de la cueillette du
    raisin.  En ce qui concerne le raisin de table, c'est lors de la
    cueillette et de l'emballage que l'exposition était la plus faible. 
    L'exposition par inhalation était minime.

         Après pulvérisation de méthomyl sur des plants de concombres et
    de tomates, on a mesuré dans l'air de la serre qui les abritait, des
    concentrations d'insecticide allant jusqu'à 4,7 µg/m3 dans la
    journée qui a suivi l'épandage.  Trois, puis sept jours après ce
    traitement, les concentrations de méthomyl dans la zone de
    respiration allaient respectivement jusqu'à 14,5 ou 0,7 µg/m3.  Dans
    l'eau de lavage des mains des jardiniers d'une serre, on a retrouvé
    des quantités de méthomyl allant de 10 à 300 µg/heure de travail. 
    Cela montre que l'exposition cutanée est une voie d'exposition plus
    importante que l'inhalation et que la durée de l'attente à observer
    avant de retourner sur les lieux doit être basée sur les données
    d'exposition cutanée.

    5.  Cinétique et métabolisme chez les animaux de laboratoire

         Après administration à des rats par voie orale, le méthomyl est
    rapidement absorbé, métabolisé et excrété, l'ensemble du processus
    étant achevé en quelques jours.  Une semaine après avoir administré à
    des rats du méthomyl radio-marqué à raison de 5 mg/kg de poids
    corporel, on a constaté que 54% de la dose était excrétés dans
    l'urine, 2 à 3% dans les matières fécales et 34% dans l'air expiré (en
    l'espace de cinq jours).  Au bout de sept jours, il restait dans les
    tissus et la carcasse 8 à 9% de la radioactivité, le carbone-14 étant
    incorporé dans les constituants endogènes.  C'est dans le sang que la
    fraction radioactive était la plus importante (2% de la dose).

         Chez ces rats, les principaux métabolites présents dans l'air
    expiré étaient du dioxyde de carbone et l'acétonitrile dans le rapport
    d'environ 2:1.  Dans les urines, le principal métabolite était
    constitué par un dérivé mercapturique du méthomyl, à hauteur de 17% de
    la dose.  On n'a pas décelé la présence de méthomyl ni de son oxime.

         On pense que la métabolisation du méthomyl s'effectue selon le
    schéma suivant:  déplacement du groupe  S-méthyle par le glutathion,
    puis transformation enzymatique en dérivé de l'acide mercapturique. 
    Il existe une autre voie métabolique, à savoir l'hydrolyse en MHTA qui
    est ensuite rapidement décomposé pour donner du dioxyde de carbone. Il
    pourrait y avoir aussi conversion du syn-méthomyl (qui est la forme
    insecticide) en isomère anti, lequel serait ensuite décomposé en
    acétonitrile par des réactions d'hydrolyse, de transposition et
    d'élimination.  Chez le singe, le métabolisme est analogue, à cela
    près que le dérivé de l'acide mercapturique ne constitue qu'un
    métabolite urinaire mineur.

         Une heure après application cutanée à des souris d'une solution
    acétonique de méthomyl marqué au 14C, on a constaté que le taux de
    pénétration était de l'ordre de 85%.  A ce moment, 3% de la dose
    étaient présents dans le sang, 5% dans le foie et 13% avaient été
    excrétés.  Au bout de huit heures, l'excrétion totale était de 54,5%.

         La décomposition et l'élimination rapides du méthomyl chez le rat
    ainsi que son absence d'accumulation tissulaire, est comparable à ce
    que l'on observe chez les ruminants.

         Du méthomyl administré à des vaches et à des chèvres a subi une
    dégradation totale.  Ni le composé initial, ni son oxime n'ont été
    retrouvés dans le lait ou les tissus.  On a montré que le méthomyl
    était métabolisé et incorporé dans les constituants naturels du lait
    et du foie.

         Après avoir fait incuber du méthomyl marqué au 14C avec du
    nitrite de sodium dans un macérat de viande séchée, dans des
    conditions simulant le milieu gastrique, on n'a pas mis en évidence la
    formation de nitrosométhomyl.

    6.  Effets sur les mammifères de laboratoire et les systèmes
        d'épreuves in vitro

         Le méthomyl présente une forte toxicité aiguë par voie orale, sa
    DL50 chez le rat allant de 17 à 45 mg/kg de poids corporel.  Il
    présente également une forte toxicité inhalatoire chez cet animal, la
    CL50 à 4 heures étant de 0,26 mg/litre lorsque le composé est inhalé
    sous forme d'aérosol.  La toxicité cutanée est très faible, la DL50
    dépassant 2000 mg/kg de poids corporel chez le lapin (peau intacte) et
    1000 mg/kg de poids corporel chez le rat (peau abrasée).  Les signes
    d'intoxication aiguë sont ceux que l'on peut attendre d'un inhibiteur

    de la cholinestérase et consistent, entre autres, en une
    hypersalivation, une lacrimation, des tremblements et un myosis.  On a
    constaté que les animaux récupéraient rapidement et l'examen de leurs
    organes n'a pas révélé la présence de lésions anatomopathologies
    visibles qui soient imputables au traitement.  Le méthomyl ne provoque
    pas d'irritation ou d'hypersensibilisation cutanée et il est
    légèrement irritant pour la muqueuse oculaire.

