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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 130





    ENDRIN









    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.

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

    First draft prepared by Dr G. T. van Esch, Bilthoven,
    Netherlands, and Dr E. A. H. van Heemstra-Lequin,
    Laren, Netherlands.

    World Health Orgnization
    Geneva, 1992


         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of
    chemicals.

    WHO Library Cataloguing in Publication Data

    Endrin.

        (Environmental health criteria ; 130)

        1.Endrin - toxicity 2.Environmental exposure 
        I.Series

        ISBN 92 4 157130 6        (NLM Classification: WA 240)
        ISSN 0250-863X

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    CONTENTS

    1.   SUMMARY AND EVALUATION; CONCLUSIONS; RECOMMENDATIONS

         1.1   Summary and evaluation
               1.1.1   Exposure
               1.1.2   Uptake, metabolism, and excretion
               1.1.3   Effects on organisms in the environment
               1.1.4   Effects on experimental animals and  in vitro
               1.1.5   Effects on human beings
         1.2   Conclusions
         1.3   Recommendations

    2    IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES,
         ANALYTICAL METHODS

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

    3.   SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1   Natural occurrence
         3.2   Man-made sources
               3.2.1   Production levels and processes, uses
                       3.2.1.1   World production figures
                       3.2.1.2   Manufacturing processes

    4.   ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1   Transport and distribution between media
               4.1.1   Air
               4.1.2   Water
               4.1.3   Soil
               4.1.4   Soil-plants
         4.2   Abiotic degradation
         4.3   Biotransformation
               4.3.1   Biodegradation
               4.3.2   Bioaccumulation and biomagnification

    5.   ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1   Environmental levels
               5.1.1   Air
               5.1.2   Soil, sediments, and sewage sludge
                       5.1.2.1   Soil
                       5.1.2.2   Sediments
                       5.1.2.3   Sewage sludge

               5.1.3   Water
                       5.1.3.1   Surface water
                       5.1.3.2   Rain and snow
                       5.1.3.3   Drinking-water
                       5.1.3.4   Groundwater
               5.1.4   Organisms in the environement
                       5.1.4.1   Birds
                       5.1.4.2   Fish and shellfish
                       5.1.4.3   Mixed species
               5.1.5   Other food and feed
                       5.1.5.1   Cereals
                       5.1.5.2   Fruit and vegetables
                       5.1.5.3   Meat, poultry, and chicken eggs
                       5.1.5.4   Milk and milk products

                       5.1.5.5   Fat and oils
                       5.1.5.6   Animal feed
               5.1.6   Miscellaneous products
         5.2   Exposure of the general population
               5.2.1   Total-diet studies
               5.2.2   Levels in human tissues
                       5.2.2.1   Adipose tissue
                       5.2.2.2   Organs
                       5.2.2.3   Blood
                       5.2.2.4   Breast milk
                       5.2.2.5   Appraisal of exposure of the general
                                 population

         5.3   Occupational exposure during manufacture, formulation,
               and use
               5.3.1   Manufacture and formulation
               5.3.2   Application
               5.3.3   Appraisal of occupational exposure

    6.   KINETICS AND METABOLISM
         6.1   Absorption, distribution, and elimination
               6.1.1   Laboratory animals
                       6.1.1.1  Oral administration
                       6.1.1.2  Intravenous administration
               6.1.2   Domestic animals
               6.1.3   Human beings
               6.1.4   Systems  in vitro
         6.2   Biotransformation
               6.2.1   Experimental animals
               6.2.2   Human beings
               6.2.3   Microorganisms
               6.2.4   Plants

    7.   EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1   Microorganisms
         7.2   Aquatic organisms
               7.2.1   Invertebrates
               7.2.2   Fish
                       7.2.2.1   Acute toxicity
                       7.2.2.2   Short-termtoxicity
                       7.2.2.3   Studies of resistance
                       7.2.2.4   Interaction with other chemicals
                       7.2.2.5   Special studies
               7.2.3   Amphibia
         7.3   Terrestrial organisms
               7.3.1   Honey bees
               7.3.2   Birds
                       7.3.2.1   Acute toxicity
                       7.3.2.2   Short-term toxicity
                       7.3.2.3   Studies of reproduction
                       7.3.2.4   Interaction with other chemicals
                       7.3.2.5   Special studies
                       7.3.2.6   Behavioural studies
               7.3.3   Mammals
                       7.3.3.1   Toxicity
                       7.3.3.2  Studies of resistance
         7.4   Effects in the field
         7.5   Appraisal of effects on organisms in the environment

    8.   EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO

         8.1   Acute toxicity of technical-grade endrin
               8.1.1   Oral administration
               8.1.2   Dermal administration
               8.1.3   Parenteral administration
               8.1.4   Toxicity of metabolites and isomers
                       8.1.4.1   Mammalian metabolites
                       8.1.4.2   Isomers
               8.1.5   Acute toxicity of formulated material
                       8.1.5.1   Oral and dermal administration
                       8.1.5.2   Inhalation
         8.2   Short-term exposure
               8.2.1   Oral administration
                       8.2.1.1   Mouse
                       8.2.1.2   Rat
                       8.2.1.3   Rabbit
                       8.2.1.4   Dog
                       8.2.1.5   Domestic animals
               8.2.2   Inhalation
               8.2.3   Dermal administration

         8.3   Skin irritation
         8.4   Reproduction, embryotoxicity, and teratogenicity
               8.4.1   Reproduction
                       8.4.1.1   Mouse
                       8.4.1.2   Rat
               8.4.2   Embryotoxicity and teratogenicity
                       8.4.2.1   Mouse
                       8.4.2.2   Rat
                       8.4.2.3   Hamster
                       8.4.2.4   Perinatal behavioural development
               8.4.3   Appraisal of reproductive effects
         8.5   Mutagenicity and related end-points
               8.5.1   Effects on microorganisms
               8.5.2   Point mutations in mammalian cells
               8.5.3   Dominant lethal mutations
               8.5.4   Chromosomal and cytogenetic effects
               8.5.5   Host-mediated effects
               8.5.6   Sister chromatid exchange
               8.5.7   Effects in  Drosophila melanogaster
               8.5.8   Effects on DNA
               8.5.9   Appraisal of mutagenicity and related end-points
         8.6   Long-term exposure
         8.7   Carcinogenicity
               8.7.1   Oral administration
                       8.7.1.1   Mouse
                       8.7.1.2   Rat
                       8.7.1.3   Tumour promotion
               8.7.2   Appraisal of carcinogenicity
         8.8   Special studies
               8.8.1   Nervous system
                       8.8.1.1   Electrophysiological studies
                       8.8.1.2   Histopathological studies
                       8.8.1.3   Neurotransmitter systems
                       8.8.1.4   Appraisal of effects on the nervous
                                 system
               8.8.2   Cardiovascular system
               8.8.3   Effects on liver enzymes
                       8.8.3.1   Mouse
                       8.8.3.2   Rat
                       8.8.3.3   Guinea-pig
                       8.8.3.4   In-vitro studies
               8.8.4   Miscellaneous studies
               8.8.5   Factors that influence toxicity
                       8.8.5.1   Nutrition
                       8.8.5.2   Potentiation

    9.   EFFECTS ON HUMAN BEINGS

         9.1   Exposure of the general population
               9.1.1   Acute toxicity
               9.1.2   Poisoning incidents

         9.2   Occupational exposure
               9.2.1   Factory workers
               9.2.2   Dose-response relationships
               9.2.3   Exposures to mixtures
               9.2.4   Appraisal of effects of occupational exposures

    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    ANNEX  I   Chemical names of endrin and its  metabolites
    ANNEX II   Medical treatment of endrin poisoning
    ANNEX III  Management of major status epilepticus in adults

    RESUME
    RESUMEN
    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA
    FOR ENDRIN

     Members

    Dr L.A. Albert, Consultores Ambientales Asociados, Xalapa, Veracruz,
        Mexico

    Dr V. Benes, Department of Toxicology and Reference Laboratory,
        Institute of Hygiene and Epidemiology, Prague, Czechoslovakia

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
        Experimental Station, Huntingdon, United Kingdom

    Dr G.J. van Esch, Bilthoven, Netherlands  (Rapporteur)

    Dr E.A.H. van Heemstra-Lequin, Laren, Netherlands  (Rapporteur)

    Dr S.K. Kashyap, National Institute of Occupational Health,
        Ahmedabad, India

    Dr Yu.I. Kundiev, Research Institute of Labour Hygiene and
        Occupational Diseases, Kiev, Ukraine  (Vice-Chairman)

    Dr Y. Osman, Ministry of Health, Riyadh, Saudi Arabia

    Dr H. Spencer, United States Environmental Protection Agency,
        Washington DC, USA  (Chairman)

    Dr C. Winder, National Institute of Occupational Health and Safety,
        Forest Lodge, New South Wales, Australia

     Secretariat

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

    Ms B. Labarthe, International Register of Potentially Toxic
        Chemicals, United Nations Environment Programme, Geneva,
        Switzerland

    Dr T.K. Ng, Office of Occupational Health, World Health
        Organization, Geneva, Switzerland

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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

                                    * * *

        A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Palais des
    Nations, 1211 Geneva 10, Switzerland (Telephone no. 7988400 or
    7985850).

                                    * * *

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

    ENVIRONMENTAL HEALTH CRITERIA FOR ENDRIN

        A WHO Task Group on Environmental Health Criteria for Endrin and
    Isobenzan met at the World Health Organization, Geneva, from 23 to 27
    July 1990. Dr K.W. Jager, IPCS, welcomed the participants on behalf of
    Dr M. Mercier, Director of IPCS, and the three IPCS cooperating
    organizations (UNEP, ILO, WHO). The Group reviewed and revised the
    draft Criteria monographs and Health and Safety Guides and made an
    evaluation of the risks to human health and the environment from
    exposure to endrin and isobenzan.

        The first drafts of these monographs were prepared in cooperation
    between Dr E.A.H. van Heemstra-Lequin and Dr G.J. van Esch of the
    Netherlands. Dr van Esch prepared the second drafts, incorporating the
    comments received following circulation of the first drafts to the
    IPCS contact points for Environmental Health Criteria monographs.

        Dr K.W. Jager of the IPCS Central Unit was responsible for the
    scientific content of the monographs, and Mrs E. Heseltine, St
    Léon-sur-Vézère, France, for the editing.

        The fact that Shell Oil Co. made available to IPCS and the Task
    Group proprietary toxicological information on their products is
    gratefully acknowledged. This allowed the Task Group to base their
    evaluation on more complete data.

        The effort of all who helped in the preparation and finalization
    of the monographs is gratefully acknowledged.

                                    * * *

        Partial financial support for the publication of this Criteria
    monograph was kindly provided by the United States Department of
    Health and Human Services, through a contract from the National
    Institute of Environmental Health Sciences, Research Triangle Park,
    North Carolina, USA, a WHO Collaborating Centre for Environmental
    Health Effects.

    1.  SUMMARY AND EVALUATION; CONCLUSIONS; RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Exposure

         Endrin is an organochlorine insecticide which has been used since
    the 1950s against a wide range of agricultural pests, mostly on cotton
    but also on rice, sugar-cane, maize, and other crops. It is also used
    as a rodenticide. It is available commercially as dusts, granules,
    pastes, and an emulsifiable concentrate.

         Endrin enters the air mainly by volatilization and aerial drift.
    In general, volatilization takes place after application to soils and
    crops and depends on many factors, such as the organic matter and
    moisture content of the soil, humidity, air flow, and the surface area
    of plants.

         The most important route of contamination of surface water is
    run-off from soil. Contamination from precipitation in the form of
    snow or rain is negligible. Local contamination of the environment may
    occur from industrial effluents and careless application practices.

         The major source of endrin in soil is from direct application to
    soil and crops. Endrin can be retained, transported, or degraded in
    soil, depending on a number of factors. The greatest retention occurs
    in soils with a high content of organic matter. The persistence of
    endrin is highly dependent upon local conditions; its half-life in
    soil can range up to 12 years. Volatilization and photodecomposition
    are the primary factors in the disappearance of endrin from soil
    surfaces. Under the influence of sunlight (ultraviolet light), the
    isomer delta-ketoendrin is formed. In intense summer sun, about 50% of
    endrin was isomerized to this ketoendrin within 7 days. Microbial
    transformation (in fungi and bacteria) takes place, especially under
    anaerobic conditions, to give the same product.

         Aquatic invertebrates and fish take up endrin rapidly from water,
    but exposed fish transferred to uncontaminated water lose the
    pesticide rapidly. Bioconcentration factors of 14-18 000 have been
    recorded after continuous exposure. Soil invertebrates may also take
    up endrin readily.

         The occasional presence of low levels of endrin in air and in
    surface and drinking-water in agricultural areas is of little
    significance from the point of view of public health. The only
    exposure that may be relevant is dietary intake. In general, however,
    the reported intake levels are far below the acceptable daily intake
    of 0.0002 mg/kg body weight established in 1970 (FAO/WHO, 1971).

    1.1.2  Uptake, metabolism, and excretion

         Unlike dieldrin, its stereoisomer, endrin is metabolized rapidly
    by animals, and very little is accumulated in fat in comparison with
    compounds of similar chemical structure.

         Both uptake and excretion after oral administration are rapid in
    rats, and its biological half-life is 1-6 days, depending on the dose
    level. A steady state, at which the excreted amount equals the daily
    intake, is reached after 6 days. A sex difference is observed, in that
    males excrete endrin and metabolites via the bile much faster than
    females, resulting in less accumulation in male adipose tissue. Rats
    excrete this compound mainly in the faeces as endrin,
     anti-12-hydroxyendrin, and a hydroxylated endrin derivative within
    the first 24 h (70-75%); a third metabolite, 12-ketoendrin,
    accumulates in tissues. Rabbits excrete 50% of the metabolites of
    endrin in urine, whereas in rats only 2% are excreted by this route;
    only unchanged endrin is found in the faeces of rabbits.

         Cows administered endrin at 0.1 mg/kg of diet for 21 days
    excreted up to 65% as metabolites in urine, 20% in faeces, partly as
    unchanged endrin, and 3% in milk, also mainly as endrin. These cows
    had residue levels of 0.003-0.006 mg/litre in milk, 0.001-0.002 mg/kg
    in meat, and 0.02-0.1 mg/kg in fat.

         Laying hens fed endrin showed residue levels (depending on the
    doses given) of up to 0.1 mg/kg in meat, 1 mg/kg in fat, 0.1-0.2 mg/kg
    in eggs (yolk), 0.4 mg/kg in kidney, and 0.5 mg/kg in liver. Except in
    liver and kidney, the residues found were mainly unchanged endrin.
    About 50% of the administered endrin was excreted in faeces, mainly as
    metabolites.

         In human beings, rats, rabbits, cows, and hens, the major
    biotransformed metabolite of endrin is  anti-12-hydroxyendrin,
    together with its sulfate and glucuronide conjugates. Four other
    metabolites were found but in only minor quantities. Mainly unchanged
    endrin is found in body tissues and milk. After this pesticide was
    applied to plants, unchanged endrin and two hydrophilic transformation
    products were identified.

    1.1.3  Effects on organisms in the environment

         The effect of endrin on soil bacteria and fungi is minimal. Dose
    levels of 10-1000 mg/kg of soil had no effect on decomposition of
    organic matter, denitrification, or generation of methane. Endrin is
    very toxic to fish, aquatic invertebrates, and phytoplankton: the 96-h
    LC50 values are mostly below 1.0 µg/litre. The lowest observed
    adverse effect level in a life cycle test on the mysid shrimp,
     Mysidopsis bahia, was established at 30 ng/litre.

         The reported tests on the acute toxicity of endrin in aquatic
    organisms were conducted in aquaria without sediment; the presence of
    sediment would be expected to attenuate the effect of endrin. Heavily
    contaminated sediment had little effect on species living in open
    water, suggesting that sediment-bound endrin has low bioavailability.
    Tests have not been conducted on aquatic animals living in sediment.

         The LD50 for terrestrial mammals and birds is in the order of
    1.0-10.0 mg/kg body weight. Mallard ducks fed up to 3.0 mg/kg body
    weight for 12 weeks showed no effect on egg production, fertility, or
    hatchability.

         Certain species of aquatic invertebrates, fish, and small mammals
    have been reported to be resistant to the toxicity of endrin, and
    exposure to several different organochlorine pesticides led to
    selection of strains resistant to endrin.

         Fish kills were observed in areas of agricultural run-off and
    industrial discharge; and declining populations of brown pelicans (in
    Louisiana, USA) and of sandwich terns (in the Netherlands) have been
    attributed to exposure to endrin in combination with other halogenated
    chemicals.