         L'administration répétée de méthomyl dans la nourriture pendant
    des périodes prolongées n'a pas conduit à une accumulation ou à un
    accroissement des effets toxiques.  Des rats et des chiens à qui on
    avait administré une nourriture contenant jusqu'à 250 mg/kg et
    400 mg/kg respectivement de méthomyl, pendant 13 semaines, n'ont
    présenté ni signes d'intoxication ni surmortalité.  Chez des rats qui
    en avaient reçu dans leur nourriture à la dose de 250 mg/kg, on a
    observé une légère diminution du gain de poids, une réduction du taux
    d'hémoglobine et une hyperplasie modérée de la lignée érythroblastique
    au niveau de la moelle osseuse.  Chez le rat, la dose sans effets
    observables était de 50 mg/kg de nourriture (soit l'équivalent d'une
    dose quotidienne de 3,6 mg/kg de poids corporel).  Des lapins, qui
    avaient subi des applications cutanées répétées de méthomyl à des
    doses quotidiennes allant jusqu'à 500 mg/kg de poids corporel, pendant
    21 jours, ont présenté une hyperactivité ainsi qu'une réduction de
    l'activité cholinestérasique plasmatique et cérébrale à la dose la
    plus élevée.  La dose sans effets nocifs observables était égale,
    selon cette étude, à 50 mg/kg de poids corporel par jour.

         Au cours d'études à long terme, des rats ont reçu du méthomyl
    dans leur nourriture à raison de 0, 50, 100 ou 400 mg/kg et des souris
    en ont reçu de la même manière, 0, 50, 75 ou 200 mg/kg.  Chez les
    rats, les effets observés à la dose la plus élevée consistaient en une
    réduction du gain de poids ainsi qu'en une diminution du taux
    d'hémoglobine et de la valeur de l'hématocrite.  La dose sans effets
    observables était de 100 mg/kg de nourriture, soit l'équivalent d'une
    dose quotidienne de 5 mg/kg de poids corporel.  Chez les souris, on a
    constaté aux deux doses les plus élevées, une augmentation du taux de
    mortalité ainsi qu'une diminution du taux d'hémoglobine et du nombre
    de globules rouges.  La dose sans effets observables a été évaluée à
    50 mg/kg de nourriture, soit l'équivalent d'une dose quotidienne de
    8,7 mg/kg de poids corporel.  Lors d'une étude toxicologique de deux
    ans chez des chiens (doses de 0, 50, 100, 400 ou 1000 mg/kg de
    nourriture), on a observé des signes d'intoxication chez certains
    animaux à la dose la plus forte, avec une anémie légère à modérée.  La
    dose sans effets observables était de 100 mg/kg de nourriture, soit
    l'équivalent d'une dose quotidienne de 3 mg/kg de poids corporel.

         Des études de deux ans sur des rats et des souris n'ont révélé
    aucun signe d'accroissement de l'incidence des tumeurs qui soient
    imputables à l'administration de méthomyl, ce qui indique que le
    méthomyl n'est pas cancérogène.  Il se s'est pas révélé non plus
    génotoxique lors d'épreuves  in vitro sur des cellules bactériennes
    ou mammaliennes et la recherche de lésions primaires de l'ADN sur des
    cellules bactériennes ou mammaliennes  in vitro ou encore
    d'aberrations chromosomiques médullaires lors d'épreuves  in vivo
    chez le rat, a donné des résultats négatifs.  On a cependant observé
    la possibilité d'effets cytogénétiques sur des lymphocytes humains
     in vivo, attestée par l'augmentation du nombre de micronoyaux et
    d'aberrations chromosomiques.  Chez des rats et des lapins qui en
    avaient reçu par gavage des doses allant jusqu'à 400 mg/kg de
    nourriture (soit une dose quotidienne de 16 mg/kg de poids corporel),
    le méthomyl n'a pas produit non plus d'effets embryotoxiques ou
    tératogènes, alors qu'à ces doses, des effets toxiques pouvaient être
    constatés chez les femelles gravides.  Lors d'une étude de
    reproduction portant sur trois générations de rats, qui avaient reçu
    50 ou 100 mg de méthomyl/kg de nourriture (soit l'équivalent quotidien
    de 50 ou 10 mg/kg de poids corporel), on n'a pas constaté d'effets sur
    la fécondité, la gestation ou la lactation qui soient imputables au
    méthomyl et aucune anomalie visible résultant de ce traitement n'a été
    observée.

         Après administration unique ou répétée de méthomyl, on n'a pas
    observé de neurotoxicité retardée.  Des rats qui en avaient reçu dans
    leur nourriture à raison de 800 mg/kg, n'ont présenté une diminution
    sensible de leur activité cholinestérasique sanguine qu'au début d'une
    étude de cinq mois.  Une étude d'alimentation de 28 jours n'a révélé
    qu'une légère diminution de l'activité cholinestérasique cérébrale à
    cette dose.  Il y a donc eu réversibilité rapide de l'effet
    anticholinestérasique du méthomyl chez les animaux au cours de la
    période d'expérimentation.   In vitro, l'activité cholinestérasique
    érythrocytaire humaine s'est révélée six fois plus sensible à l'action
    inhibitrice du méthomyl que celle du rat, mais la réactivation
    spontanée s'est produite sensiblement à la même vitesse.

         Des études menées sur diverses espèces ont montré que l'atropine
    est le meilleur antidote d'une intoxication par le méthomyl.

    7.  Effets sur l'homme

         La lecture des rapports sur les intoxications accidentelles et
    les suicides par empoisonnement avec du méthomyl éclaire quelque peu
    sur la gravité des effets et les possibilités de récupération. Sur
    cinq victimes d'une intoxication accidentelle due à la consommation
    d'aliments contaminés, trois sont décédées dans les trois heures
    suivant le repas.  On estime que les victimes avaient ingéré environ 
    12 à 15 mg de méthomyl/kg de poids corporel.  Une femme âgée de 31 ans

    et son fils de six ans, qui étaient tous les deux décédés par suite
    d'un empoisonnement volontaire, présentaient des concentrations
    hépatiques de méthomyl respectivement égales à 15,4 et 56,5 mg/kg. 
    Les doses ont été estimées à 55 mg/kg de poids corporel pour la mère
    et 13 mg/kg de poids corporel pour l'enfant.  Chez une femme qui avait
    ingéré environ 2,25 g de méthomyl, on a retrouvé dans son sang six
    heures plus tard une quantité de méthomyl égale à 1,6 mg/kg. 
    Vingt-deux heures après l'ingestion, alors que la patiente se
    remettait, on n'a plus retrouvé de méthomyl.