    1.1.4  Effects on experimental animals and in vitro

         Endrin is a highly toxic pesticide, the signs of intoxication
    being neurotoxic. The oral LD50 of technical-grade endrin for
    laboratory animals is in the range of 3-43 mg/kg body weight; the
    dermal LD50 for rats is 5-20 mg/kg body weight. No substantial
    difference in acute oral or dermal toxicity was found between
    technical-grade and formulated (emulsifiable concentrate and wettable
    powder) products.

         Short-term experiments for oral toxicity have been carried out
    using mice, rats, rabbits, dogs, and domestic animals. In mice and
    rats, the maximum tolerated doses for 6 weeks were 5 and 15 mg/kg diet
    (equivalent to 0.7 mg/kg body weight), respectively. Rats survived a
    16-week exposure to 1 mg/kg diet (equivalent to 0.05 mg/kg body
    weight); rabbits died after receiving repeated doses of 1 mg/kg body
    weight. In dogs, a dose of 1 mg/kg of diet (approximately equivalent
    to 0.025 mg/kg body weight), given over 2 years, was without effect.

         The neurological basis of the observed signs of intoxication is
    inhibition of gamma-aminobutyric acid (GABA) function at low doses.
    Like other chlorinated hydrocarbon insecticides, endrin also affects
    the liver, and stimulation of enzyme systems involved in the
    metabolism of other chemicals is evident, as shown by, for instance,
    decreased hexobarbital sleeping time in mice.

         Doses of 75-150 mg/kg applied dermally as a dry powder for 2 h
    daily caused convulsions and death in rabbits but did not result in
    skin irritation. Production of systemic toxicity without irritation at
    the site of contact is noteworthy.

         Long-term studies of toxicity and carcinogenicity have been
    performed in mice and rats. No carcinogenic effect was found, but
    these studies had shortcomings, including poor survival of the
    animals. The no-observed-effect level for toxicity in a two-year study
    in rats was 1 mg/kg of diet (equivalent to about 0.05 mg/kg body
    weight). Tumour promoting effects were not demonstrated when endrin
    was tested in combination with subminimal quantities of chemicals
    known to be carcinogenic to animals. The Task Group concluded that the
    data are insufficient to indicate that endrin is a carcinogenic hazard
    to humans.

         Endrin was found to be nonmutagenic in several studies.

         In most studies, it was not teratogenic to mice, rats, or
    hamsters, even at doses that caused maternal or fetotoxicity. The
    no-observed-adverse-effect level was 0.5 mg/kg body weight in mice and
    rats and 0.75 mg/kg body weight in hamsters. Endrin did not induce
    reproductive effects in rats over three generations when given at a
    dose of 2 mg/kg of diet (about 0.1 mg/kg body weight).

         A number of the metabolites of endrin have similar or higher
    acute toxicities than the parent compound. The transformation product,
    delta-ketoendrin, is less toxic than endrin, but 12-ketoendrin is
    considered to be the most toxic metabolite of endrin in mammals, with
    an oral LD50 in rats of 0.8-1.1 mg/kg body weight.

    1.1.5  Effects on human beings

         Several episodes of fatal and non-fatal accidental and suicidal
    poisoning have occurred. Cases of acute non-fatal intoxication due to
    accidental over-exposure were observed in workers in an endrin
    manufacturing plant. The oral dose that causes death has been
    estimated to be approximately 10 mg/kg body weight; the single oral
    dose that causes convulsions was estimated to be 0.25-1.0 mg/kg body
    weight.

         The primary site of action of endrin is the central nervous
    system. Exposure of humans to a toxic dose may lead within a few hours
    to such signs and symptoms of intoxication as excitability and
    convulsions, and death may follow within 2-12 h after exposure if
    appropriate treatment is not administered immediately. Recovery from
    non-fatal poisoning is rapid and complete.

         Endrin does not accumulate in the human body to any significant
    degree. No long-term adverse effects were reported in 232
    occupationally exposed workers (length of exposure, 4-27 years) under

    medical supervision (observation time, 4-29 years). The only effect
    observed was indirect evidence of a reversible stimulation of drug
    metabolizing enzymes.

         Endrin was detected in virtually none of a large number of
    samples of adipose tissue, blood, and breast milk analysed in many
    countries. The Task Group attributed the absence of endrin in human
    samples to the low exposure of the general population to this
    pesticide and to its rapid metabolism.

         Endrin was detected in blood (at up to 450 µg/litre) and in
    adipose tissue (at 89.5 mg/kg) in cases of fatal accidental poisoning.
    No endrin was found in workers under normal circumstances. The
    threshold level of endrin in blood, below which no sign or symptom of
    intoxication occurs, has been estimated to be 50-100 µg/litre. The
    half-life of endrin in blood may be in the order of 24 h.

    1.2  Conclusions

         Endrin is an insecticide with high acute toxicity. It may cause
    severe poisoning in cases of over-exposure caused by careless handling
    during its manufacture and use or by consumption of contaminated food.
    The general public is exposed to endrin mainly as its residues in
    food; however, the reported intake of endrin is generally far below
    the acceptable daily intake established by FAO/WHO. Such exposures
    should not constitute a health hazard to the general population. When
    good work practices, hygiene measures, and safety precautions are
    enforced, endrin is unlikely to present a hazard to exposed workers.

         It is clear that uncontrolled discharges of endrin during its
    manufacture, formulation, and use can result in acute environmental
    problems associated with its high toxicity. The effects on wildlife of
    its agricultural use are less clear, although fish and fish-eating
    birds are at risk from surface run-off. Declines in the populations of
    some avian species have been associated with the presence of high
    levels of residues of various organochlorines in the tissues of adults
    and in eggs. Endrin has been measured in some of these species;
    however, it is very difficult to separate the effects of the different
    organochlorines present.

    1.3  Recommendations

         1.   Endrin should not be used unless it is indispensable and
         only when no less toxic alternative is available.

         2.   For the health and welfare of workers and the general
         population, the handling and application of endrin should be
         entrusted only to competently supervised, well-trained operators
         who will follow adequate safety measures and apply endrin
         according to good agricultural practices.

         3.   The manufacture, formulation, agricultural use, and disposal
         of endrin should be managed carefully to minimize contamination
         of the environment, particularly surface water.

         4.   People exposed regularly to endrin should undergo periodic
         health evaluations.

         5.   Epidemiological studies of exposed worker populations should
         be continued.

         6.   In countries where endrin is still used, food should be
         monitored for endrin residues.

         7.   If the use of endrin continues, more information should be
         obtained on the presence, ultimate fate, and toxicity of
         12-ketoendrin and delta-ketoendrin.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    CAS chemical name:           (1a-alpha,2ß,2aß,3-alpha,6-alpha,6aß,
                                 7ß,7a-alpha)-3,4,5,6,9.9-hexachloro
                                 1a,2,2a,3,6,6a,7,7a-octahydro-2,7:3,6-
                                 dimethanonaphth[2,3-b]oxirene
                                 (9CI-CAS)

    Former CAS chemical name:    1,2,3,4,10,10-hexachloro-6,7-epoxy-
                                 1,4,4a,5,6,7,8,8a-octahydro-1,4-
                                  endo,endo-5,8-dimethanonaphthalene

    IUPAC chemical name:         1 R,4 S,4a S,5 S,6 S,7 R,8 R,8a 
                                  R)-1,2,3,4,10,10-hexachloro-
                                 1,4,4a,5,6,7,8,8a-octahydro-6,7-
                                 epoxy-1,4:5,8- dimethanonaphthalene

    Chemical structure:

    FIGURE 1

    Endrin is the  endo,endo stereoisomer of dieldrin

    Empirical formula:           C12H8Cl6O

    Relative molecular mass:     380.93

    Common name:                 Endrin

    CAS registry number:         72-20-8

    RTECS registry number:       I01575000

    Synonyms:                    Endrex, Experimental Insecticide 269,
                                 Hexadrin, Nendrin, NCI-COO157,
                                 ENT17251, OMS 197, and Mendrin

    Trade name:                  Endrin

    Purity:                      Not less than 92%. Impurities include
                                 dieldrin (0.42%), aldrin (0.03%),
                                 isodrin (0.73%), endrin half-cage
                                 ketone (1.57%), endrin aldehyde
                                 (0.05%), and heptachloronorbornene
                                 (0.09%) (Donoso et al., 1979).

    2.2  Physical and chemical properties

    Table 1. Physical and chemical properties of endrin
                                                                 
    Physical state           Crystalline solid

    Colour                   White to light-tan

    Odour                    Mild chemical

    Melting-point            226-230 °C
                             (decomposes at above 245 °C)

    Flash-point              None (dry powder is non-flammable,
                             but commercial solutions contain
                             inflammable liquids with flash-points
                             as low as 27 °C)

    Explosion limits         Non-explosive

    Specific gravity
     (density)               1.64 g/ml at 20 °C

    Vapour pressure          2.7 x 10-7 mmHg at 25 °C
                             (36 µPa at 25 °C)

    Solubility in water      Practically insoluble
                             (0.23 mg/litre at 25 °C)

    Solubility in organic    Sparingly soluble in alcohol and
    solvents                 petroleum hydrocarbons; moderately
                             soluble in aliphatic hydrocarbons;
                             and quite soluble in solvents such
                             as acetone, benzene, carbon
                             tetrachloride, and xylene

    Log P octanol/water      5.34
    partition coefficient
                                                                 
    Stability:    Technical-grade endrin is stable in storage at ambient
                  temperatures. Endrin is stable in formulations with
                  basic reagents, alkaline oxidizing agents, emulsifiers,
                  wetting agents, and solvents. It isomerizes under the
                  influence of ultraviolet light. It reacts with
                  concentrated mineral acids, acid catalysts, acid
                  oxidizing agents and active metals. When mixed with
                  certain catalytically active carriers, endrin tends to
                  decompose; however, most active dust carriers can be
                  deactivated by the addition of hexamethylenetetramine
                  and form stable mixtures with endrin. When heated to
                  above 200 °C, endrin undergoes molecular rearrangements
                  to form delta-ketoendrin, a compound that is less active
                  as an insectide (IARC, 1974; Donoso et al., 1979).


    2.3  Conversion factors

         1 ppm = 16 mg/m3 at 20 °C
         1 mg/m3 = 0.063 ppm at 20 °C

    2.4  Analytical methods

         Most of the analytical procedures used since the early 1960s have
    been based on the following steps:

         (i)    extraction using a suitable solvent;

         (ii)   clean-up by liquid/liquid partition followed by column
                chromatography;

         (iii)  further separation from co-extractives by gas
                chromatography (GC); and

         (iv)   quantification using an electron-capture, coulometric, or
                Hall electrolytic detector

         General procedures based on these steps are not specific for
    endrin; therefore, its identity must be confirmed in environmental
    samples. This can be achieved by chemical derivatization and mass
    spectrometry (Chau & Cochrane, 1969, 1971; Belisle et al., 1972; Chau,
    1974; Safe & Hutzinger, 1979).

         Roos et al. (1987) used size exclusion chromatography to clean-up
    pesticides after extraction with ethyl acetate from fish oils, animal
    fat, cereals, vegetables, fruit, and liver. The recoveries of endrin
    were 90-95%, at a limit of detection of 0.02 mg/kg. This method was
    found to be adequate for screening and requires only 15% of the amount
    of solvents normally used.

         Gübeli & Clerc (1988) described a relatively simple gas-liquid
    chromatography method for the detection and approximate quantification
    of chlorinated pesticides in ethanolic extracts of medicinal plants
    (tinctures). The method was based on extraction with hexane and
    capillary GC/63Ni-electron-capture detection. The limit of detection
    for endrin was 0.005 mg/kg with a recovery of 77.5%.

         Suzuki et al. (1974) separated many pesticides from extracts of
    crops and soil into different groups by column chromatography prior to
    thin-layer chromatography to obtain systematic identification and
    determination. Silica gel was used for the column chromatography and
    for the thin-layer plates; glass columns packed with different
    absorbents were used for GC separation. Determination was done using
    electron-capture detection with a 63Ni source.

         To improve the separation by heat of 28 organochlorine
    insecticides, including endrin, using gas-liquid chromatography with
    electron capture detection, Suzuki & Morimoto (1986) tested three
    chemically bonded, fused silica capillary columns. The column prepared
    with OV-17 performed best. The method was used with minimal clean-up
    and gave good results in the analysis of extracts of several soil
    samples, avoiding the disadvantages of low resolution of peaks in
    packed columns, handling of glass capillary columns and the high cost
    of GC-mass spectrometry systems.

         Kiang & Grob (1986) developed a screening procedure for the
    determination of 49 pollutants of high priority, including endrin, in
    soil or sludge. Methylene chloride at two pH values was used in the
    extraction procedure, which was followed by capillary GC. No clean-up
    procedure was carried out. Separation and identification were
    performed with a GC-mass spectrometry system involving a 30-m fused
    silica column; a 60-m column was used for quantification. Recovery of
    endrin from soil in the base-neutral extract was 92 ± 14% from 2.04
    mg/kg but only 70 ± 8% from 20.4 mg/kg.

         Japenga et al. (1987) described a rapid clean-up procedure for
    the simultaneous determination of groups of micropollutants in
    sediment. The samples were pretreated with acid, mixed with silica,
    and extracted on a Soxhlet column with a mixture of benzene and
    hexane. Humic substances and elemental sulfur were removed by passing
    the extract through a chromatographic column containing basic alumina
    on which sodium sulfite and sodium hydroxide were absorbed. After
    silica fractionation, the concentrations of polycyclic aromatic
    hydrocarbons, polychlorinated biphenyls, and chlorinated pesticides
    were determined by GC. The recovery of endrin was reported to
    fluctuate between 93 and 103%.

         The efficiency of clean-up with sulfuric acid and confirmation
    with potassium hydroxide-ethanol hydrolysis was studied for 22
    organochlorine pesticides and polychlorinated biphenyls in water
    samples (Hernandez et al., 1987); analysis was by GC/electron-capture
    detection, and the pesticides were extracted by partition with 15%
    diethyl ether in hexane. After clean-up with sulfuric acid, only 4.9%
    of the endrin was recovered; however, with the potassium
    hydroxide-ethanol treatment, 97-100% was recovered, depending on the
    endrin concentration and the length of treatment.

         Method 8080 of the US Environmental Protection Agency (EPA)
    (Manual, SW-846) was evaluated in a single laboratory study by Lopez-
    Avila et al. (1988). Since the Florisil clean-up procedure recommended
    does not separate organochlorine pesticides from polychlorinated
    biphenyls, GC analysis on a packed column may result in false
    identifications; therefore, silica gel was substituted for Florisil,
    a capillary glass column was used instead of the packed column, and a
    procedure to remove elemental sulfur incorporated. Detection limits
    for liquid matrices ranged from 0.02 to 0.09 µg/litre for
    organochlorine pesticides; for solid matrices, a range of 1-6 µg/kg
    was found. The recovery of endrin in liquid waste was up to 102% at a
    spiked concentration of 1.0 µg, but for a sandy loam soil it varied
    from 47 to 74%.

         Donahue et al. (1988) compared two techniques for quantifying
    environmental contaminants in human serum: peak area matching and
    linear regression. No statistically significant difference was seen in
    the results obtained by these two methods when the concentration of
    chlorinated pesticides was > 0.5 µg/litre.

         The sampling and determination of endrin in air were described in
    detail by NIOSH (1989).

         A method for determining residues of the metabolite
    anti-12-hydroxy-endrin, present as the ß-glucuronide, in urine was
    described by Baldwin & Hutson (1980). Following oxidation with sodium
    metaperiodate and hydrolysis with a mild base, the metabolite is
    determined by gas-liquid chromatography with electron-capture
    detection.

         Polychlorinated biphenyls and 21 chlorinated pesticides,
    including endrin, were analysed in samples of water, soil, and
    sediment in six laboratories using uniform calibration solutions,
    analytical methods, and special software operating on minicomputers to
    control the operation of the mass spectrometer. The results obtained
    for solid samples with four combinations of methods for extraction and
    clean-up were compared; although no combination was optimal for all
    samples, shaker and sonicator extraction, both with Florisil clean-up,
    gave the best results. Several factors that affected the quality of
    the results were identified, including errors in computation and
    transcription and inadequate review of data (Alford-Stevens et al.,
    1988).

         Seventeen laboratories participated in an international
    comparison of analyses for organochlorine compounds (Holden, 1970).
    The results for endrin, summarized in Table 2, were more variable than
    those for other insecticides. In an inter-laboratory collaborative
    study reported by a Committee of the Ministry of Agriculture,
    Fisheries, and Food of the United Kingdom (Anon., 1979) for the
    determination of endrin in pork fat (fortified to 0.019 mg/kg), the
    mean recovery in 11 laboratories was 84%, but the range was 5-131%.

    
    Table 2.  Results for endrin of an inter-laboratory study of
              the analysis of organochlorine compounds (Holden, 1970)
                                                                                                           
    Type of      No. of laboratories   Mean concentration    Standard     Coefficient     Range
    sample       with results for      (mg/litre or mg/kg)   deviation    of variation
                 endrin                                                   (%)
                                                                                                           
    Solution           17                      5.929b        1.01         17.1            4.9-8.2
    in hexanea

    Cod liver          14                      0.02            -           -              NDc-0.20d
    oil

    Chicken            16                      0.136         0.073        54              0.07-0.3e
    egg

    Sprat              14                      0.132         0.039        29              0.09f-0.21
                                                                                                           
    a  Containing endrin and five other organochlorine insecticides
    b  True (nominal, fortified) value, 7.05 mg/litre
    c  Twelve laboratories reported no detectable residue
    d  Value reported to be suspect
    e  Excluding one laboratory that reported suspected presence of endrin
    f  Excluding one laboratory that reported a 'trace' of endrin

 

   Table 3.  Methods for the analysis of endrin
                                                                                                                                    
    Sample type       Extraction           Clean-up               Detection and          Recovery    Limit of      Reference
                                                                  quantificationa        (%)         detection
                                                                                                                                    
    Adipose tissue    Acetone:hexane       Fractionation by       Capillary column       > 100                     Lebel & Williams
                      (15:85 v/v)          gel permeation         gas chromatography                               (1986)
                                           chromatography with    columns of different
                                           methylene              polarity, GC-MS
                                           chloride-cyclo-hexane
                                           Florisil column

    Air               Hexylene glycol/     Florisil               GLC/ECD                77          0.1 ng/m3     Stanley et al.
                      Greenburg Smith      column                                                                  (1971)
                      impinger; alumina
                      column

    Air               Toluene              -                      GLC/ECD (63Ni)         -           0.02µg/       NIOSH (1989)
                                                                                                     sample

    Water             Hexane:ethyl ether   -                      GLC/ECD                65-97       0.002         Lichtenberg
                                                                                                     µg/litre      et al. (1970)

    Soil/sediment     Acetone:hexane       Alumina                GLC/ECD                83          0.1 µg/kg     Goerlitz & Law
                                           column                                                                  (1974)

    Soil/sediment     Acetone:petroleum    Alumina                GLC/ECD                90          0.01 mg/kg    Wegman & Hofstee
                      ether                column                                                                  (1982)

    Soil/sediment     Hexane               Alumina/               GLC/ECD                -           0.01 mg/kg    McIntyne & Lester
                                           silver nitrate +                                                        (1984)
                                           silica gel
                                           column
                                                                                                                                    

    Table 3 (contd)
                                                                                                                                    
    Sample type       Extraction           Clean-up               Detection and          Recovery    Limit of      Reference
                                                                  quantificationa        (%)         detection
                                                                                                                                    
    Crops             Hexane:isopropanol;  Carbon absorption      GLC/ECD                93-107      -             Kathpal & Dewan
                      or acetonitrile      (Nuchar C-190N)                                                         (1975)

    Fatty foods,      Hexane:acetone       Alumina                GLC/ECD                68-100      5-10 µg/kg    Telling et al.
    vegetable oils,                        column                                                                  (1977)
    fish oils

    Viscera           Diethyl ether        Celite                 GLC/ECD                72-92       -             Kurhekar et al.
                                           column                                                                  (1975)

    Birds' brain      Petroleum ether:     Florisil               GLC/ECD                70          0.05 mg/kg    Ludke (1976)
    samples           ethyl ether          column

    Cows' milk        Diethyl ether:       Silica gel             GLC/ECD                90          0.0001 mg/kg  Baldwin et al.
                      hexane + ether                                                                               (1976)

    Hens' eggs        Hexane:acetone       Silica gel             GLC/ECD                76          0.05 mg/kg    Baldwin et al.
    (yolks)                                                                                                        (1976)

    Crops, soil,      Hydrocarbon          Florisil:Celite +      Reduction with         75-100      1 mg/kg       Terriere (1964)
    milk, animal      solvent              magnesia column,       metallic sodium;
    tissues           (Skellysolve         after alkaline         phenyl azide
                      B) + isopropanol     hydrolysis, if         colorimetry
                                           appropriate
                                                                                                                                    
    -a  GC-MS, gas chromatography-mass spectometry; GLC-ECD, gas-liquid chromatography-electron capture detection
    
         Thier & Stijve (1986) reported a comparative study among 53
    laboratories in Switzerland on the analysis of a vegetable fat spiked
    with 13 organochlorine and five organophosphorus compounds. Endrin was
    present at a concentration of 0.08 mg/kg and was identified by 77% of
    the laboratories.

         Some of the methods that are used for the analysis of endrin are
    summarized in Table 3; the estimates given of the accuracy of the
    procedures and the limits of detection refer to the specific
    investigations and are not absolute values. The percentage recoveries
    are an indication of the accuracy of the methods; the precision of
    individual method is of interest particularly in regard to
    inter-laboratory comparisons.

         The many publications on specific procedures are reviewed in the
    Codex Alimentarius Commission publication  Recommendations for Methods
     of Analysis of Pesticide Residues, CAC/PR8-1986 (FAO/WHO, 1986a).
    That review lists 14 individual publications; it also lists the
    following compendia of methods, which may be consulted.

         --  Official Methods of Analysis of the Association of Official
     Analytical Chemists, 14th Edition, 1984

         --  Pesticide Analytical Manual, Washington DC, Food and Drug
    Administration

         -- Manual on Analytical Methods for Pesticide Residues in Foods,
    Ottawa, Health Protection Branch, Health and Welfare Canada, 1985

         -- Methodensammlung zur Rückstandsanalytik von
     Pflanzenschutzmitteln (Methods for Analysing Residues of Plant
    Protection Agents), Weinheim, Verlag Chemie GmbH, 1984

         --  Chemistry Laboratory Guidebook, Washington DC, US Department
    of Agriculture

         Whatever procedure is adopted should be carried out following the
    requirements of the Codex Alimentarius Commission publication  Codex
     Guidelines on Good Laboratory Practice in Pesticide Residue Analysis,
    CAC/PR7-1984 (FAO/WHO, 1984).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

              Endrin does not occur naturally.

    3.2  Man-made sources

    3.2.1  Production levels and processes, uses

         Endrin is a foliar insecticide which acts against a wide range of
    agricultural pests at doses of the active material of 0.2-0.5 kg/ha.
    It has a broad spectrum of control and is particularly effective
    against Lepidoptera. It is used mainly on cotton but also against
    pests of rice, sugar cane, maize, and other crops. It is also used as
    a rodenticide (IARC, 1974). An endrin emulsion of 2% killed 40% of
     Achatina fulica snails, an agricultural pest, in India (Singh,
    1988).

         A general indication of the possible uses of endrin can be
    derived from the maximal residue limits recommended by FAO/WHO (1986b;
    see section 10).

    3.2.1.1  World production figures

         Endrin was developed by J. Hyman & Co. and licensed to be
    manufactured by Shell International Chemical Co. and Velsicol Chemical
    Co. in 1950 (Thompson, 1976). It was made in the USA by Shell and
    Velsicol and in the Netherlands by Shell. Its use has been banned in
    many countries and severely restricted in others (Donoso et al., 1979;
    Gips, 1987; Pearce, 1987). Shell discontinued manufacture of endrin in
    1982; it is still manufactured in Mexico.

         Whetstone (1964) estimated that 2.3-4.5 million kg of endrin were
    sold in the USA in 1962. Imports of endrin into Japan in 1970 were 72
    000 kg. The annual quantities of endrin that were used in paddy rice
    production in Bali over the period 1963-72 varied from 171 to 10 700
    kg (Machbub et al., 1988). After 1972, endrin was no longer used.

    3.2.1.2  Manufacturing process

         Endrin is produced by condensing vinyl chloride with
    hexachloro-cyclopentadiene, dehydrochlorinating the adduct, and
    subsequent reaction with cyclopentadiene to form isodrin, which is
    epoxidized by peracetic or perbenzoic acid (Whetstone, 1964). The
    intermediate isodrin can be manufactured via 1,2,3,4,7,7-
    hexachloronorbornadiene (US EPA, 1985).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

    4.1.1  Air

         Endrin can enter the air by volatilization, evaporation, and
    aerial drift during application, and as a vapour from manufacturing
    and formulating plants. Most studies showed rapid volatilization
    following application to soils and crops, the extent of vaporization
    depending upon a large number of factors, including soil organic
    matter, moisture content, air humidity, air flow, and surface area of
    plants (Donoso et al., 1979).

    4.1.2  Water

         Endrin can reach surface water by several routes, including
    effluents and waste disposal from endrin manufacturing and formulating
    plants and careless aerial application, but by far the most important
    route of contamination is surface run-off from soil and crops. Run-off
    is affected by numerous, complex factors, such as intensity of
    precipitation, irrigation practices, soil permeability, topographic
    relief, organic content of the soil, and the degree of vegetative
    cover. Soils of low permeability and low organic content allow copious
    run-off after heavy precipitation (Donoso et al., 1979). Contamination
    of surface water by industrial effluents and careless practices and
    disposal (such as washing of drums and spray equipment in streams)
    results in regional effects.

         In 1961, studies were conducted in the Bayou Yokely basin in
    Louisiana, USA, where 3300 acres (1335 ha) of sugar-cane were treated
    with nearly 2000 lb (907 kg) of endrin between June and August. Of 18
    water samples taken between April and November, six contained endrin
    at levels of 0.001-0.36 µg/litre, with an average of 0.1 µg/litre. In
    1964, the area was treated with 1200 lb (544 kg) of endrin, and the
    pattern of residues was the same. The mean residue levels in samples
    taken in September were 0.44 µg/litre in grab samples and 0.53
    µg/litre in carbon adsorption samples; after three months, the average
    levels were 0.03 and 0.04 µg/litre, respectively. Sediment samples
    contained 165 µg/kg; after three months, this level had decreased to
    70 µg/kg (Lauer et al., 1966).

         Another, less important source of water contamination is run-off
    from endrin-coated seeds. Marston et al. (1969) found that although
    approximately 11% of the initial amount was washed off by water under
    laboratory conditions, in field conditions the loss was smaller. The
    total amount detected in the watershed 6 days after aerial application
    of endrin-coated seed was 0.12% of the applied dose. The highest
    concentration found in the water was 0.07 µg/litre.

         A third possible source of contamination is fall-out by
    precipitation in the form of rain and snow, but the measured levels
    are negligible (see section 5.1.3.2).

    4.1.3  Soil

         The major source of endrin in soil is from direct application to
    soil and crops. The amount of endrin that reaches the soil depends on
    the type of crop and the method of application. The fate of endrin in
    soil determines the degree to which the rest of the environment (water
    and atmosphere) is contaminated. In soil, endrin can be retained,
    transported, or degraded, depending on a large number of interrelated
    factors (Donoso et al., 1979). When endrin was applied to tall, dense
    crops such as tobacco, no residue appeared in the soil; when it was
    applied to soil, the amount that remained depended on the retentive
    ability of the soil. Although endrin has strong absorptive properties
    in soils such as clay and sandy loam, limited residues were found. Far
    greater retention was found in soils with a high organic content, in
    which it was adsorbed quickly and was difficult to remove. The degree
    to which endrin was retained in the soil depended not only on the soil
    type but on numerous other factors such as volatilization, leaching,
    wind erosion, surface run-off, and crop uptake (Harris et al., 1966).
    In general, the persistence of endrin is highly dependent upon local
    conditions, and residue levels can range from traces to milligrams per
    kilogram. Its half-life in soil can be as long as 12 years (Donoso et
    al., 1979).

         The factors that affect the degree to which endrin is retained in
    soil (Donoso et al., 1979) can be generalized as follows:

         (a)  Endrin appears to be less persistent if it is applied to the
              soil surface or to crops rather than being mixed into the
              soil.

         (b)  Volatilization and photodecomposition are the primary routes
              for the disappearance of endrin from soil surfaces.

         (c)  Microbial degradation of endrin occurs anaerobically and is
              accelerated by conditions such as flooding and soil depth.

         (d)  Soil cultivation and crop rotation accelerate the
              dissipation of endrin.

         (e)  When the percentage of organic matter is high, as in muck -
              soils, the persistence of eldrin is greater. In sandy soils,
              volatilization is high and persistence is low.

    4.1.4  Soil-plants

         River and basin sediment was brought on land near Rotterdam, the
    Netherlands, after dredging. Once the sediment had settled for several

    years, the land was used for agriculture. Some of the sediment came
    from a basin near a pesticide manufacturing plant and was contaminated
    with many organochlorine hydrocarbons, including the pesticides
    hexachlorobenzene, aldrin, dieldrin, and endrin. The mean
    concentration of endrin in the sediment of the basin near the plant
    (expressed in mg/kg on a dry weight basis) was 0.48 (range, 0.01-2.6)
    in 1976 and 0.59 (< 0.01-3.6) in 1977. In crops, the concentration of
    endrin ranged from none detected to 0.06 mg/kg of product; in carrots,
    however, levels up to 0.73 mg/kg were found (Wegman et al., 1981).

    4.2  Abiotic degradation

         When endrin was heated to above 200 °C, as can occur during
    gas-liquid chromatography at 230 °C, the molecule was isomerized to a
    ketone, delta-ketoendrin (1, Fig. 1) and an aldehyde (3). A minor
    product of the thermal rearrangement was an isomeric alcohol (4).
    Endrin is also transformed to delta-ketoendrin (1) under
    acid-catalysed conditions (Phillips et al., 1962).

         Irradiation with ultraviolet light for 48 h also results in
    rearrangement to this ketone (37%) and, to a much lesser extent, to
    the aldehyde (9%) (Rosen et al., 1966; Plimmer, 1972; Mukerjee, 1985).
    Endrin underwent a photolytic reaction in hexane and in cyclohexane
    after irradiation at 253.7 and 300 nm, resulting in a half-cage
    ketone, pentachloro photoproduct (2), in 80% yield. This photolytic
    product has also been identified in the field and was found to be
    highly resistant to oxidation and reduction (Plimmer, 1972; Zabik et
    al., 1971; Mukerjee, 1985). When an acetone solution of endrin was
    irradiated with light from a mercury lamp in a quartz cell for 24 h,
    three metabolites were formed by the loss of one chlorine atom from
    the initially produced delta-ketoendrin; one of these was compound 2
    (Dureja et al., 1987).

         Endrin has been reported to isomerize to delta-ketoendrin during
    5 years' storage in the dark at room temperature (Plimmer, 1972.

         In sunlight, mainly the ketone is formed (Soto & Deichmann, 1967;
    Rosen, 1972); approximately 50% isomerization to the ketone took place
    within 7 ± 2 days with exposure to intense summer sun (Burton &
    Pollard, 1974).

         The photochemical products are important as terminal residues:
    delta-ketoendrin was found on cotton plants and on cabbage and apple
    leaves after application of endrin (Plimmer, 1971; Mukerjee, 1985).

    4.3  Biotransformation

         The mechanisms by which endrin is removed from the environment
    include photodecomposition and bacterial degradation. These factors
    and their effects on the persistence of endrin have been reviewed by
    the US Environmental Protection Agency (Donoso et al., 1979).

    FIGURE 1

    4.3.1  Biodegradation

         Microbial degradation of endrin depends on the presence of an
    appropriate microbial species and suitable soil conditions; it occurs
    under anaerobic conditions (Donoso et al., 1979). Biodegradation is
    aided by fungi and bacteria such as  Trichoderma, Pseudomonas, and
     Bacillus. The major transformation product is delta-ketoendrin
    (Patil et al., 1970).

         About 150 isolates from various soil samples were screened to
    investigate the role of these microorganisms in degrading endrin; 25
    of the 150 isolates were active. At least seven metabolites were
    found, but conversion of endrin into the ketoendrin was common
    throughout (Matsumura et al., 1971).

    4.3.2  Bioaccumulation and biomagnification

         The bioconcentration factors cited below are simple ratios of the
    exposure concentration and the concentration in organic tissues. They
    should be used with caution as indicators of bioaccumulation
    potential: a high bioconcentration factor can represent little uptake
    of a low concentration, and a low bioconcentration factor can be found
    with considerable uptake of a high concentration. The bioconcentration
    factor should therefore always be cited with the pertinent exposure
    concentration of endrin.