         Un travailleur chargé d'épandre des pesticides, qui n'avait pas
    pris la moindre précaution alors qu'il préparait une bouillie à base
    de méthomyl en poudre pour traiter des légumes, a présenté des
    symptômes d'intoxication au bout d'une heure avec réduction à 40% de
    la normale de son activité cholinestérasique sanguine au bout de 12
    heures, la récupération à 80% de la normale intervenant 36 heures plus
    tard.  D'autres travailleurs, qui avaient pris les précautions
    d'usage, n'ont présenté aucun symptôme ou effet sur l'activité de leur
    cholinestérase érythrocytaire ou plasmatique lors de l'épandage de
    méthomyl par voie aérienne.

    8.  Effets sur les organismes non visés au laboratoire et dans leur
        milieu naturel

         Le méthomyl n'a eu aucun effet sur des populations de champignons
    ou de bactéries terricoles, et en particulier sur leur action
    nitrifiante ou sur l'activité de la déshydrogénase, lorsqu'il était
    appliqué aux doses recommandées.

         Des études en laboratoire ont permis de fixer à 6,5 mg/litre la
    concentration sans effets observables sur la croissance des algues.

         Le méthomyl est moyennement à fortement toxique pour les
    poissons, les valeurs de CL50 à 96 heures se situant, pour diverses
    espèces, dans l'intervalle 0,5-2 mg/litre.  Une étude à long terme (21
    jours) a montré que la CL50 pour des alevins de truite exposés à du
    Lannate 20L (21,5% de méthomyl), était égale à 1,3 mg de méthomyl par
    litre.  Lors d'une étude toxicologique portant sur de jeunes
    cyprinidés de l'espèce Pimephales promelas, la MATC (concentration
    maximale acceptable de substance toxique) a été trouvée comprise entre
    57 et 177 µg/litre.

         Des études de toxicité aiguë portant sur d'autres organismes
    aquatiques ont montré que Daphnia magna était l'espèce la plus
    sensible au méthomyl, la CL50 à 48 heures étant de 0,032 mg/litre. 
    Lors d'une étude de 21 jours au cours de laquelle on a étudié la
    survie, la croissance et la capacité de reproduction de Daphnia magna,
    on a constaté que la concentration maximale acceptable de substance
    toxique (MATC) pour le méthomyl était comprise entre 1,6 et
    3,5 µg/litre.

         Le méthomyl est toxique pour les abeilles, la DL50 par contact
    étant de 1,29 µg/insecte et la DL50 par voie orale, de
    0,2 µg/insecte.

         On a évalué la toxicité aiguë du méthomyl chez plusieurs espèces
    d'oiseaux, les valeurs caractéristiques de DL50 aiguë par voie orale
    se situant à 10 mg/kg de poids corporel chez les pigeons et à 34 mg/kg
    de poids corporel chez la caille japonaise.  Il est relativement moins
    toxique lorsqu'il est mêlé à la nourriture, la CL50 à 8 jours étant
    dans ce cas de 1100 mg/kg de méthomyl (mêlé à la nourriture) pour le
    colin de Virginie et de 2883 mg de méthomyl/kg de nourriture pour le
    colvert.  Lors d'études qui ont duré de 18 à 20 semaines et ont porté
    sur une génération, on a évalué à 150 mg/kg de méthomyl dans la
    nourriture, la concentration sans effets nocifs observables pour le
    colin de Virginie et le colvert.

         Aucun effet n'a été observé chez des colins de Virginie qui
    avaient été exposés à une série de pulvérisations de méthomyl aux
    doses recommandées.  Après un épandage de méthomyl sur une zone
    forestière et des champs de houblon, aux doses recommandées, on a
    effectué deux études sur des populations aviaires sauvages.  Elles
    n'ont pas révélé de modification de l'activité des oiseaux et n'ont
    provoqué aucun effet, en particulier aucun effet létal.  Par rapport
    aux témoins, on a constaté qu'il y avait réduction des dépôts
    graisseux chez les oiseaux chanteurs des forêts traitées;  on estime
    qu'il s'agit là d'un effet indirect dû à la réduction des populations
    d'insectes dont se nourrissent ces oiseaux.

    9.  Evaluation des risques pour la santé humaine et des effets sur
        l'environnement

         Le méthomyl est un carbamate qui inhibe la cholinestérase et dont
    le mode d'action toxique est bien connu.  Il présente une toxicité
    particulièrement élevée lorsqu'il est absorbé par voie orale ou par
    inhalation, ainsi que le montrent les études sur l'animal, mais sa
    toxicité par voie cutanée est faible.  Chez l'animal, les signes
    d'intoxication aiguë sont caractéristiques d'une inhibition de la
    cholinestérase.  Cette intoxication est rapidement réversible, avec
    une disparition rapide des symptômes et une désinhibition également
    rapide des cholinestérases sanguine et cérébrale.  Cette prompte
    récupération est due au fait que l'inhibition par le méthomyl de la
    cholinestérase est rapidement réversible, et d'ailleurs facilitée par
    la vitesse d'excrétion élevée de ce composé.  Ce que l'on sait des
    intoxications humaines accidentelles ou volontaires montre que la
    toxicité aiguë du méthomyl est du même ordre chez l'homme que chez
    l'animal de laboratoire.