         Soil invertebrates such as slugs and earthworms had
    bioconcentration factors of 14 to 103. Bioconcentration factors in a
    number of aquatic organisms are given in Table 4. These ratios differ
    extensively between different types of aquatic organisms.
    Bioconcentration factors of 140 to 222 were found for four blue-green
    algae  (Microcystis aeruginosa, Anabaena cylindrica, Scenedesmus
     quadricauda, and an  Oedogonium species) after 7 days' exposure to
    endrin at a concentration of 1 mg/litre of water( Vance & Drummond,
    1969). In a study of the accumulation of endrin in stoneflies
     (Pteronarcys dorsata) exposed to 0.03, 0.07, and 0.15 µg/litre of
    water, the bioconcentration factor ranged from 1130 to 348, decreasing
    with increasing water concentrations over the 28-day exposure period
    (Anderson & DeFoe, 1980). In bullheads  (Ictalurus melas), the
    bioconcentration factor was 3700 after exposure for 4 days to 0.60
    µg/litre and 6200 after exposure for 7 days to 0.26 µg/litre (Anderson
    & DeFoe, 1980). The bioconcentration factors for endrin in sub-adults
    of leopard frogs  (Rana sphenocephala) exposed to 0.01, 0.012, 0.016,
    0.022, and 0.030 mg/litre were 71.4, 34.4, 51.8, 59.4, and 94.3,
    respectively. Sub-adults exposed to 0.01, 0.012, and 0.016 mg/litre
    for 96 h and sacrificed 60 h later had bioconcentration factors of
    6.1, 4.8, and 1.2, respectively (Hall & Swineford, 1980), indicating
    a relatively rapid elimination of residues. In daphnids and molluscs,
    a direct linear relationship was found between the logarithm of the
    equilibrium bioconcentration factor (and the reciprocal clearance rate
    constant) and the log P octanol/water partition coefficient for

    non-degradable, lipophilic compounds with partition coefficients
    ranging from 2 to 6. This relationship permits calculation of the
    times required for equilibrium and for significant bioconcentration of
    lipophilic chemicals, which were found to be shorter for molluscs than
    for daphnids. The equilibrium biotic concentration for both molluscs
    and daphnids decreased with increasing chemical hydrophobicity. The
    relationship between the bioconcentration factor and log P
    octanol/water partition coefficient was linear for compounds that did
    not attain equilibrium within a finite exposure time (Hawker &
    Connell, 1986).

         In a study of the bioaccumulation of endrin from food by lobsters
     (Homarus americanus), endrin dissolved in methanol was added to sea
    water, and mussel tissue was soaked in the solution for 2 h to provide
    a concentration of endrin of 4.7 mg/kg wet weight. Lobsters were fed
    the prepared food every other day for 2 weeks, and excretion was
    followed for an additional 4 weeks during which time the lobsters were
    fed uncontaminated tissue. Liver and muscle were analysed from two or
    three lobsters sampled after feedings 1, 2, 3, 5, and 7, and from one
    or two lobsters sampled during the excretion phase at 1, 2, and 4
    weeks. The concentration of endrin reached a maximum of 1.95 mg/kg wet
    weight in the liver after 2 weeks of feeding; this level declined by
    about 65% after 4 weeks of excretion. The time to 90% equilibrium
    (uptake) was 15 weeks, and the time to 50% clearance (excretion) was
    4 weeks (McLeese et al., 1980).

         Bluegill sunfish  (Lepomis macrochirus) exposed to water
    containing 14C-labelled endrin at 1 µg/litre at temperatures of
    20-22 °C rapidly absorbed the radioactivity, and, within 48 h, 91% of
    the radioactive endrin had been taken up (6% was lost by
    volatilization from a control tank without fish). Within 8 days after
    the fish had been replaced in clean water, less than 15% of the
    absorbed label had been eliminated; for three fish left for a longer
    period, the half-life of loss was about 4 weeks, the loss curve being
    linear (Sundershan & Khan, 1980). Endrin accumulated rapidly in the
    tissues of channel catfish  (Ictalurus punctatus) exposed to nominal
    concentrations of 0.04, 0.4, or 4.0 mg/kg of diet for 198 days. After
    that time, all groups were fed an endrin-free diet. Endrin was not
    detected 28 days later in fish that had received 0.04 or 0.4 mg/kg,
    and the level in the group that had received 4.0 mg/kg decreased to
    0.011 mg/kg of tissue in 28 days and was below the limit of detection
    within 41 days (Argyle et al., 1973). Similar results were obtained
    for  Leiostomus xantharus exposed to 0.05 µg/litre of water: at the
    end of the study at 5 months, a residue level of 78 µg/kg tissue was
    found, and no endrin was detected in fish after 18 days in
    uncontaminated water (Lowe, 1966). Endrin thus seems to disappear
    rapidly from tissues. In 20  Tilapia zilli (Alexandria strain) fry
    (3.36 cm, 825 mg) exposed to 0.025 µg/litre (one-tenth of the 96-h
    LC50) for 28 days, the total content of endrin was 327.4, 167.4,
    297.6, 446.5, and 595.4 µg/kg after 4, 7, 14, 21, and 28 days,
    respectively (El-Sebae, 1987).

    
    Table 4.  Bioconcentration factors for endrin in aquatic species
                                                                                   
    Species         Concentration   Length of   Bioconcentration     Reference
                    of endrin in    exposure    factor
                    water (µg/litre)
                                                                                   
    Clam                1           5 days         480               Duke & Dumas
     (Mercenaria                                                      (1974)
     mercenaria)

    Mussel             10           24 days         38               Ryan et al.
     (Hyridella                                                       (1972)
     australis)

    Eastern oyster      0.05        7 day         2780               Mason & Rowe
     (Crassostrea                                                     (1976)
     virginica)

    Water flea          1.0         1 day         2600               Metcalf et al.
     (Daphnia                                                         (1973)
     magna)

    Fathead             0.015       -           10 000               Mount & Putnicki
    minnow                                                           (1966)
     (Pimephales
     promelas)

    Spot                0.05        8 months      1340               Lowe (1966)
     (Leiostomus
     xanthurus)

    Flag fish           0.3         -           10 000               Hermanutz
     (Jordanella         0.21        15 days      7 900               (1974)
     floridae)           0.29                    18 400               Hermanutz et
                        0.39                     7 100               al. (1985)
                                                                                   
    Table 4 (contd)
                                                                                   
    Species         Concentration   Length of   Bioconcentration     Reference
                    of endrin in    exposure    factor
                    water (µg/litre)
                                                                                   
    Mosquito            1.0         1 day        2 100               Metcalf et al.
    larvae  (Culex                                                    (1973)
     ipiensquinque
     fasciatus)

    Mosquito fish       1.0         1 day          800               Metcalf et al.
     (Gambusia                                                        (1973)
     affinis)

    Channel catfish     0.5         5-19       400-760               Argyle et al.
     (Ictalurus                                                       (1973)
     punctatus)
                                                                                   
    
         Sheepshead minnow  (Cyprinodon variegatus) were exposed for 23
    weeks to endrin at levels of 0.027-0.72 µg/litre of water, from the
    embryonic stage through hatching until adulthood and spawning (see
    section 7.2.2.2). Four-week-old juvenile fish accumulated 2500 times
    the concentration in the water, adults, 6400 times, and their eggs,
    5700 times (Hansen et al., 1977).

         The transfer of endrin through the food chain
    lichen-reindeer-humans was studied in the northern part of Sweden by
    analysing lichen  (Cladonia alpestris), a major food source for
    reindeer during the winter, together with samples of tissues from
    reindeer, which are eaten in considerable quantities by Lapps. One
    4-year-old reindeer was slaughtered in 1979 and a 3-year-old in 1981,
    and muscle and liver were taken for analysis. The annual uptake by
    reindeer was 2.0 mg. The average level of endrin in lichen was 1.91
    (range, 1.27-2.78) µg/kg; 1.45 and 2.4 µg/kg were found in the muscle
    samples from the two reindeer and 0.55 and 0.72 µg/kg in liver. The
    calculated transfer of endrin from lichen to reindeer was 0.7%. The
    estimated annual consumption of reindeer muscle by Lapps was 70 kg for
    males and 32 kg for women; consumption of liver was 3 and 1.1 kg,
    respectively. The annual intake of endrin was thus 30.3 µg for males
    and 13.8 µg for females (Villeneuve et al.,1985).

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         Many of the data reported in this chapter are measurements taken
    at a time when endrin was used much more widely than at present or
    with little control or restriction. They are therefore a reflection of
    a historical situation in many countries. These data are included in
    the document as an indication of the result of indiscriminate use and
    disposal of endrin. Data from countries where endrin may still be used
    are scarce or unavailable.

    5.1  Environmental levels

         The levels of residues associated with the use of endrin in
    agriculture or with the discharge of industrial effluents containing
    endrin are summarized in Tables 5-9; the levels of residues less
    easily associated with specific uses or discharges are given in Table
    10.

    5.1.1  Air

         A critical summary of studies on the atmospheric levels of
    pesticides in the USA, e.g., in community air, was made by Donoso et
    al. (1979). Some of their conclusions are worth repeating: "Endrin
    concentrations are highest in the atmosphere over agricultural areas
    and probably reach their peak levels during the pesticide use season.
    Of all urban communities those surrounded by farmlands run the highest
    chance of atmospheric contamination. Urban communities far removed
    from agricultural areas are unlikely to experience significant
    contamination." The maximum level of endrin in air, 58.5 ng/m3, was
    found in a rural town in an agricultural area in the south of the USA,
    but the normal weekly variation was between 0.8 and 6.5 ng/m3
    (Stanley et al., 1971). In a later study of the same town, the average
    annual atmospheric levels were 3.2 ng/m3 in 1972, 2.3 ng/m3 in
    1973,and 5.3 ng/m3 in 1974, with the highest levels in August; in
    1974, this was 27.2 ng/m3 (Arthur et al., 1976). The results of a
    national monitoring programme for pesticides in the air of various
    states of the USA showed the occasional presence of endrin over
    agricultural areas at levels of the same order of magnitude: mean of
    positive samples (8%), 2.6 ng/m3, with a maximum value of 19.2
    ng/m3 (Kutz et al., 1976).

         Endrin was not found in rain-water collected at different
    location in the United Kingdom, using a method with a detection level
    of 1 ng/litre of water (Tarrant & Tatton, 1968), nor in atmospheric
    air (Abbott et al., 1966); however, endrin has never been used
    extensively in the United Kingdom.

         The mean daily intake of endrin by inhalation in the western part
    of the Netherlands was calculated on the basis of an air concentration
    of 41 pg/m3 (maximum, 300 pg/m3) to be 0.8 µg/day or 0.3 mg/year,
    on the basis of air samples taken in the period 1975-81 (Guicherit &
    Schulting, 1985).


        Table 5.  Concentrations of endrin in organisms collected in the Netherlands, 1965-71
                                                                                                                                   
    Place and      Type of sample             No. of     Concentration (mg/kg)   Comments                  Reference
    period                                    samplesa                      
                                                         Mean      Rangeb
                                                                                                                                   
    Coast          Mussel  (Mystilus edulis);       22     0.029     0.009-0.056   Composites of 25          Koeman (1971)
     1965          composites of flesh                                           mussels from 22
                                                                                 sampling  stations

    Netherlands    Fish, 3 species;              103     0.13      0.07-0.45     Food of the sandwich      Koeman et al. (1967)
     1965          whole body                                                    tern

     1966          Fish, 3 species;               37     0.10      0.07 -0.29
                   whole body
                   Sandwich tern
                    (Sterna sandvincensis)

     1965          Liver                           8     0.23      0.07-0.80     Shot or killed

     1965-66       Liver                          25     0.49      0.10-1.3      Found dead

     1965-66       Egg                            33     0.19      0.08-0.36

    Wadden Sea     Mussel (2 species);          20/4     LD        LD            Limit of detection,       Koeman (1971)
     1969          composites of flesh                                           0.005 mg/kg

    Coast          Mussel  (Mytilus edulis);     199/8     < 0.016   LD-0.024                                Koeman (1971)
     1970          composites of flesh

    Wadden Sea     Zooplankton (marine)            1     LD        LD                                      Koeman (1971)
     1969-70

                   Shrimp  (Crangon              50/1     LD        LD
                    vulgaris)
                                                                                                                                   

    Table 5. (contd)
                                                                                                                                   
    Place and      Type of sample             No. of     Concentration (mg/kg)   Comments                  Reference
    period                                    samplesa                      
                                                         Mean      Rangeb
                                                                                                                                   
                   Marine fish (4 species);     37/5     0.014     0.008-0.034
                   composites of whole
                   body

     1967          Freshwater fish                28     LD        LD-0.02       Measurable concentration
                   (3 species)                                                   (0.02 mg/kg) in one fish
                                                                                 only; limit of detection,
                                                                                 0.005 mg/kg

     1970          Pike (whole body)              10     LD        LD            Limit of detection,
                                                                                 0.005 mg/kg

     1971          Roach (whole body)              6     LD        LD

     1968-69       Hawks and falcons              16     < 0.1     LD-0.16       Birds found
                                                                                 dead or dying;            Koeman et al. (1969)
                   (4 species); liver                                            measurable concentration
                                                                                 (0.16 mg/kg) in one hawk
                                                                                 (buzzard)

                   Owls (2 species); liver         3     < 0.1     LD-0.13       Measurable concentration
                                                                                 (0.13 mg/kg) in one
                                                                                 long-eared owl; limit of
                                                                                 detection not specified

     1970          Sandwich tern eggs             10     LD        LD            Limit of detection,       Koeman (1971)
                                                                                 0.02-0.008 mg/kg

     1971          Grey heron                   27/4     LD        LD
                    (Ardea cinerea);
                   composite of eggs
                                                                                                                                   

    Table 5. (contd)
                                                                                                                                   
    Place and      Type of sample             No. of     Concentration (mg/kg)   Comments                  Reference
    period                                    samplesa                      
                                                         Mean      Rangeb
                                                                                                                                   
     1969-71       Sparrowhawk                  28/3     LD        LD
                    (Accipiter nisus);
                   composite of eggs
                                                                                                                                   

    a Sample numbers expressed as n/m correspond to n individuals sampled in m composites analysed
    b LD, limit of detection

    Table 6.  Concentrations of endrin in samples collected in North America
                                                                                                                                   
    Place and           Type of sample         No. of    Concentration (mg/kg)  Comments                         Reference
    period                                     samplesa                     
                                                         Mean      Rangeb
                                                                                                                                   
    Mississippi River
    USA
     December 1963      Channel catfish; blood     3     0.44      0.41-0.56    Found dead or dying in areas     Anon. (1964)
                                                                                of extensive fish kills

     December 1963      Fish, various species;    24     0.18      0.14-0.26
                        blood

     January-           Fish, various species;    82     0.06      LD-0.21      Caught alive; limit of
     February 1964      blood                                                   detection not specified

     July 1964-         Water                     12     < 0.01    LD-0.01      4 samples contained              Novak & Rao (1965)
     June 1965                                                                  measurable concentrations
                                                                                (0.01 mg/kg or litre)

                        Mud                       12     < 0.01    LD-0.01

                        Oysters                   12     LD        LD           Limit of detection,
                                                                                0.005 mg/kg or litre
                        Shrimp                    12     LD        LD

                        Fish (2 species)          24     < 0.01    LD-0.02      9 samples of fish contained
                                                                                measurable concentrations:
                                                                                8 of 0.01 mg/kg and 1 of
                                                                                0.02 mg/kg

    Mississippi, USA    Eastern oysters          470     LD        LD           15 or more oysters per           Butler (1973)
    1965-72              (Crassostrea virginica);                                 composite from 8 sampling
                        composites of flesh                                     stations; limit of detection,
                                                                                0.01 mg/kg
                                                                                                                                   
    Table 6. (contd)
                                                                                                                                   
    Place and           Type of sample         No. of    Concentration (mg/kg)  Comments                         Reference
    period                                     samplesa                     
                                                         Mean      Rangeb
                                                                                                                                   
    Bayous in the       Water                    148     LD        LD-0.0002    4 samples contained              Rowe et al. (1971)
    Mississippi delta,                                                          measurable amounts
    USA, October                                                                (0.00009-0.0002 mg/litre),
    1968-May 1969                                                               4 samples contained traces;
                                                                                remainder less than limit of
                                                                                detection

                        Sediment                  44     LD        LD-0.005     7 samples contained
                                                                                measurable amounts
                                                                                (0.004-0.005 mg/kg); one
                                                                                sample contained a trace

                        Eastern oyster           111     LD        LD-0.006     79 samples contained
                         (Crassostrea virginica)                                  < 0.001 mg/kg

    Mississippi         Water                     26     LD        LD           Samples collected from           Leard et al. (1980)
    stream systems                                                              13 sampling stations in
     1972-73                                                                    5 major river basins; limit
                                                                                of detection, 0.0005 mg/litre

                        Freshwater bivalves       58     LD        LD-0.1       Residues below limit of
                        (7 species); flesh                                      detection (0.02 mg/kg), except
                                                                                for traces (< 0.1) in 1973 in
                                                                                one river which drains from an
                                                                                agricultural area

    Ontario, 3          Fish (9 species)                 LD        LD           Residues below limit of          Miles & Harris
    streams, 1971                                                               detection, 0.01 mg/kg            (1973)
                                                                                                                                   

    Table 6. (contd)
                                                                                                                                   
    Place and           Type of sample         No. of    Concentration (mg/kg)  Comments                         Reference
    period                                     samplesa                     
                                                         Mean      Rangeb
                                                                                                                                   
    Gulf coast          Whole fish            139/48     < 0.02    LD-0.27      Reseidues below limit of         Henderson et al.
    streams, USA        (various species);                                      detection (0.001 mg/kg)          (1969)
                        composites                                              in 33 composites

    Mississippi                              657/202     < 0.01    LD-0.11      Residues in 184 composites
    River system,                                                               below limit of detection
    USA                                                                         (0.001 mg/kg)

    Louisiana, USA      Brown pelican                                           Eggs collected from nests of     Blus et al. (1979)
                         (Pelecanus occidentalis);                                birds transplanted as nestlings
                        eggs                                                    from Florida, 1968-76; limit
     1971                                          3     0.10      0.08-0.12    of detection not specified
     1972                                         12     0.18      0.11-0.29
     1973                                         21     0.16      0.03-0.46
     1974                                         25     0.30      LD-0.73
     1975                                         30     0.50      0.29-1.06
     1976                                         25     0.29      LD-1.47
                                                                                                                                   
    aSample numbers expressed as n/m correspond to n individuals sampled in m composites analysed
    bLD, limit of detection
    
        Table 7.  Concentrations of endrin in organisms collected in a
              cotton-growing area in the Republic of Chad in 1969
                                                                                
    Sample            No. of      Concentration (mg/kg)  Comments
                      samples     Mean      Range
                                                                                
    Fish, two           31        0.02      LD-0.083     Cotton-growing area,
    species                                              endrin and DDT used
                                                         for pest control; limit

    Kingfishers and     46        0.02      LD-0.075     of detection, 0.008
    cormorants; liver                                    mg/kg

    Birds, non-aquatic,                                  Birds found dead
    various species                                      soon after insecticide
        Brain           12        0.51      0.10-0.77    application; deaths
        Liver           12        0.88      0.13-1.42    of some birds attributed
                                                         to endrin
                                                                                
    From Everaarts et al. (1971); LD, limit of detection
    
    5.1.2  Soil, sediments, and sewage sludge

    5.1.2.1  Soil

         In the US National Soil Monitoring Program, 1486 soil samples
    from 37 states were analysed in 1971. Fourteen samples were found to
    contain endrin, at a geometric mean level of < 0.001 (maximum,
    0.02-1.00) mg/kg dry weight (Carey et al., 1978). The mean endrin
    concentration in 29 soil samples in Kyushu District, Japan, was 0.183
    mg/kg (range, 0.016-0.629 mg/kg) dry matter (Suzuki et al., 1973).