         Comme l'action du méthomyl est rapidement réversible pendant la
    période d'administration, il a rarement été possible d'observer des
    signes d'intoxication aiguë et d'inhibition de la cholinestérase
    sanguine au cours des études où on l'administrait mêlé à la
    nourriture.  Les observations les plus régulièrement rapportées à
    l'occasion d'études à long terme consistent, aux doses les plus
    élevées dans l'alimentation, en une réduction du gain de poids chez
    les rongeurs et une diminution des paramètres érythrocytaires chez les
    rongeurs et les chiens.  Trois études de longue durée chez des
    rongeurs n'ont pas permis de mettre en évidence d'activité
    cancérogène.  Le composé ne s'est pas non plus montré génotoxique lors
    d'épreuves  in vitro portant sur divers paramètres biotoxicologiques,
    néanmoins il y a une possibilité d'effets cytogénétiques sur les
    lymphocytes humains. Une étude chromosomique effectuée  in vivo sur
    la moelle osseuse de rats s'est également révélée négative.

         Chacune des études à long terme sur l'animal a permis, à partir
    de la réduction du gain de poids et des paramètres érythrocytaires,
    d'obtenir une valeur de la dose sans effets nocifs observables.  Elle
    se situait à 5 mg/kg de poids corporel par jour chez le rat, à
    8,7 mg/kg de poids corporel par jour chez la souris et à 3 mg/kg de
    poids corporel par jour chez le chien.  Faute d'une différenciation
    marquée des effets toxiques entre les différentes espèces, il ressort
    de ces études que la dose sans effets nocifs observables chez le
    chien, c'est-à-dire 3 mg/kg de poids corporel par jour, peut être
    utilisée pour évaluer le risque chez l'homme.

         Le méthomyl est faiblement à modérément adsorbé aux particules du
    sol, et ne s'en désorbe pratiquement pas.  Dans le sol, il se
    décompose en aérobiose (avec une demi-vie d'environ une semaine)
    environ deux fois plus vite qu'en anaérobiose.

         Une fois déposé sur les feuilles de végétaux, le méthomyl est
    rapidement absorbé à hauteur de 50% de la dose - les 50% restant étant
    adsorbés - et rien n'indique qu'il y ait transport à l'intérieur de la
    plante.  La concentration du méthomyl absorbé par les cultures
    vivrières tombe rapidement à environ 5% de sa valeur initiale en
    l'espace d'une semaine.

         Plusieurs invertébrés aquatiques, et en particulier les daphnies,
    sont très sensibles au méthomyl avec des valeurs de la CL50 de
    l'ordre de 10 à 100 µg/litre.

         Les poissons, qu'il s'agisse d'espèces d'eau douce ou d'espèces
    estuarielles, y sont moins sensibles, puisque les valeurs de la CL50
    s'étagent entre 0,5 et 7 mg/litre.  Etant donné la faible persistance
    du méthomyl et sa toxicité aiguë relativement faible pour les
    poissons, le risque encouru par ces derniers est relativement faible.

         Aux doses d'emploi recommandées, le méthomyl n'a pas d'effets
    nocifs sur l'activité microbienne terricole en climat tempéré.

         Le méthomyl est classé comme hautement toxique pour les abeilles
    avec une DL50 topique d'environ 0,1 µg/insecte.

         Les valeurs de la DL50 aiguë par voie orale varient entre 10 et
    40 mg/kg de poids corporel chez diverses espèces d'oiseaux.  Les
    valeurs de CL50 à cinq jours par voie alimentaire vont de 1100 à
    3700 mg/kg de nourriture.  Il y a risque d'intoxication aiguë pour les
    oiseaux, en particulier lorsque le méthomyl est sous forme de
    granulés;  son absorption à partir de nourriture contaminée ne devrait
    cependant pas être mortelle pour les oiseaux.

         La forte toxicité aiguë du méthomyl pour les mammifères de
    laboratoire permet de conclure qu'il est tout aussi dangereux pour les
    mammifères sauvages.

    10.  Conclusion

         Compte tenu des aspects qualitatifs et quantitatifs de la
    toxicité du méthomyl, le groupe de travail a conclu qu'une dose
    quotidienne de 0,03 mg/kg de poids corporel ne devrait probablement
    pas causer d'effets nocifs chez l'homme, quel que soit le mode
    d'exposition.

    Resumen

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         El metomilo es un sólido cristalino blanco con un punto de fusión
    de 77°C y una presión de vapor de 0,72 mPa (25°C).  Tiene una
    solubilidad en agua de 54,7 g/litro y su coeficiente de reparto
    octanol/agua (Kow) es de 1,24.  Es estable en agua estéril a pH 7,
    pero se descompone a pH más elevado, con una semivida de 30 días a pH
    9 y 25°C.

         El procedimiento analítico para la determinación del metomilo en
    muestras diferentes es la extracción seguida de limpieza y análisis
    mediante cromatografía líquida de alto rendimiento o cromatografía
    gas-líquido.  En algunos casos, el metomilo se convierte en su
    derivado oxima o en un derivado fluoróforo (después de la columna)
    antes de su determinación analítica.

    2.  Fuentes de exposición humana y ambiental

         El metomilo de produce haciendo reaccionar el  S-metil- N-
    hidroxitioacetimidato (MHTA) en cloruro de metileno con isocianato de
    metilo gaseoso a 30-50°C.  Es un insecticida de tipo carbamato
    utilizado en una gran diversidad de cultivos en todo el mundo.  Entre
    los cultivos protegidos figuran frutales, vides, lúpulo, hortalizas,
    cereales, soja, algodón y plantas ornamentales.  En espacios cerrados
    se utiliza en establos o vaquerías para luchar contra las moscas.

         Las formaciones principales son polvos hidrosolubles y líquidos
    hidromiscibles, que se diluyen en agua para el rociado superficial o
    aéreo de los cultivos.  Las proporciones normales del principio activo
    son de 0,15-1,0 kg/ha.  La exposición humana ocurre principalmente
    durante la preparación y aplicación de estos productos y por ingestión
    de residuos que quedan en los alimentos cosechados (véase la
    sección 5.3.1.4).

    3.  Transporte, distribución y transformación en el medio ambiente

         En estudios de laboratorio se ha observado que el metomilo se
    adsorbe poco al suelo.  Se ha demostrado una adsorción débil a los
    minerales arcillosos, sobre todo la ilita; la adsorción a la materia
    orgánica del suelo es 50 veces mayor, pero sigue siendo relativamente
    escasa.  Prácticamente no hay desorción del residuo adsorbido.  Estas
    características llevan a prever que el metomilo tendrá movilidad en el
    suelo.

         En condiciones medioambientales naturales, su degradación
    abiótica por hidrólisis o fotólisis es lenta o no se produce.

         La degradación aerobia en el suelo es alrededor de dos veces más
    rápida que la anaerobia.  Las semividas notificadas para el metomilo
    en el suelo varían entre unos días y más de 50.  Las condiciones secas
    retrasan la degradación.  En la práctica, la mayor parte de las
    aplicaciones en el campo deberían dar lugar a una semivida de
    alrededor de una semana.

         En condiciones de campo, el metomilo no sufre lixiviación en el
    suelo a profundidades superiores a 20-30 cm y no contamina las aguas
    subterráneas.

         El 14C-metomilo aplicado a las hojas de las plantas es
    absorbido, pero no transportado a otras partes de la planta.  Se si lo
    aplica en el sistema radicular, la planta lo absorbe y el componente
    principal del residuo que queda es el propio metomilo.  Los productos
    volátiles derivados de su descomposición son CO2 y acetonitrilo.  El
    resto de la actividad se incorpora a los componentes naturales de la
    planta, tales como lípidos, ácidos del ciclo de Krebs y azúcares.  La
    semivida del metomilo en el follaje de la planta es de unos pocos
    días.

         No se han encontrado indicios de acumulación del metomilo en
    truchas irisadas expuestas al compuesto durante 28 días en un sistema
    de flujo continuo.

    4.  Niveles medioambientales y exposición humana

         Los análisis de diversas fuentes de agua tras la aplicación de
    las dosis recomendadas del compuesto indican que los niveles de
    metomilo en las aguas subterráneas probablemente serán muy bajos o
    inferiores al límite de detección (< 0,02 mg/litro).

         En los cultivos de productos alimenticios y de otro tipo se
    observan niveles bajos de residuos de metomilo en el momento de la
    recolección; su concentración depende de diversos factores, como la
    cantidad aplicada, el periodo transcurrido desde la última aplicación
    y el tipo de cultivo.  Los residuos están formados básicamente por
    metomilo.

         Los residuos de metomilo en los productos lácteos no son
    detectables o son muy bajos.  No se observaron residuos detectables de
    metomilo ni del metabolito MHTA en la leche ni en los tejidos
    (< 0,02 mg/kg) de vacas lactantes que habían recibido en el pienso
    cápsulas de metomilo en una concentración equivalente a 80 mg/kg
    durante 28 días.  No se detectó la presencia de metomilo en los huevos
    ni en los tejidos de gallinas ponedoras a las que se habían
    administrado cantidades de 1 ó 10 mg/kg en los alimentos durante
    cuatro semanas.

         En los Estados Unidos de América se hicieron análisis de
    regímenes completos de alimentación y de determinados alimentos; en
    los estudios de muestreo correspondientes, las concentraciones de
    metomilo resultaron inferiores al límite de detección o muy bajas. 
    Los niveles de residuos se reducen aún más por efecto de procesos
    tales como el lavado, pelado y guisado de los alimentos.

         En estudios sobre la exposición de quienes regresan a zonas
    tratadas, en particular en las condiciones del desierto de California,
    se ha observado que los trabajadores que volvieron a los viñedos
    cuando los residuos foliares que podían desprenderse se habían
    reducido a 0,1 µg/cm2, sufrieron la mayor exposición en la parte
    superior del cuerpo y en la cabeza durante el atado de los racimos y
    en la parte superior del cuerpo y en las manos durante la vendimia. 
    La recogida y el embalado de las uvas de mesa dieron lugar a la
    exposición más baja.  La exposición por inhalación fue mínima.

         Tras haberse rociado con metomilo plantas de pepino y tomate, las
    concentraciones en el aire del invernadero llegaban a 4,7 µg/m3 al
    día siguiente del rociado.  Tres y siete días después del rociado, las
    concentraciones de metomilo en la zona de respiración ascendían a
    14,5 y 0,7 µg/m3, respectivamente.  Los valores del metomilo en el
    agua de lavarse las manos oscilaban entre 10 y 322 µg por hora de
    trabajo en un invernadero.  Esto indicaba que la vía de exposición
    cutánea era más importante que la inhalación y que los intervalos
    previos al regreso al lugar tratado deberían basarse en los datos
    sobre la exposición cutánea.

    5.  Cinética y metabolismo en animales de laboratorio

         La absorción, el metabolismo y la excreción del metomilo tras la
    administración oral a ratas es muy rápida, completándose el proceso en
    unos pocos días.  En un plazo de siete días después de la
    administración a ratas de 5 mg/kg de peso corporal de metomilo
    radiomarcado, el 54% se excretó en la orina, el 2-3% en las heces y el
    34% en el aire expirado (en cinco días).  Después de siete días, en
    los tejidos y en el esqueleto quedaba el 8-9% de la dosis de 14C,
    que se había incorporado a los constituyentes endógenos.  La mayor
    concentración de radiactividad se detectó en la sangre (equivalente al
    2% de la dosis).

         Los componentes metabólicos principales en el aire expirado por
    las ratas eran el anhídrido carbónico y el acetonitrilo, en una
    proporción de 2:1.  El principal metabolito en la orina fue el
    derivado mercaptúrico del metomilo, que era igual al 17% de la dosis. 
    No se detectó metomilo ni su derivado oxima.