    5.1.2.2  Sediments

         In 1964, levels in the sediment of Cypress Creek, Memphis, TN,
    USA, upstream and downstream of a pesticide manufacturing plant,
    reached 12 800 mg/kg dry weight. In 1967, water from the Creek
    contained levels of 0.27-2.03 µg/litre and sediment contained levels
    of 47.4-10 676 mg/kg dry weight (Barthel et al., 1969).

         Endrin was found in 17% of samples of bottom sediment from 59
    sites on the Detroit River, USA, at levels up to 43 µg/kg (limit of
    detection, 1.0 µg/kg) (Hamdy & Post, 1985). No endrin was detected in
    sediment samples collected in 1980-82 from riverine and pothole
    wetlands at 17 locations in the north-central USA (Martin & Hartman,
    1985) or in samples of sediment from 34 stations on the upper Great
    Lakes in 1974 (< 1 µg/kg) (Glooschenko et al., 1976).

    
    Table 8.  Concentrations of endrin in organisms collected in a rice-growing area in Wageningen, Surinam
                                                                                                                                    
    Date                Type of sample                  No. of       Concentration (mg/kg)b    Comments
                                                        samplesa                          
                                                                     Mean       Rangeb
                                                                                                                                    
    October 1971        Snail kite (Rostrhamus             5/1       LD         LD  --         Pesticides, including endrin, applied
                        sociabilis); brain /liver                                     |        to rice fields
                                                                                      |
                        Black vulture (Coragyps            5/1       LD         LD    |
                        astratus); brain/liver                                        |
                                                                                      |
                        Egrets (3 species); brain/        30/1       LD         LD    |        Samples collected at end of growing
                        liver                                                         |--      season before insecticide application
                                                                                      |        for next growing season; limit of
                        Purple gallinule                  10/1       LD         LD    |        detection, 0.01 mg/kg
                        (Porphyrula martinica);                                       |
                        brain/breast muscle                                           |
                                                                                      |
                        Spectacled caiman (Caiman         10/1       LD         LD    |
                        crocodilus); brain/liver                                    --

    November 1971       Snail (Pomocea sp.)               10/1       LD         LD  --
                                                                                      |
                        Frog (Pseudis paradoxa);           6/1       LD         LD    |        Found dead after application of
                        whole-body composites                                         |        pentachlorophenol; lower limit of
                                                                                      |        detection, 0.01 mg/kg
                        Kwi kwi (Hoplosternum              8/1       LD         LD    |
                        littorale); whole-body                                        |
                        composites                                                  --
                                                                                                                                    

    Table 8. (contd)
                                                                                                                                    
    Date                Type of sample                  No. of       Concentration (mg/kg)b    Comments
                                                        samplesa                          
                                                                     Mean       Rangeb
                                                                                                                                    
                        Srieba (Astyanax bimaculatus);     8/1       LD         0.1 --         Found dead after application
                        whole-body composites                                         |        of pentachlorophenol; lower
                                                                                      |--      limit of detection 0.01 mg/kg
                                                                                      |
                        Krobia (Cichlasoma                 8/1       LD         LD    |
                        bimaculatum); whole-body                                      |
                        composites                                                  --

                        Fish (3 species listed above);    21/3       3.36       1.96-5.35      Found dead after application
                        whole-body composites                                                  of endrin

    28 November-        Snail kite; brain                   17       LD         LD             Found dead; deaths
    4 December 1971                                                                            attributed to pentachlorophenol
                                                                                               poisoning

    2-9 December 1971   Aquatic birds (4 species);           5       0.11       0.06-0.16      Found dead after application
                        brain                                                                  of endrin

    2-9 December 1971   Wattled jacana                       1       2.71                      Death attributed to endrin
                        (Jacana jacana)                                                        poisoning

    5-11 December 1971  Common egret (Egretta alba);         2       0.23       0.14-0.32      Found dead or sick in roost
                        brain

    2-11 December 1971  Common egret (Egretta alba);                                           Found dead or sick in rice
                        Brain                                9       0.25                      fields; about half the total
                        Liver/kidney                       7-9       0.08                      endrin was applied during
                                                                                               the first half of December
                                                                                                                                    
    From Vermeer et al. (1974)
    aSample numbers expressed as n/m correspond to n individuals sampled in m composites analysed
    bLD, limit of detection

    Table 9.  Concentrations of endrin collected in drainage water from irrigated land, California, USA
                                                                                                                                    
    Geographical        Type of sample           No. of   Concentration (mg/kg or mg/litre)         Comments
    area and year                                samples                                 
                                                          Mean         Range
                                                                                                                                    
    Tule Lake and       Water                    44       0.000011     LD-0.0001            Limit of detection, < 0.000003 mg/litre
    Klamath Lake,
    National
    Wild-life
    Refuge,
    USA, 1964

    Refuge, Northern    Suspended  matter        8        0.011        LD-0.058 --
     California, USA,   Vascular plants          7        0.006        LD-0.013   |
     April 1965-        (two species)                                             |--       Limit of detection, 0.005 mg/kg
    February 1967       Algae (Cladophora sp.)   5        0.007        LD-0.022   |
                        Clam homogenates         3        0.013        LD-0.034 --
                        Gonidea sp.)
                        Fish (Siphateles sp.)    5        0.05         0.004-0.198          Samples collected at a pumping station
                                                                                            discharging water from irrigated land.
                                                                                            Peak concentrations of endrin occurred
                                                                                            during the growing season when endrin
                                                                                            was applied.
                                                                                                                                    
    From Godsil & Johnson (1968); LD, limit of detection

    Table 10.  Concentrations of endrin in environmental samples; residues not associated with particular local use or industrial
    effluent
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    North America

    North Carolina,       Soil (tobacco fields)        19          LD        LD                                        Reeves et al.
    USA,1971              Sediment (ponds)             40          LD        LD           Limit of detection,          (1977)
                          Frog  (Rana sp.)              13          LD        LD-0.01      0.01 mg/kg
                          Turtle (4 species)           41          LD        LD-0.01
                          Bluegill  (Lepomis            20          LD        LD
                           macrochirus)
                          Tiger beetle                 23          0.02      LD-0.05
                           (Megacephala
                           carolina)

    Rice-growing          Invertebrates, aquatic       1313/24     LD        LD-trace     A total of 192 dead or       Flickinger &
    area, Gulf Coast,     and terrestrial (various                                        dying birds were found in    King (1972)
    Texas, USA,           species); whole-body                                            three rice-growing areas in
    1967-71               composites of live                                              which rice seed dressed
                          specimens, except for                                           with aldrin/ceresan had
                          4 composites of                                                 been used. Endrin residues
                          crayfish                                                        attributed to use in cotton-
                                                                                          growing areas. Limit of
      1968                Fish (4 species);            542/4       LD        LD           detection not defined;
                          whole-body composites                                           trace found in one
                                                                                          composite of dead
      1968                Cricket frog  (Acris          18/3        LD        LD           crayfish
                           crepeitans blanchardi);
                          whole-body composites

      1968-70             Turtles (2 species);         5/2         LD        LD
                          whole-body composites
                          of live specimens
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
                          Snakes (3 species); sick     3           LD        LD
                          specimens

                          Bobcat (sick) and dead       2           LD        LD
                          rice rat; brain

                          Great horned owl; dead       2           LD        LD
                          specimen; brain

    Rice- growing         Aquatic birds (10            26          0.22      LD-0.4
    area, Gulf Coast      species) found dead
    USA, 1967-71          or dying; brain

      1967                Fulvous tree duck            14          0.1       LD-0.3
                           (Dendrocygna bicolor);
                          eggs

    Galveston Bay         Oyster composites            10          0.01      LD-0.02      Limit of detection,          Casper (1967)
    Texas, USA, 1964                                                                      0.01 mg/kg

    National Monitoring   Fish (various species);      400                                93% of samples below         Henderson et
    Program: Great Lakes  whole-body composites                                           limit of detection,          al. (1969)
    and major river                                                                       0.001 mg/kg
    basins, USA (excluding
    Gulf Coast, Mississippi
    River system; see
    Table 6); 1967-68

    Atlantic coast streams                                         741/141   0.002        LD-1.50
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    Great Lakes drainage  Fish (various species);      378/66      0.001     LD-0.02
                          whole-body composites

    Hudson Bay, Canada,                                51/13       LD        LD
    drainage

    Colorado River, USA                                112/24      0.008     LD-0.71

    Interior basins                                    120/25      0.001     LD-0.01

    California, USA,                                   90/24       0.002     LD-0.02
    streams

    Columbia River, USA,                               246/64      0.001     LD-0.01
    systems

    Pacific coast, USA,                                83/20       LD        LD
    streams

    Alaska, USA, streams                               105/24      LD        LD

    National Monitoring   Fish (various species);      666/147     LD        LD           Limit of detection,          Henderson et
    Program; 50 sampling  whole-body composites                                           0.005 mg/kg                  al. (1971)
    stations, USA, 1969

    Estuaries,            Giant Pacific oyster         1656/138    0.005     LD-0.01      Measurable concentration     Modin (1969)
    California, USA        (Crassostrea gigas);                                             in only one oyster; limit
    1966-67               Mussel  (Mytilus edulis);      432/36      LD        LD           of detection, 0.01 mg/kg
                          composites of shellfish
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    Arkansas and          Catfish from commercial      108-162/54  0.06      LD-0.4       Limit of detection,          Crockett et
    Mississippi, USA      fish farms; composites                                          0.01 mg/kg; 13               al. (1975)
    1970                  of edible portions                                              composites contained
                                                                                          < 0.01 mg/kg

    Intensive cotton-                                              0.063     (0.030-      2 composites contained
    growing areas,                                                            0.122)a     > 0.3 mg/kg. Significantly
    Mississippi, USA                                                                      higher residues in intensive
                                                                                          cotton-growing areas

    Less intensive cotton-                                         0.010     (0.005-                                   Crockett et
    growing areas,                                                           00.019)a                                  al. (1975)
    Mississippi, USA

    Major watersheds,     Fish (various species);      582/58      LD        LD           Limit of detection not       Veith et al.
    USA, 1976             whole-body composites                                           specified. Intermediate      (1979)
                                                                                          in the manufacture of
                                                                                          cyclodiene insecticides
                                                                                          detected (mass
                                                                                          spectrometry) in Wabash
                                                                                          River, Indiana

    Major watersheds      Fish (various species);      138/6       LD        LD           Limit of detection not       Veith et al.
    near Great Lakes,     whole-body composites                                           specified. Endrin            (1981)
    USA, 1978                                                                             identified by mass
                                                                                          spectometry in fish from
                                                                                          Wabash River, Indiana,
                                                                                          together with manufacturing
                                                                                          intermediates (concentration
                                                                                          not quantified)
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    Arkansas and          Catfish from commercial      50          0.05      LD-0.41      Limit of detection, 0.01     Hawthorne
    Mississippi, USA,     fish farms, edible portion                                      mg/kg; 14 fish contained     et al. (1974)
    1970                                                                                  < 0.01 mg/kg

    Continental rise      Bathyl-demersal fish         4           LD        LD           Limit of detection,          Meith-Avcin
    south-east of          (Antimora rostrata);                                             0.01 mg/kg. Samples          et al. (1973)
    Cape Hatteras, USA,   liver                                                           collected by trawling at a
    1972                                                                                  depth of 2500 m

    Lake Michigan, USA,   Amphipods  (Pontoporeia       24/8        0.08      0.04-0.33    Limit of detection,          Peterson &
    1969-72                affinis) collected from                                         0.005 mg/kg                  Ellarson
                          oesophagi of old squaws                                                                      (1978)

      December 1969       Old squaws  (Clangula         37          0.18      0.1-0.2      Birds caught in fishing
                           hyemalis); carcasses                                            nets or shot

      March-April 1970                                 44          0.28      0.2-0.4

      December 1970-                                   108         0.31      0.1-0.9
      May 1971

      January-February                                 8           0.6       0.2-1.0
      1972

    Northwest Territories                              99          0.1       LD-0.3
    and wintering areas
    other than Lake
    Michigan, 1971-73
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    Canada and USA,       Bald eagles  (Haliaeetus       29          0.02      LD-0.1       Limit of detection,          Reichel et al.
    1965                   leucocephalus) found                                             0.05 mg/kg.                  (1969)
                          dead; brain                                                     Concentration in 24
                                                                                          specimens below limit
                                                                                          of detection

    Connecticut &         Bald eagles found dead;      2           LD        LD-0.1       Limit of detection not       Reichel et al.
    Florida, USA,         brain, liver, carcass                                           defined; apparent            (1969)
    1967-68                                                                               concentration of
                                                                                          0.1 mg/kg in Florida
                                                                                          eagle not conformed
                                                                                          by thin-layer
                                                                                          chromatography

    Continental USA       Bald eagle; brain                                               Limit of detection,          Mulhern et al.
      1966                                             21          LD        LD           0.05 mg/kg                   (1970)
      1967                                             21          LD        LD
      1968                                             26          LD        LD

      1969                Bald eagle; brain            28          LD        LD           Limit of detection,          Belisle et
                                                                                          0.05 mg/kg                   al. (1972)
      1970                                             11          LD        LD

      1971-72             Bald eagle; brain            37          LD        LD           Limit of detection,          Cromartie et
                                                                                          0.05 mg/kg                   al. (1975)
      1973-74             Bald eagle; brain            81          LD        LD           Limit of detection,          Prouty et al.
                                                                                          0.05 mg/kg                   (1977)

      1975                Bald eagle; brain            49          0.07      LD-0.50      Limit of detection,          Kaiser et al.
                                                                                          0.05 mg/kg.                  (1980)
                                                                                          Concentrations in 46
                                                                                          specimens < 0.05 mg/kg
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
      1976                                             50          0.08      LD-0.71      Concentrations in 44
                                                                                          specimens below limit of
                                                                                          detection. Death of one
                                                                                          eagle attributed to endrin
                                                                                          poisong

      1977                                             69          0.08      LD-1.2       Concentrations in 64
                                                                                          specimens below limit of
                                                                                          detection. Death of one
                                                                                          eagle attributed to endrin
                                                                                          poisoning

    Wisconsin, Maine,     Bald eagle; eggs             26          LD        LD           Limit of detection,          Krantz et al.
    Florida, USA,                                                                         0.05 mg/kg                   (1970)
    1968

    USA,                  Golden eagle  (Aquila         102         LD        LD-0.3       Limit of detection,          Reidinger &
    1964-71                chrysaetos) found dead                                          0.1 mg/kg. Concentrations    Crabtree
                          or dying; body fat                                              in 97 specimens below        (1974)
                                                                                          limit of detection

    Coast of California,  Gray whale                   23          LD        LD                                        Wolman &
    USA, 1968-69           (Eschrichtius robustus);                                                                      Wilson (1970)
                          blubber

                          Sperm whale  (Physeter         6           LD        LD
                           catodon); blubber
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    South Atlantic and    Small cetaceans (10          69          LD        LD-0.24      Limit of detection,          O'Shea et al.
    Pacific Oceans,       species); blubber,                                              0.1 mg/kg. Measurable        (1980)
    1968-69               brain, muscle                                                   concentrations (0.22 and
                                                                                          0.24 mg/kg) found in two
                                                                                          specimens

    Maryland, USA,        Little brown bat  (Myotis     87          LD        LD           Limit of detection,          Clark &
    1976                   lucifugus); carcass                                              0.1 mg/kg                    Krynitsky
                                                                                                                       (1978)

    Missouri, USA         Gray bat  (Myotis             20          LD        LD           Limit of detection,          Clark et al.
    1976-77                grisescens) found dead;                                          0.1 mg/kg                    (1980)
                          carcass (lipid basis)

    Washington Sate       18 bird species (total                                                                       Blus et al.
    (orchards),           number of birds, 91)                                                                         (1983)
    October 1981-            Brain                     78                    LD-> 0.8
    July 1982                Eggs                      53                    LD-1.7

    Detroit River,        Herring gulls  (Larus                     LD        LD                                        Struger et al.
    Niagara River,         argentatus); eggs                                                                            (1985)
    Saginaw Bay, USA,
    1978-82

    North-west            Fish species;                700         0.008     LD-0.026                                  Stout (1980)
    Atlantic Ocean,       muscle
    Gulf of Mexico,
    USA, 1973-75

    South-east Montana,   Merlins  (Falco                           LD        LD                                        Becker & Sieg
    USA, 1978-81           columbarius); eggs                                                                           (1987)
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    New Jersey,           Snapping turtles             11          LD        LD           Limit of detection,          Albers et al.
    Maryland, USA          (Chelydra serpentina)                                            0.1 mg/kg                    (1986)

    Florida, USA          Snail kite  (Rostrhamus                    LD        LD           Limit of detection,          Sykes (1985)
                           sociabilis); eggs, nestlings                                     0.05 mg/kg

    Missouri, USA,        Gray bats  (Myotis              7         LD        LD                                        Clawson &
    1982                   grisescens)                                                                                  Clark (1989)
                          Red bats  (Lasiurus             7         LD        LD
                           borealis)
                          Pipstrelles  (Pipistrellus      2         LD        LD
                           subflavus)

    Denver, Colorado,     Tree swallows                32          LD        LD                                        Deweese et al.
    USA, 1980-81           (Tachycineta bicolor)                                                                        (1985)

    North-east Alberta,   Otter  (Lutra canadensis);    158         LD        LD            Limit of detection,          Somers et al.
    Canada, 1980-82       carcass                                                         0.001 mg/kg                  (1987)

    Africa

    Lake Nakuru,          Fish  (Tilapia grahami);      10-20/2     LD        LD            Limit of detection:          Koeman &
    Kenya, 1970           whole-body composites                                           fish, 0.002 mg/kg;           Santiago
                          African cormorant                                               birds, 0.009 mg/kg           (1972)
                           (Phalacrocorax africanus)     3           LD        LD
                          liver
                          White pelican                1           LD        LD
                           (Pelicanus onocratalus);
                          Lesser flamingo              5           LD        LD
                           (Phoeniconaias minor)
                                                                                                                                    

    Table 10. (contd)
                                                                                                                                    
    Place and             Type of sample               No. of      Concentration (mg/kg)  Comments                     Reference
    period                                             samples                        
                                                                   Mean        Range
                                                                                                                                    
    Europe

    Province of Leon,     Kestrels  (Falco              4           -         LD-2.0       Liver, 0.01; brain, 0.016;   Sierra &
    Spain, 1986            tnnunculus); 5 organs                                           kidneys, 0.027; muscle,      Santiago
                          or tissues                                                      0.054 mg/kg                  (1987)

                          Sparrowhawk                  3                     LD-2.0       Liver, 0.139; kidneys, 0.4;
                           (Accipiter nisus)                                                fat, 1.068; brain, 0.031;
                                                                                          muscle, 0.047 mg/kg

                          Red kite                     2                     LD-2.0       Kidneys, 0.005; brain,
                           (Milvus milvus)                                                  0.103; fat, 2.035 mg/kg

    1984-87               Barn owl  (Tyto alba)                               0.001-0.22    Liver, 0.036; brain, 0.052;  Sierra et al.
                                                                                          kidneys, 0.034; fat, 0.014;  (1987)
                                                                                          muscle, 0.020 mg/kg

    North Sea             Gadus morhua and             12                    0.0001-0.0023                             Von Westernhagen
                           Merlangius merlangus;          4                    < 0.001-0.0011                            et al. (1987)
                          ovary

    North Sea              Merlangius merlangus                                                                          Von Westernhagen
                             Ovary                     56                    LD-0.001                                  et al. (1989)
                             Testis                    16                    LD
                             Liver                     30                    LD
                                                                                                                                    
    Sample numbers expressed as n/m correspond to n individuals sampled in m composites analysed; LD, limit of detection
    a95% confidence interval
    

         None of 60 samples of bottom deposit collected in 1974 from 19
    rivers and their estuaries in Japan contained endrin (< 0.01 mg/kg)
    (Japanese Environmental Agency, 1975).

         No endrin was detected in sediment and particulates from the
    River Elbe in Germany in 1983-85 (Sturm et al., 1986). Sediment from
    Rotterdam Harbour contained a total of 3-59 µg/kg aldrin, dieldrin,
    and endrin. No endrin was found at seven sites in the Elbe Estuary
    (Japenga et al., 1987). A housing estate in the Netherlands,
    comprising about 800 houses and public buildings, was built in 1983
    directly on a 4-m-thick layer of harbour sludge transferred in 1962-64
    from about 20 harbour basins in Rotterdam and the industrial area
    around the Nieuwe Waterweg. Organic solvents, polycyclic aromatic
    hydrocarbons, heavy metals, and endrin and related pesticides, were
    detected in the sludge. One-third of the soil samples collected in the
    gardens (71 locations), 0-40 cm below the surface, contained endrin
    and related pesticides at a mean concentration of 1.2 mg/kg and a
    maximal concentration of 19.5 mg/kg dry weight (Van Wynen & Stijkel,
    1988).

         In surface sediments from five sites in Manukan Harbour, New
    Zealand, only traces (none detected to < 0.1 µg/kg dry weight) of
    endrin were found (Fox et al., 1988).

         Particulates from two sites in the Shatt al Arab River in Iraq
    contained endrin at 84 and 154 µg/kg, and a site in the Tigris River
    contained 217 µg/kg. No endrin was found in the Euphrates River. The
    mean concentration of endrin in surface and subsurface sediment from
    the Shatt al Arab River ranged from 3 to 18 (range, none detected to
    32) µg/kg; no endrin was found in surface and subsurface sediment from
    the Tigris River. None was found in surface sediment from the
    Euphrates River, but in subsurface sediment a mean concentration of 11
    (5-25) µg/kg was detected (DouAbul et al., 1988).

    5.1.2.3  Sewage sludge

         Endrin was found in only a few of 444 sludge samples analysed
    from sewage treatment works in the United Kingdom. The mean
    concentration was 0.11 mg/kg of sludge, with a range of 0.01-0.71
    mg/kg (McIntyre & Lester, 1984). All samples of non-disinfected
    influent at a pilot plant in Jefferson Parish, LA, USA, contained
    endrin, at an average concentration of 0.67 (0.25-1.58) ng/litre
    (Lykins et al., 1986).

         Sludge from three main waste water treatment plants in Kuwait was
    analysed over a 6-month period in 1984-85. Two grab samples were taken
    from each plant every month to give a total of 36 samples. The mean
    endrin levels for the three plants were 0.02, 0.02, and 0.06 mg/kg
    (Samhan & Ghobrial, 1987). Sewage plant effluents before and after
    treatment were analysed in Baghdad (Iraq) in 1982-83. Endrin was found
    in 8/15 samples taken before treatment, at a mean concentration of

    0.291 (0.081-2.637) µg/litre, and in 6/15 samples taken after
    treatment, at a mean concentration of 0.194 (0.072-1.197) µg/litre
    (Al-Omar et al., 1985a).

    5.1.3  Water

    5.1.3.1  Surface water

         Data on the concentrations of endrin in surface water concern
    mainly those regions in the USA where use of endrin was widespread,
    such as in Mississippi and Missouri, over the period 1957-65. The
    highest concentrations were found in 1963 in the Lower Mississippi,
    with a maximum level of 0.214 µg/litre. The concentrations and the
    rate of occurrence decreased considerably later (Breidenbach et al.,
    1967). In a survey in 1964-68, a maximal level of 0.133 µg/litre was
    reported to have been found in the Missouri basin in 1967. No endrin
    was detected in 1968 (Lichtenberg et al., 1970). In 1974, the
    concentrations in the Lower Mississippi was 0.0045 µg/litre in
    August-November (Brodtmann, 1976).

         In one sample from the Potomac River, at Quantico, endrin and
    endrin aldehyde were identified at concentrations of 0.005 and 0.006
    µg/litre, respectively (Hall et al., 1987). Endrin was not found in
    the waters near the Los Angeles County ocean outfalls (< 0.00005
    µg/litre) (Green et al., 1986) or in surface water in Louisiana in
    1980 (< 1.0 ng/litre) (McFall et al., 1985). In a programme to
    monitor surface water in the USA in 1976-80, endrin was found in only
    0.1% of samples, at a maximum value of 0.04 µg/litre (Carey & Kutz,
    1985).

         No endrin was found in water from 33 sites in the Upper Great
    Lakes in Canada (< 0.01 µg/litre) (Glooschenko et al., 1976). In
    Ontario, where endrin was used only sparingly, no residues were found
    in 1971 or 1975-77 (Miles & Harris, 1973; Frank et al., 1981). In
    water samples taken 1 m below the surface at 14 stations on Lake
    Ontario in 1983, endrin was found in concentrations of
    0.000044-0.000145 µg/litre (Biberhofer & Stevens, 1987).

         In a survey of the aquatic environment in The Netherlands,
    including drinking-water, 1826 samples were taken at 99 sampling sites
    between September 1969 and 1977; traces of endrin were reported
    occasionally (Wegman & Greve, 1978, 1980). Studies of surface water in
    other areas in Europe failed to show the presence of endrin (Wilson
    Committee, 1969; Engst & Knoll, 1973; Uhnak et al., 1974; Galassi &
    Provini, 1981;Hrubec, 1988). In 1984-85, water from a number of rivers
    in Germany contained endrin at levels of none detected to 0.30
    µg/litre (Braun ,1985); surface water in Greece occasionally contained
    levels of 0.0003-0.0004 µg/litre (Albanis et al., 1986).

         No endrin was found in surface or drinking-water in the state of
    Saž Paulo (Brazil) (Lara & Barreto, 1972), but it was found in water
    reservoirs of basins in Saž Paulo at concentrations of none detected
    to 1.02 µg/litre (Celeste & Caceres, 1987; Caceres et al., 1987).
    Endrin was also found accidentally in two lagoons in north-west Mexico
    (Rosales et al., 1985).

         None of 60 water samples collected in 1974 from 19 rivers and
    their estuaries in Japan contained endrin (< 0.1 µg/litre) (Japanese
    Environmental Agency, 1975).

         Endrin was found at five places in the River Nile at
    concentrations of 0.0038-0.0189 µg/litre in March-September 1982
    (El-Dib & Badawy, 1985). In analyses of the water of the Shatt al
    Arab, Euphrates, and Tigris Rivers, endrin was found only in the
    Euphrates River, but in all samples at a mean concentration of 0.024
    (0.014-0.036) µg/litre (DouAbul et al., 1988). It occurred in 75% of
    samples of urban, industrial, and continental water from the Moroccan
    Mediterranean coast, at concentrations of none detected to 13 µg/litre
    (Kassabi et al., 1988). Three of 15 grab samples of surface water
    sources in Southern Africa (Orange Free State) contained endrin, at a
    concentration of 2-4 µg/litre (Hassett et al., 1987).

         Endrin was present in the Kalinadi River in India as a result of
    runoff, especially from agricultural areas, at a concentration of 2
    µg/litre (Kudesia & Bali, 1985). In the Chao Phraya River and klongs
    in Bangkok, Thailand, no endrin (< 0.001 µg/litre) was found in 1984
    (Onodera & Tabucanon, 1986). Analyses in Bali of 16 samples of river
    water in the dry season and 15 samples in the rainy season showed the
    presence of endrin at 40 µg/litre once, in the rainy season (Machbub
    et al., 1988).

    5.1.3.2  Rain and snow

         No endrin was found (limit of detection, 1-2 ng/litre) in
    atmospheric precipitation in the form of snow (17 samples in 1976) and
    rain (81 samples in 1976 and 1977) on the Canadian side of the Great
    Lakes and inland in areas remote from any nearby industrial or urban
    contamination (Strachan et al., 1980). Four of 16 samples of
    rain-water collected at four sites in Canada had levels of
    0.00013-0.00044 µg/litre and another sample had 0.0048 µg/litre; no
    endrin was detected in the other 11 samples. The mean endrin contents
    in samples taken at another site in 1977, 1981, 1983, and 1984 were
    none detected, 0.000065, 0.000085, and 0.000049 µg/litre, respectively
    (Strachan, 1988). Endrin was not detected in snow samples collected at
    12 sites in the Northwest Territories of Canada in 1985-86 (Gregor &
    Gummer, 1989).

    5.1.3.3  Drinking-water

         Data obtained in 1964-67 from selected municipal drinking-water
    treatment plants in Mississippi and Missouri, USA, showed that the
    concentration in approximately 10% of the samples exceeded 0.1
    µg/litre in the first year but that the concentrations were lower in
    1965-67 (Schafer et al., 1969). The most recent study on US
    drinking-water was done on finished water in New Orleans, LA, in 1974,
    where the highest concentration measured was 4 ng/litre (US EPA,
    1974).

         During 1976, endrin was found at a mean concentration of 4
    ng/litre (range, 1-7 ng/litre) in drinking-water in Ottawa, Canada
    (Williams et al., 1978).

         The mean concentration of endrin in drinking-water at the
    El-Abbasia station, Egypt, in 1986 was 3.507 ± 1.45 ng/litre in 10
    samples taken before purification and 1.845 ± 1.29 ng/litre after
    purification (Abdel-Razik et al., 1988).

         Drinking-water from the North Coast region of New South Wales,
    Australia, was analysed in 1986-87: 147 of 659 samples contained
    traces of endrin (none detected [< 0.005] to 0.05 µg/litre) (Ang et
    al., 1989).

    5.1.3.4  Groundwater

          Water in wells used as a source of water for mixing pesticides
    in fruit orchards in West Virginia (USA) was found to contain endrin
    at about 1 ng/litre in 1985 and in 1986. The water in these wells was
    not used for drinking-water. Endrin had not been used in the area
    since 1970, and the authors cite their results as evidence for the
    persistence of endrin and its capacity to contaminate groundwater many
    years after cessation of use (Hogmire et al., 1990).

    5.1.4  Organisms in the environment

    5.1.4.1  Birds

         Endrin was found in the carcasses of four of 16 turkey vultures
     (Cathartes aura) in southern California, USA, in 1981, at levels of
    0.11-0.23 mg/kg wet weight, but in none of six common ravens  (Corvus
     corax). It was also found in two of four vulture eggs, at 0.10
    (range, none detected to 0.52) mg/kg wet weight, but in none of 30
    raven eggs (Wiemeyer et al., 1986).

         Endrin was found in eggs of shag  (Phalacrocorax aristotelis)
    and cormorants  (Phalacrocorax carbo) at one of five collection sites
    in the east, south-east, and south of Ireland, at a geometric mean
    concentration of 0.30 (range, 0.06-1.60) µg/kg (Wilson & Earley,
    1986). Eggs from two species of passerine birds, three species of

    gull, four species of tern, and the night heron were collected in
    Italy in 1982-83. Endrin was found in 30 eggs of the night heron
     (Nicticorax nycticorax), at an average concentration of 0.11
    (0.03-0.27) mg/kg, in 50 eggs of the gull-billed tern  (Gelochelidon
     nilotica), at a concentration of 0.28 (0.05-1.31) mg/kg, and in 38
    eggs of the tree sparrow  (Passer montanus) and 33 eggs of the hooded
    crow  (Corvus corone), at concentrations of 0.17 (0.09-0.33) and 0.21
    (0.07-0.31) mg/kg. It was not detected in eggs of the other species
    (Fasola et al., 1987).