         La vía metabólica propuesta comprende el desplazamiento del grupo
     S-metilo por el glutatión, seguido de una transformación enzimática
    que da lugar al derivado mercaptúrico.  Otra vía es la hidrólisis, por
    la que se produce MHTA, que se descompone rápidamente hasta dar
    anhídrido carbónico.  Otra vía posible es la conversión del
     sin-metomilo (la forma insecticida) en su  anti-isómero, que sufre
    reacciones de hidrólisis, recomposición y eliminación hasta dar
    acetonitrilo.  El metomilo se metaboliza de forma semejante en el
    mono, salvo que el derivado mercaptúrico es un componente secundario
    en la orina.

         La penetración del 14C-metomilo una hora después de haber sido
    aplicado a ratones por vía cutánea en una solución de acetona se
    estimó en un 85%. Para entonces, el 3% de la dosis se hallaba presente
    en la sangre, el 5% en el hígado y el 13% se había excretado.  En un
    plazo de 8 horas la excreción total era del 54,5%.

         La descomposición y eliminación rápidas del metomilo en la rata,
    junto con su falta de acumulación en los tejidos, son comparables a lo
    observado en rumiantes.

         El metomilo sufre una descomposición completa en las vacas y
    cabras que han recibido una dosis.  No se detectaron metomilo ni su
    derivado oxima en la leche ni en los tejidos de estos animales.  Se
    puso de manifiesto que el producto se metabolizaba e incorporaba a los
    componentes naturales de la leche y del hígado.

         No se detectó la presencia de nitrosometomilo después de haberse
    incubado 14C-metomilo con nitrito sódico en un macerado de carne
    curada, en condiciones que simulaban las del estómago.

    6.  Efectos en mamíferos de laboratorio y en sistemas de prueba
        in vitro

         El metomilo administrado por vía oral tiene una elevada toxicidad
    aguda, con una DL50 oral de 17-45 mg/kg de peso corporal en la rata. 
    También es muy tóxico para la rata por inhalación; en aerosol, la
    CL50 a las 4 horas es de 0,26 mg/litro.  La toxicidad cutánea es muy
    baja; la DL50 es de más de 2000 mg/kg de peso corporal en conejos
    (piel intacta) y > 1000 mg/kg de peso corporal en ratas (piel
    raspada).  Los signos de toxicidad aguda son los que cabe esperar de
    un inhibidor de la colinesterasa, entre otros salivación profusa,
    lacrimación, temblor y contracción pupilar.  La recuperación de estos
    efectos fue rápida.  En los órganos examinados no se observaron
    efectos patológicos graves.  El metomilo no irrita ni sensibiliza la
    piel, pero irrita levemente los ojos.

         La administración repetida de metomilo con los alimentos durante
    periodos más largos no produjo aumento de los efectos tóxicos ni
    acumulación.  Las ratas y perros cuya alimentación contenía metomilo
    en cantidades de hasta 250 mg/kg y 400 mg/kg, respectivamente, durante
    13 semanas no mostraron signos de toxicidad ni acusaron mortalidad. 
    Las ratas que recibieron con los alimentos 250 mg/kg mostraron una
    pequeña disminución en el aumento del peso corporal, niveles de
    hemoglobina más bajos e hiperplasia eritroidea moderada de la médula
    ósea.  El NOEL en ratas fue de 50 mg/kg en los alimentos (equivalentes
    a 3,6 mg/kg de peso corporal por día).  Los conejos que recibieron
    aplicaciones cutáneas repetidas de metomilo en dosis de hasta
    500 mg/kg de peso corporal por día durante 21 días mostraron
    hiperactividad y una reducción de la actividad colinesterásica
    plasmática y cerebral con la dosis más elevada.  El NOAEL en este
    estudio fue de 50 mg/kg de peso corporal por día.

         Se realizaron estudios de larga duración en ratas que recibían
    metomilo en los alimentos en concentraciones de 0, 50, 100 ó 400 mg/kg
    y en ratones que recibían 0, 50, 75 ó 200 mg/kg.  Los efectos de la
    dosis más alta en las ratas fueron una disminución del aumento de peso
    y una reducción de la concentración de hemoglobina y del valor
    hematócrito.  El NOEL fue de 100 mg/kg de alimentos, equivalente a
    5 mg/kg de peso corporal por día.  En el estudio en ratones, se
    observó aumento de la tasa de mortalidad y una reducción de la
    hemoglobina y del número de eritrocitos en los dos niveles de dosis
    más elevados.  El NOEL fue de 50 mg/kg de alimentos, equivalente a
    8,7 mg/kg de peso corporal por día.  En un estudio de dos años sobre
    toxicidad en perros (0, 50, 100, 400 ó 1000 mg/kg de alimentos) con la
    dosis más elevada se detectaron síntomas de toxicidad en algunos
    animales, junto con anemias de ligeras a moderadas.  El NOEL fue de
    100 mg/kg de alimentos, equivalentes a 3 mg/kg de peso corporal por
    día.

         En estudios de dos años en ratas y ratones no se encontró ningún 
    indicio de aumento de la incidencia de tumores relacionado con el
    tratamiento, signo de que el metomilo no es carcinógeno.  No fue
    genotóxico en célula de bacterias o de mamíferos  in vitro y las
    pruebas realizadas para determinar la presencia de lesiones primarias
    del ADN en células de bacterias y de mamíferos  in vitro dieron
    resultados negativos; un estudio cromosómico  in vivo de médula ósea
    de rata también dio resultados negativos.  El potencial citogenético
    del metomilo en linfocitos humanos  in vitro se puso de manifiesto
    mediante un aumento del número de micronúcleos y de aberraciones
    cromosómicas.  El metomilo no produjo efectos embriotóxicos ni
    teratogénicos en ratas ni en conejos en dosis de hasta 400 mg/kg en

    los alimentos y de 16 mg/kg de peso corporal por día administrados por
    sonda, respectivamente; a esos niveles produjo efectos tóxicos en las
    madres.  En un estudio de reproducción de tres generaciones en ratas
    con dosis de 50 ó 100 mg/kg de alimentos (equivalentes a 5 ó 10 mg/kg
    de peso corporal por día), el metomilo no tuvo efectos sobre los
    índices de fecundidad, gestación o lactación y no se produjeron
    anomalías graves relacionadas con el tratamiento.