         No endrin was found in 98 eggs or in the livers of 112 nestlings
    of rooks  (Corvus frugilegus) collected from five rookeries in
    northern Germany in 1982-83 (Beyerbach et al., 1987) or in 45 eggs and
    the livers of eight young lapwings  (Vanellus vanellus) collected in
    1984 and 1986 (Beyerbach et al., 1988).

         Detectable residues of the commonest organochlorine pesticides
    were found in 0.9% of 112 pools (mostly of 10 birds) of starlings
     (Sturnus vulgaris) collected in 129 sites in the USA in 1979 and in
    1.6% of 129 pools in 1982. In most states, no endrin was detected, but
    levels of 0.01 and 0.17 mg/kg wet weight were found in two (Bunck et
    al., 1987).

         Endrin was present at microgram levels per kilogram of wet weight
    in 272 samples of liver, muscle, fat, and eggs from northern fulmars
     (Fulmarus glacialis), black-legged kittiwakes  (Rissa tridactyla),
    and thick-billed murres  (Uria lomvia) collected in 1975-77 on Prince
    Leopold Island, Northwest Territories, Canada (Nettleship & Peakall,
    1987). It was found in 8 of 108 carcasses of herons analysed in the
    USA since 1966, at levels of 0.10-0.86 mg/kg wet weight (Ohlendorf et
    al., 1981) but was not found in 255 pools of wings from black ducks
     (Anas rubripes) and mallards  (A. platyrhynchos) collected in the
    USA in 1981-82 (Prouty & Bunck, 1986).

         Endrin was not detected in six eggs of Forster's tern  (Sterna
     forsteri) collected on Green Bay and Lake Poygan, Michigan, USA in
    1983 (Kubiak et al., 1989). None was found in a total of 107 eggs
    collected in 1975-80 from 10 species of colonial waterbirds nesting in
    areas around Green Bay and Lake Michigan. The species were little
    gulls  (Lares minutes), green-backed herons  (Butorides striatus),
    black terns  (Chlidonias niger), herring gulls  (L. argentatus),
    ring-billed gulls  (L. delawarensis), common terns  (S. hirundo),
    Forster's tern  (S. forsteri), double-crested cormorants
     (Phalcrocorax auritis), black-crowned night herons  (Nycticorax
     nycticorax), and cattle egrets  (Bubulcus ibis). The limit of
    detection was 0.1 mg/kg in 1977 and 0.05 mg/kg in 1978 (Heinz et al.,
    1985).

         Of five eggs from peregrine falcons  (Falco peregrinus)
    collected in Arizona, USA, in 1978-82, one collected in 1978 contained
    endrin at 0.20 mg/kg dry weight, one collected in 1981 contained no

    detectable amount (< 0.01 mg/kg) and three collected in 1982
    contained 0.02-0.04 mg/kg (Ellis et al., 1989).

         No endrin was detected in 27 eggs from tree sparrows  (Passer
     montanus), 4 eggs from house martins  (Delichon urbica), 28 eggs
    from white storks  (Ciconia ciconia), or eggs from nine other species
    of bird in Germany in 1984. The livers of 25 nestling, 13 young, and
    17 adult white storks also contained no detectable level of this
    pesticide (limit of detection, 0.001 mg/kg) (Heidmann et al., 1989).

    5.1.4.2  Fish and shellfish

         The endrin concentrations in red mullet  (Mullet barbatus)
    collected at six locations in the Pagassitikos Gulf (Greece) in
    1986-87 were < 0.005-0.5 µg/kg fresh weight of fillets (Satsmadjis et
    al., 1988). The mean concentrations in liver, brain, kidneys, and
    muscle of 22 trout  (Salmo trutta fario L.) taken from four rivers in
    Leon, Spain, in 1985 were 0.104, 0.123, 0.157, and 0.157 mg/kg wet
    weight. The incidence in the four organs was 4.54-22.73% (Teran &
    Sierra, 1987). Endrin was found in 29 samples of fish collected in
    Italy, at a median concentration of 0.019 mg/kg (Cantoni et al.,
    1988). Organochlorine compounds were measured in three samples of
    liver from cod  (Gadus morhua) collected in three areas of the North
    Sea in 1977-87; endrin was present at a concentration of < 5 µg/kg of
    product (De Boer, 1989).

         Endrin was not detected (< 0.01 mg/kg) in two or three replicate
    samples, each comprising three to five bluegill  (Lepomis macrochirus)
    and common carp  (Cyprinus carpio), collected from downstream sites
    exposed to irrigated agriculture and from non-irrigated upstream sites
    on the San Joaquin River and tributaries in California, USA (Saiki &
    Schmitt, 1986). Endrin was also not found in water near Los Angeles
    County ocean outfalls (< 0.00005 µg/litre) or in mussels  (Mytilus
     californianus) (< 0.1 µg/kg wet weight) that had been suspended at
    the monitoring site for 2 months to provide a measure of the
    bioaccumulation of chlorinated hydrocarbon contaminants (Green et al.,
    1986). No endrin was detected in fish samples taken at nine locations
    in north-central USA (Martin & Hartman, 1985), and endrin was not
    detectable (< 0.001 mg/kg) in 527 samples of edible fin fish
    harvested from Chesapeake Bay and its tributaries (Maryland) over the
    period 1976-80 or in 20 samples of roe and gonadal tissue (Eisenberg
    & Topping, 1985).

         No detectable quantity (< 1 µg/kg) of endrin was found in two
    species of crayfish  (Procambarus clarkii and  P. acutus)
    commercially harvested from dual-cropped ponds and from waters of the
    Atchafalaya River Basin and the Mississippi River in southern
    Louisiana, or in sediment and water collected from several ponds and
    at the Basin three times during 1986 and 1987 (Madden et al., 1989).

         Endrin was measured at levels of 0.4 and 66 µg/kg in American
    eels  (Anguilla rostrata) sampled at various sites between Lake
    Ontario and the mouth of the St Lawrence river in 1982 (Castonguay et
    al., 1989). Endrin was not detectable (< 0.002 mg/kg) in 'most'
    composite samples (1-15 fish of 10 different species) collected from
    10 sites on the Great Lakes and tributaries between 1980 and 1981,
    although in a few cases concentrations up to 0.01 mg/kg were found
    (Devault, 1985). Endrin was not present (< 0.005 mg/kg) in fillets of
    Fall Run Coho salmon  (Oncorhynchus kisutch) taken from 14 sites on
    the Great Lakes in 1984. In most cases, three samples per site were
    analysed, and the fish were 2-3 years old (Devault et al., 1988).
    Johnson et al. (1988) measured the input of organochlorine pesticides
    from precipitation and runoff to five small lakes peripheral to the
    Canadian Great Lakes and the levels of residues in fish caught in the
    lakes. While endrin was detectable in precipitation (at 0.46 and 0.54
    ng/litre at the two sampling sites), none was measured in runoff water
    and no detectable residue was found in fish.

         The mean concentrations of endrin in 13 commercially important
    fish species collected in the north-west Arabian Gulf varied between
    1 and 28 µg/kg, and those in five species collected from Hor al-Hammar
    Lake in Iraq in 1985 were 3-67 µg/kg wet weight of edible tissue.
    Endrin residues were detected in approximately 90% of the fish
    (DouAbul et al., 1987a). Samples of  Barbus xanthopetrus collected in
    the Shatt al Arab River and in Hor al Hammar Lake contained average
    concentrations of 4 (none detected to 9) and 20 (11-27) µg/kg, while
    Indian shed  (Tenualosa ilistra) from the Shatt al Arab River
    contained 80 (57-108) µg/kg (wet weight). Shrimp  (Metapanaeus
     affinis) did not contain endrin (DouAbul et al., 1987b). In 1984,
     B. xanthopetrus from the River contained a mean concentration of 16
    µg/kg wet weight, and those from the Lake, 154 µg/kg (range, 13-355);
    Indian shed had mean concentrations of 41-147 µg/kg (range, none
    detected to 236) (DouAbul et al., 1987c). Freshwater mussel
     (Corbicula fluminea) collected in the Shatt al Arab River contained
    166-540 µg/kg (range, 140-583) (DouAbul et al., 1988). Endrin was
    present at concentrations of 1.9-12.2 µg/kg of muscle tissue (wet
    weight) in three fish species and at 0.88-7.7 µg/kg in three  Tilapia
    species collected near Alexandria, Egypt, in 1985 (El Nabawi et al.,
    1987).

         Endrin was present at 0.003-0.004 mg/kg in black pomfret
     (Parastromateus niger), mackerel  (Rastrelliger kanagurta), and
    marine vala  (Chirocentrus sp.) and at 0.08 mg/kg in tuna  (Euthynnus
     affinis) collected off the Indian coast (Radhakrishnan & Antony,
    1989). It was found in one sample of fish at 0.019 mg/kg wet weight
    and in one shellfish sample at 0.034 mg/kg but in none of 312 other
    specimens of 11 types of fish, crustaceans, and molluscs obtained from
    five sites in Java, Indonesia (limit of detection, 0.01 mg/kg) (Koeman
    et al., 1974).

         No endrin was found (< 0.005 mg/kg) in 60 samples of fish and
    shellfish collected in 19 rivers and their estuaries in Japan in 1974
    (Japanese Environmental Agency, 1975).

         The median concentration of endrin in the eggs of 15 adult
    chinook salmon  (Onchorhynchus tshawytscha) collected in Lake
    Michigan in 1982 was 23.5 µg/kg wet weight (range, 3.9-126.3) (Giesy
    et al., 1986).

         Composite samples of whole fish of selected species were
    collected in 1983 near the shores of 13 tributaries of Lake Michigan
    and Grand Traverse Bay. Two of each of the following species were
    collected from each site: common carp  (Cyprinus carpio), bowfin
     (Amia calva), channel catfish  (Ictalurus punctatus), pumpkinseed
     (Lepomis gibbosus), rock bass  (Ambloplites rupestris), small-mouth
    bass  (Micropterus dolomieui), large-mouth bass  (M. salmoides),
    lake trout  (Salvelinus namaycush), and pike  (Esox lucius); the
    composites comprised 3-11 fish. Endrin was not detected (limit, 0.005
    mg/kg) (Camanzo et al., 1987).

         Yellow perch  (Perca flavencens) were sampled in eight
    reservoirs and lakes in Ohio and Wisconsin, USA, in 1978-79. Endrin
    was found in four fish at levels of 0.008-0.02 mg/kg, which were much
    lower than the levels found of polychlorinated biphenyls, DDT and
    dieldrin (Carline & Lawal, 1985).

    5.1.4.3  Mixed species

         Herons  (Nyctanassa violacea), water snakes  (Natrix spp.),
    raccoons  (Procyon lotor), channel catfish  (Ictalurus punctatus),
    crappies  (Pomoxis spp.), frogs  (Rana spp.), and crawfish
     (Procambarus clarkii) were collected from three watersheds in
    Louisiana, USA in 1978-79. Endrin was found in a heron at 0.014 mg/kg
    and in a catfish at 0.022 mg/kg, but in no other case (limit of
    detection, < 0.05 mg/kg) (Dowd et al., 1985).

    5.1.5  Other food and feed

    5.1.5.1  Cereals

         Endrin has been used extensively for the control of insect pests
    in rice. Typically, one to four applications are made, depending on
    local conditions, the last application usually not later than one
    month before harvest. Data on residue levels are available from India
    (1969-70), Thailand (1968-70), the Philippines, Indonesia (1966), and
    Venezuela (1969). The levels in polished rice were 0.01-0.04 mg/kg of
    product (mean, 0.014 mg/kg), except in India where higher levels in
    the order of 0.12 mg/kg were found. Bran, which is used mainly as a
    component of poultry feed, contained a mean level of 0.35 mg/kg
    (range, < 0.01-2.3 mg/kg), and low levels of delta-ketoendrin were
    found (FAO/WHO, 1971).

         Endrin has been used to only a limited extent on grain crops. The
    residues in different types of treated grains in the USA were
    generally below 0.05 mg/kg of product, except in oats in which levels
    up to 0.5 mg/kg were found. In India, up to five applications on
    sorghum gave residue levels below 0.02 mg/kg; in the USA, the levels
    in sorghum were below 0.05 mg/kg. Straw of cereals contains higher
    levels: rice straw had up to 3 mg/kg,, and sorghum straw up to 0.4
    mg/kg (FAO/WHO, 1971).

         Wheat imported into the United Kingdom in 1987-88 did not contain
    endrin (< 0.01 mg/kg) (Osborne et al., 1989).

    5.1.5.2  Fruit and vegetables

         Endrin is occasionally used for control of field mice (voles). No
    residue was found in apples at harvest (detection limit, 0.01-0.002
    mg/kg of whole fruit) when it was sprayed on the ground under trees in
    orchards in autumn or spring. The levels were sometimes higher in
    fallen fruit, ranging from < 0.002 to 0.02 mg/kg of product (Horsfall
    et al., 1970; FAO/WHO, 1971).

         Only 14 of 15 000 samples of fruit and vegetables imported into
    Sweden during the period 1981-84 contained endrin, at a maximum
    concentration of 0.02 mg/kg (Anderson, 1986). The pesticide analysis
    programme of the Swedish National Food Administration on fruit and
    vegetables, including potatoes, showed no residue of endrin above the
    limit of detection of 0.02 mg/kg in 13 724 samples analysed in 1985-87
    (B.G. Ericsson, personal communication, 1990). The mean endrin
    concentration in 137 samples of grape products (including seeds,
    skins, marc and lees) in Italy was 6.2-16.2 µg/kg (Marinelli et al.,
    1986). Seven of 306 samples of apples (five types) collected in
    1980-83 from five regions of Italy contained endrin (limit of
    detection, 0.001 mg/kg) (Foschi et al., 1985).

         In Pakistan, in 16 samples of cucumber sprayed at the time of
    maturity with a 0.05% endrin solution at a rate of 100 gallons/acre
    (1123 litres/ha), the endrin concentrations ranged from 3.04 to 6.69
    mg/kg. The residues persisted in the edible portion of cucumber up to
    14 days and diminished thereafter (Illahi et al., 1986). Endrin was
    found in 17% of samples of peas collected from fields and markets in
    Faisalabad, Pakistan, at a level of 1.3-4.32 µg/kg. The residues
    persisted for up to 12 days and then decreased (Illahi et al., 1987).
    No endrin was found (< 0.02 mg/kg) in 141 samples of fruit and
    vegetables from Pakistan in 1982-83 (Masud & Farhat, 1985).

         In an analysis of soya bean and soya bean straw in a US
    monitoring programme, seven of 177 samples of soya beans contained a
    geometrical mean of < 0.001 (maximum, 0.03) mg/kg, and one of eight
    straw samples contained < 0.01 mg/kg (Carey et al., 1978). Endrin was
    used in up to four applications on sugar-cane in the USA, with an
    interval of 45 days or longer between the last application and

    harvest. The residues found in cane were usually < 0.05 mg/kg of
    product (FAO/WHO, 1971).

    5.1.5.3  Meat, poultry, and chicken eggs

         Bovine fat (40 samples), pig fat (45 samples), calf fat (45
    samples), sheep fat (22 samples), poultry fat (42 samples), and eggs
    (44 samples) analysed in the Netherlands in 1983 had a median endrin
    concentration of < 0.04 mg/kg (Dutch Agricultural Advisory Commission
    on Environmental Pollutants, 1983). No endrin was found (detection
    limit, 0.005 mg/kg) in samples of beef, pork, goat, mutton, poultry,
    or eggs analaysed in Italy in 1985-87 (Cantoni et al., 1988) or in
    'most' samples of pork, rabbit, or poultry analysed in
    Rheinland/Pfalz, Germany, in 1981-84 (Kampe, 1985). Dietary surveys in
    the United Kingdom demonstrated no endrin in meat (detection limit,
    0.02 mg/kg) (United Kingdom Ministry of Agriculture, Fisheries and
    Food, 1989).

         Endrin was present in 10.8% of 2032 samples of bovine fat from
    carcasses collected from slaughterhouses in Brazil, at a mean level of
    0.01 mg/kg; the highest level was 0.09 mg/kg of tissue (De Paula
    Carvalho et al., 1984). Endrin was present in hens' eggs from four of
    five areas in Mexico, at concentrations of 0.004-0.11 mg/kg of whole
    egg, and in 11 of 16 samples of chicken meat, at an average
    concentration of 0.12 (none detected to 0.6) mg/kg on a fat basis
    (Albert, 1990).

         Endrin was detected in 86 of 221 samples of hens' eggs (78 native
    and 143 commercial) collected in 1975-77 in Iran, at a mean
    concentration of 0.017 (range, 0.003-0.13) mg/kg (Hashemy-Tonkabony &
    Mosstofian, 1979). No endrin was found (limit of detection, 0.02
    mg/kg) in samples of about 25 eggs of  sawah ducks collected on 11
    local markets in Java, Indonesia, in 1972 (Koeman et al., 1974).