         No se observó neurotoxicidad retardada después de la
    administración de una sola dosis o de una serie de dosis de metomilo. 
    En un estudio de cinco meses en el que se suministraron a ratas
    800 mg/kg de alimentos se observó una reducción importante de la
    actividad de la colinesterasa sanguínea sólo en las fases iniciales. 
    En un estudio de 28 días, la administración de esa misma dosis con los
    alimentos dio lugar a una reducción ligera solamente de la actividad
    de la colinesterasa cerebral.  Esto indica que la inhibición de la
    actividad de la colinesterasa por el metomilo es reversible
    rápidamente en los animales durante los periodos de ingestión.
     In vitro, la actividad de la eritrocito colinesterasa humana fue
    seis veces más sensible a la acción inhibidora del metomilo que la de
    la rata, aunque los índices de reactivación espontánea fueron
    semejantes.

         Los resultados obtenidos en estudios realizados con varias
    especies mostraron que la atropina es el antídoto de eficacia más
    general contra la intoxicación por metomilo.

    7.  Efectos en el ser humano

         Las notificaciones de intoxicaciones accidentales y suicidas con
    metomilo proporcionan alguna información sobre los niveles de efectos
    y la recuperación.  Tres de cinco víctimas accidentales de
    intoxicación por una comida contaminada murieron antes de que
    transcurrieran tres horas desde la ingestión.  Se estimó que las
    víctimas habían consumido alrededor de 12-15 mg de metomilo/kg de peso
    corporal.  Una mujer de 31 años y su hijo de seis, que murieron a
    causa de un envenenamiento deliberado, tenían en el hígado
    concentraciones de metomilo de 15,4 y 56,5 mg/kg, respectivamente. 
    Las dosis estimadas fueron de 55 mg/kg de peso corporal para la madre
    y de 13 mg/kg de peso corporal para el hijo.  Seis horas después de
    haber ingerido unos 2,25 g de metomilo, la sangre de una mujer
    contenía 1,6 mg de metomilo/kg.  A las 22 horas de la ingestión no se
    podía detectar la presencia de metomilo y la mujer se estaba
    recuperando.

         Un operario que manipulaba plaguicidas había mezclado, sin tomar
    precauciones, una formulación de metomilo en polvo para el rociado de
    hortalizas; antes de una hora manifestó síntomas de intoxicación y
    después de 12 horas la actividad de colinesterasa sanguínea se había
    reducido al 40% de la normal; a las 36 horas la recuperación llegaba
    al 80% de la actividad normal.  Otros operarios que habían tomado las
    precauciones recomendadas no acusaron ningún síntoma ni efectos en la
    actividad de la colinesterasa eritrocitaria y plasmática durante
    actividades de aplicación aérea de metomilo.

    8.  Efectos en organismos no destinatarios en el laboratorio y sobre
        el terreno

         No se observaron efectos en poblaciones de hongos y bacterias del
    suelo, en particular en su acción nitrificante y en la actividad de la
    deshidrogenasa después de haberse aplicado metomilo en las dosis
    recomendadas.

         En estudios de laboratorio se determinó una NOEC de
    6,5 mg/litro para el crecimiento de las algas.

         El metomilo tiene una toxicidad entre moderada y alta para los
    peces, con una CL50 a las 96 horas de 0,5 a 2 mg/litro para una
    serie de especies.  En un estudio de mayor duración (21 días),
    utilizando la formulación Lannate 20L (21,5% de metomilo), la CL50
    para los alevines de trucha fue de 1,3 mg/litro.  En un estudio de
    toxicidad de 28 días durante la primera fase de la vida de piscardos
     (Pimaphales promelas), la máxima concentración intoxicante aceptable
    (MATC) estimada fue de > 57 y < 117 µg/litro.

         En pruebas de toxicidad aguda con otros organismos acuáticos,
    Daphnia magna fue una de las especies más vulnerables al metomilo, con
    una CL50 de 0,032 mg/litro a las 48 horas.  En un estudio de 21 días
    sobre la capacidad de supervivencia, crecimiento y reproducción de
    Daphnia magna, la máxima concentración intoxicante aceptable para el
    metomilo fue de > 1,6 y < 3,5 µg/litro.

         El metomilo es tóxico para las abejas melíferas; se ha notificado
    una DL50 por contacto de 1,29 µg/abeja y una DL50 oral de
    0,2 µg/abeja.

         Se ha evaluado la toxicidad aguda del metomilo en varias especies
    de aves; los valores característicos de la DL50 oral aguda son de
    10 mg/kg de peso corporal en palomas y de 34 mg/kg de peso corporal en
    la codorniz japonesa.  El metomilo es relativamente menos tóxicos si
    se ingiere con los alimentos; en ese caso, la CL50 en ocho días es
    de 1100 mg/kg de metomilo en los alimentos para la codorniz  Colinus
     virginianus y de 2883 mg/kg de metomilo en los alimentos para el
    pato silvestre.  En estudios de una generación realizados durante 18 a
    20 semanas, la NOEC fue de 150 mg/kg de metomilo en los alimentos para
    la codorniz  Colinus virginianus y para el pato silvestre.

         No se observaron efectos sobre Colinus virginianus tras su
    exposición a una serie de aplicaciones de metomilo por rociado en las
    dosis recomendadas.  En dos estudios sobre poblaciones de aves
    silvestres, después de haberse rociado con metomilo tierras forestales
    y campos de lúpulo en las dosis recomendadas, no se observó ningún
    cambio manifiesto en la actividad de las aves ni se produjeron efectos
    ni mortalidad relacionados con el tratamiento.  Los depósitos de grasa
    de las aves canoras de los bosques tratados se redujeron en
    comparación con el grupo testigo; se consideró que se trataba de un
    efecto indirecto de la disminución de los insectos que les sirven de
    alimento.

    9.  Evaluación de los riesgos para la salud humana y efectos en el
        medio ambiente

         El metomilo es un inhibidor de la carbamato colinesterasa
    mediante un mecanismo bien conocido de acción tóxica.  En estudios
    realizados en animales se ha observado una toxicidad aguda
    particularmente alta por vía oral y respiratoria, pero la toxicidad
    por vía cutánea es baja.  Los signos de toxicidad aguda en animales
    son los característicos de los inhibidores de la colinesterasa.  La
    reversibilidad de la acción tóxica aguda es rápida; los supervivientes
    se recuperan con rapidez de los signos tóxicos y de la inhibición de
    la colinesterasa en la sangre y el cerebro.  La pronta remisión de los
    efectos tóxicos se debe a la rápida reversibilidad de la inhibición de
    la colinesterasa, reversibilidad favorecida por la eliminación rápida
    del metomilo del organismo.  Los datos sobre intoxicaciones humanas
    accidentales e intencionales muestran que el nivel de toxicidad aguda
    del metomilo en el ser humano es semejante al observado en los
    animales de laboratorio.

         Habida cuenta de la reversibilidad rápida de la acción del
    metomilo durante los periodos de ingestión, en los estudios realizados
    raramente se observaron síntomas de toxicidad aguda e inhibición de la
    colinesterasa sanguínea.  Los resultados más constantes en los
    estudios de mayor duración con niveles de alimentación más elevados
    fueron una reducción del aumento del peso corporal en roedores y una
    disminución del número de glóbulos rojos en roedores y perros.  No se
    observaron indicios de carcinogenicidad potencial en tres estudios de
    larga duración realizados en roedores.  El compuesto dio resultados
    negativos en las pruebas de genotoxicidad  in vitro en las que se
    investigaron varios puntos finales, en cambio mostró potencial
    citogenético en linfocitos humanos.  El resultado de un estudio
    cromosómico realizado  in vivo sobre médula ósea de rata fue
    negativo.

         Se identificaron los NOEL en cada uno de los estudios de larga
    duración realizados con animales, teniendo en cuenta la reducción del
    aumento del peso corporal y el número de eritrocitos.  Los NOEL
    resultaron ser de 5 mg/kg de peso corporal por día en ratas, 8,7 mg/kg
    de peso corporal por día en ratones y 3 mg/kg de peso corporal por día
    en perros.  Como esos estudios no revelaron diferencias acentuadas
    entre especies en cuanto a los efectos tóxicos, se debería utilizar el
    NOEL en el perro, que es de 3 mg/kg de peso corporal por día, a
    efectos de la estimación del riesgo en el ser humano.

         La adsorción del metomilo al suelo es de baja a moderada, y
    prácticamente no hay desorción.  La degradación aerobia en el suelo
    (con una semivida de alrededor de una semana) es aproximadamente dos
    veces más rápida que la degradación anaerobia.

         La aplicación de metomilo a hojas de plantas da lugar a una
    absorción rápida de casi la mitad de la cantidad aplicada (la otra
    mitad se adsorbe) y no hay indicios de transporte.  La concentración
    del metomilo absorbido en los cultivos de productos alimenticios
    disminuye rápidamente hasta alrededor del 5% en una semana.

         Varios invertebrados acuáticos, en particular los dáfnidos, son
    muy sensibles al metomilo, con CL50 del orden de 10 a 100 µg/litro.

         Los peces, tanto de agua dulce como estuarinos, son menos
    sensibles, oscilando la CL50 entre 0,5 y 7 mg/litro.  Dada la escasa
    persistencia del metomilo y su toxicidad aguda relativamente baja para
    los peces, se supone que el riesgo es bajo.

         En las dosis de aplicación recomendadas, el metomilo no menoscaba
    la actividad microbiana en suelos templados.

         Este producto está clasificado como muy tóxico para las abejas
    melíferas y su DL50 tópica es de aproximadamente 0,1 µg/abeja.

         La DL50 aguda por vía oral para varias especies de aves oscila
    entre 10 y 40 mg/kg de peso corporal.  Los valores de la CL50 en la
    alimentación (cinco días) varían entre 1100 y 3700 mg/kg de alimentos. 
    El metomilo, sobre todo en forma de gránulos, constituye un riesgo
    agudo para las aves, pero no se prevé que la ingestión de alimentos
    contaminados con metomilo pueda causarles la muerte.

         La elevada toxicidad aguda del metomilo para los mamíferos de
    laboratorio indica que existe un peligro semejante para los mamíferos
    silvestres.

    10.  Conclusiones

         Teniendo en cuenta las características cualitativas y
    cuantitativas de la toxicidad del metomilo, el Grupo de Trabajo llegó
    a la conclusión de que 0,03 mg/kg de peso corporal al día
    probablemente no causarían efectos adversos en el ser humano por
    ninguna vía de exposición.
    


    See Also:
       Toxicological Abbreviations
       Methomyl (HSG 97, 1995)
       Methomyl (ICSC)
       Methomyl (PDS)
       Methomyl (WHO Pesticide Residues Series 5)
       Methomyl (Pesticide residues in food: 1976 evaluations)
       Methomyl (Pesticide residues in food: 1977 evaluations)
       Methomyl (Pesticide residues in food: 1978 evaluations)
       Methomyl (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Methomyl (Pesticide residues in food: 1989 evaluations Part II Toxicology)
       Methomyl (JMPR Evaluations 2001 Part II Toxicological)