         It was found in 14 of 367 hens' eggs collected from 61 farms in
    11 districts of Kenya in 1984; in three of the eggs, the level was >
    0.2 mg/kg (Mugambi et al., 1989).

         Heating, baking, frying, and steaming of tissues obtained from
    broilers fed endrin at 10 mg/kg of diet for 8 weeks did not
    significantly reduce the level of residues: raw, 28.2; baked, 20.8;
    fried, 22.7; and steamed, 19.4 mg/kg of dry tissue (Ritchey et al.,
    1972).

    5.1.5.4  Milk and milk products

         The mean endrin concentration in 20 samples of fresh buffalo milk
    in Kalubia, Egypt, was 0.02 mg/kg of milk fat (range, < 0.01-0.03
    mg/kg (Abdou et al., 1983). Cows' milk (39 samples) collected in four
    areas of Bagdad, Iraq, in 1981-82 contained a mean of 60 (none
    detected to 400) µg/litre (Al-Omar et al., 1985b).

         The average concentration of endrin in 10 samples of evaporated
    cows' milk from three main cities in the agricultural region of Mexico
    was < 0.007 mg/litre of milk fat (Albert et al.,1982). Endrin was
    found in powdered milk at an average concentration of 0.06 mg/kg and
    in cheese at a concentration of 10-27.2 mg/kg on a fat basis (Albert,
    1990).

         The level of endrin in milk in the USA was < 0.001 mg/litre (on
    a fat basis) (FAO/WHO, 1971). No endrin (< 0.5 µg/litre) was found in
    308 samples from bulk transports of milk collected in Ontario, Canada,
    in 1977 (Frank et al., 1979) or in 359 samples collected in 1983
    (Frank et al., 1985).

         No residue was found (detection limit, < 0.005 mg/kg) in samples
    of milk, cream, butter, and cheese in Italy (Cantoni et al., 1988) or
    in 12 samples of cows' milk collected in 1984-86 from different areas
    of Spain (< 0.01 mg/kg fat) (Barcelo & Puignou, 1987).

    5.1.5.5  Fat and oils

         The most important use of endrin is for the control of insects in
    cotton, the number of applications being 1-12; cottonseed oil is used
    for cooking and for the manufacture of margarine, while the extracted
    cake is used as cattle feed. Endrin is thus present both in the
    cottonseed and in the edible oil and cakes. In a study of the
    extraction processes, it was found that alkali washing and bleaching
    had no marked effect but that deodorization reduced the endrin levels
    to below the limit of detection (0.03 mg/kg) (Smith et al., 1968).

         In field studies carried out in the USA, cottonseed contained
    endrin at a maximum of 0.1 mg/kg, although the levels were usually
    much lower. delta-Ketoendrin was not detected. The levels in crude,
    decolourized, and deodorized oil in Venezuela and Brazil were all <
    0.02 mg/kg of product. Spot samples of refined cottonseed oil from
    California, USA, contained < 0.03 mg of endrin and < 0.02 mg of
    delta-ketoendrin ( limits of detection) (FAO/WHO, 1971).

         One-hundred-and-ten samples of raw oil and of oil at various
    stages of processing, i.e., neutralized, hydrogenated, decolourized,
    deodorized, and shortenings, were collected from seven oil processing
    factories in Iran in 1974. Endrin was found only in raw and
    neutralized vegetable oils, at concentrations of 0.004-0.005 mg/litre.
    Raw imported and native oils contained < 0.01 mg/litre, except for
    native sunflower oil which contained 0.026 mg/litre (Hashemy-Tonkabony
    & Soleimani-Amiri, 1976).

         Endrin was found in 60 samples of six varieties of the major
    edible oils and oil seeds used in India, including groundnut, sesame,
    mustard, coconut, and hydrogenated vegetable oils, collected from a
    market in Lucknow. Vegetable oil contained 6 µg/litre, mustard oil, 72
    µg/litre, and sesame oil, 1690 µg/kg. Of the different types of oil

    seeds, only mustard seed contained endrin, at 22 µg/kg (Dikshith et
    al., 1989a).

         Endrin was found at a mean concentration of 0.184 (0.097-0.288)
    mg/kg in samples of cod-liver oil analysed in Germany in 1985 (Ali,
    1986). No residue was found in vegetable oils and fats imported into
    the United Kingdom (detection limits, 0.02 and 0.001 mg/kg,
    respectively) (Abbot et al., 1969).

    5.1.5.6  Animal feed

         Residues of endrin in pressed cottonseed cakes arise primarily
    from the 1-5% of oil left in the cake after extraction. The residues
    in cakes from Brazil, India, the USA, and Venezuela were mainly <
    0.01-0.02 mg/kg product, levels up to 0.08 mg/kg were found
    occasionally (FAO/WHO, 1971). The mean concentration of endrin in 32
    samples of cattle feed from a local market in India was 0.020 mg/kg
    (range, 0.013-0.027 mg/kg) (Dikshith et al., 1989b). No endrin was
    found in 79 samples of cattle feed in Pakistan (Parveen & Masud,
    1987). Endrin was not present in samples of domestic and imported
    animal feed analysed in the USA in 1981-86 (Luke et al., 1988).

         None of 42 samples of chicken feed collected from 61 farms in 11
    districts of Kenya in 1984 contained endrin (Mugambi et al., 1989).

    5.1.6  Miscellaneous products

         Endrin was found in 5 of 25 tobacco samples imported into Germany
    at concentrations of 25-50 µg/kg (Cetinkaya, 1988). No endrin was
    found in cigarettes of 14 brands collected in Finland in 1960-84
    (Mussalo-Rauhamaa et al., 1986). An average content of 0.006
    µg/cigarette (range, none detected to 0.02 µg/cigarette) was found in
    Switzerland (Zimmerli & Marek, 1973).

         When raw cotton imported into Germany from 15 countries was
    analysed, endrin was found in samples from the USSR and Mexico at a
    concentration of 3 µg/kg (Cetinkaya & Schenek, 1987).

    5.2  Exposure of the general population

    5.2.1  Total-diet studies

         Studies on complete prepared meals in the USA, started in May
    1961 and continued to the present, have shown the occasional presence
    of small amounts of endrin (Williams, 1964; Cummings, 1965, 1966;
    Duggan et al., 1966, 1967; Martin & Duggan, 1968; Corneliussen, 1969,
    1970, 1972; Manske & Corneliussen, 1974; Manske & Johnson, 1975;
    Johnson & Manske, 1976, 1977; Manske & Johnson, 1977; Johnson et al.,
    1981a, 1984). These measurements indicate that the total average daily
    intake of endrin from food decreased from 0.009 µg/kg body weight in
    1965 to 0.0005 µg/kg body weight in 1970 (Duggan & Lipscomb, 1969;

    Duggan & Corneliussen, 1972), with a further decrease subsequently. In
    total-diet studies of adults in the USA, representative foods were
    purchased in 27 US cities in 1980-82; the daily intake of endrin was
    found to be < 0.001 µg/kg body weight in 1978, but none was detected
    in 1979, 1980, or 1981-82 (Gartrell et al., 1986a).

         Further studies involved retail purchase of 234 food items
    representative of the total diet of eight US population groups in
    1982-84 and preparing them for consumption. The daily intake of endrin
    in the groups, which included people aged 6-11 months, 2 years, 14-16
    years (females), 14-16 years (males), 25-30 years (females), 25-30
    years (males), 60-65 years (females), and 60-65 years (males), was
    0.1-0.2 ng/kg body weight (FDA, 1988; Gunderson, 1988).

         Endrin was not present in the total diets of infants and toddlers
    in the USA during 1974-75 (Johnson et al., 1979). It was found in one
    infant food sample at 0.011 mg/kg and in one sample of toddler food at
    0.009 mg/kg of food in a study in 1975-76 (Johnson et al., 1981b).
    Very low residue levels were found occasionally in market-basket
    samples representing the average 2-week diets of infants (98 samples)
    and toddlers (110 samples) collected in 10 cities in four geographic
    areas of the USA in 1977-78 (Podrebarac, 1984). In total-diet studies
    of infants and toddlers in the USA, representative foods were
    purchased in 13 US cities in 1980-82; the daily intake of endrin by
    infants was found to be < 0.001 µg/kg body weight in 1978, and that
    by toddlers, < 0.001 µg/kg body weight in 1979, but none was detected
    in the other years (Gartrell et al., 1986b).

         Fresh food was bought from four retail grocery stores in Toronto,
    Canada, in 1985 and combined in five food composites: fresh meat and
    eggs, root vegetables (including potatoes), fresh fruit, leafy and
    other surface vegetables, and cows' milk. The concentrations of endrin
    in the five composites were used to estimate the annual dietary intake
    of endrin from products in Ontario. Endrin was detected in all
    composites except eggs and meat; the concentrations were 0.32 µg/kg in
    leafy vegetables, 0.27 µg/kg in fruit, 0.37 µg/kg in root vegetables,
    and 0.27 µg/kg in milk. The total annual intake was estimated to be
    31.8 µg/person (Davies, 1988).

         In a total-diet study carried out in the United Kingdom in
    1985-88, 25 samples were obtained in 1984-85 which comprised the 16
    food groups considered most likely to contain residues of
    organochlorine compounds. No endrin was detected (limit of detection,
    0.001-0.02 mg/kg, depending on the food group). Endrin was also not
    detected (< 0.01 mg/kg) in 176 samples of pulses purchased from
    retail outlets in 1986-87, except in 3 of 20 samples of mung beans in
    which a mean value of < 0.01 mg/kg (range, none detected to 0.06
    mg/kg) was found (United Kingdom Ministry of Agriculture, Fisheries
    and Food, 1989). No endrin was detected in complete prepared meals
    during surveys in the United Kingdom in 1965 (Robinson & McGill, 1966;
    McGill & Robinson, 1968). Similar results were obtained in Switzerland

    in 1973 (Zimmerli & Marek, 1973), and very low levels were found in
    two of 73 samples analysed in 1985 (Wüthrich et al., 1985). No endrin
    residues were found in total-diet studies carried out in the
    Netherlands in 1976-78 (De Vos et al., 1984).

    5.2.2  Levels in human tissues

         Although the concentrations of many chlorinated hydrocarbon
    insecticides, such as DDT, dieldrin, hexachlorocyclohexanes, and
    hexachlorobenzene, and of their metabolites in blood or adipose tissue
    of the general population or of occupationally exposed workers have
    been found to be an excellent index of the level of exposure of the
    general population, this is not the case for endrin, because it is
    eliminated rapidly.

    5.2.2.1  Adipose tissue

         Except in a few cases, endrin was not demonstrated in adipose
    tissue samples from the general population in the USA in 1962-66
    (Hoffman et al., 1964, 1967), 1964 (Hayes et al., 1965; Zavon et al.,
    1965), 1970-74 (Kutz et al., 1979a,b), and 1975-79 (US EPA, 1983);
    Canada in 1967-68 (Kadis et al., 1970); Mexico in 1975 (Albert et al.,
    1980); Argentina in 1968-69; (Wassermann et al., 1969); Belgium in
    1968-69 (Wit, 1971); the United Kingdom in 1961 (Hunter et al., 1963),
    1964 (Robinson et al., 1965), and 1965-67 (Egan et al., 1965; Abbott
    et al., 1968, 1972); the Netherlands in 1969 (Wit, 1971); Switzerland
    in 1972 (Zimmerli & Marek, 1973); Germany in 1970 (Acker & Schulte,
    1974); France in 1971 (Fournier et al., 1972); Spain in 1978 (Herrera
    Marteache et al., 1978); India in 1964 (Dale et al., 1965); or Western
    Australia in 1965-66 (Wassermann et al., 1968).

         No endrin was found in 91 samples of adipose tissue obtained at
    autopsy in Kingston, Ontario, Canada, in 1979 and 1981 or in 84
    samples from Ottawa in 1980 and 1981 (Williams et al., 1984), or in
    adipose tissue obtained at autopsy from 92 males and 49 females in
    Ontario municipalities in 1984 (limit of detection, 2.4 µg/kg)
    (Williams et al., 1988).

         These results indicate that endrin is either absent or present at
    very low levels in the adipose tissue of the general population. It is
    therefore surprising that Kanitz & Castello (1966) reported the
    presence of endrin in nine adipose tissue samples from Liguria, Italy,
    at a mean concentration of 0.93 mg/kg of tissue. The highest
    concentration was 2.49 mg/kg. Pavan et al. (1987) found endrin at 0.1
    and 0.3 mg/kg in 2 of 92 samples of adipose tissue obtained at surgery
    from people living in the Province of Turin, Italy. In areas where
    endrin has been used extensively, however, such as India and the lower
    Mississippi, it has never been found in human adipose tissue (Brooks,
    1974).

         One of 62 adipose tissue samples obtained at surgery from people
    in Ciudad Juarez, Mexico, in 1977-78 contained endrin at 0.02 mg/kg
    (Redetzke et al., 1983).

    5.2.2.2  Organs

         In samples of liver, kidney, gonad, and brain obtained from the
    general population of Alberta (Canada), no residue of endrin was
    detected (Kadis et al., 1970).

    5.2.2.3  Blood

         No endrin was detected (limit of detection, 0.01 mg/kg) in 4000
    blood samples from the general US population in 1976-80 (US E P A,
    1983), or in areas where endrin has been used extensively, such as
    India and the lower Mississippi (Brooks, 1974), or in 26 blood samples
    from the general population in Nigeria (Atuma, 1985).

    5.2.2.4  Breast milk

         Endrin was not detected in breast milk in studies in the USA in
    1966-78 (Strassman & Kutz, 1977; Currie et al., 1979; Kutz et al.,
    1979a; Barnett et al., 1979), in El Salvador and Guatemala (De Campos
    & Olszyna-Marzys, 1979), in Belgium, Italy, and The Netherlands
    (Kanitz & Castello, 1966; Hendrickx & Maes, 1969; Wegman & Greve,
    1974), and in Japan (Yakushiji et al., 1979). No endrin was detected
    (< 0.01 mg/litre) in 50 breast milk samples from mothers (aged 18-32
    years) in Leiden, The Netherlands, in 1969 (Tuinstra, 1971). It was
    found in one of 12 samples from mothers aged 21-37 in Pavia, Italy, in
    1988, at a concentration of 0.01 µg/kg of whole milk, but not in four
    samples collected in Crotone, southern Italy (Bianchi et al., 1988).

    5.2.2.5  Appraisal of exposure of the general population

         The occasional presence of low concentrations of endrin in the
    air of areas where endrin is used in agriculture cannot be considered
    a significant source of contamination for the general public. The very
    low concentrations that have been found in surface and drinking-water
    are also of little significance for public health.

         The source of exposure that may be relevant is dietary intake.
    Apart from accidental contamination, however, intake of endrin by the
    general population in the countries examined has been and is still far
    below the maximum acceptable daily intake of 0.2 µg/kg body weight
    established by the Joint FAO/WHO Meeting in 1970 (FAO/WHO, 1971). This
    applies equally to the total intake, when the intake from dietary
    sources is added to that from air and water.

         Endrin has not been demonstrated in the large number of samples
    of organs, adipose tissue, blood, and breast milk analysed in
    different countries, even in areas where endrin is or was used
    extensively.

    5.3  Occupational exposure during manufacture, formulation and use

    5.3.1  Manufacture and formulation

         Endrin has not been detected in the blood, plasma, or urine of
    workers exposed occupationally to endrin (Hayes & Curley, 1968; Jager,
    1970). Endrin was detected in blood only after accidental
    over-exposure. Jager (1970) estimated that the threshold level of
    endrin in the blood, below which signs or symptoms of intoxication do
    not occur, lies between 0.05 and 0.10 mg/litre. He estimated the
    half-life of endrin in the blood to be in the order of 24 h.

         The total exposure of workers in a manufacturing and formulation
    plant was estimated on the basis of determinations of the quantity of
    the endrin metabolite  anti-12-hydroxyendrin in urine. Urine of
    workers exposed to endrin for seven days had concentrations of up to
    360 µg/g of creatinine; no unchanged endrin was found. Assuming an
    average daily excretion of 1.5 g creatinine per day, the total daily
    excretion of  anti-12-hydroxyendrin in the urine may be up to 540 µg.
    This gives a minimal absorption of 0.5 mg endrin, indicating that
    inhalation of dusts and absorption through the skin may be significant
    during occupational exposures in manufacture. It is not unreasonable
    to assume that, as in other species, approximately half of all the
    endrin absorbed is excreted in the urine as  anti-12-hydroxyendrin,
    since both endrin and this metabolite are present in the faeces of
    workers (Ottevanger &Van Sittert, 1979; Baldwin & Hutson, 1980 ).
    Thus, 1 mg/day may be the more accurate figure for exposure in this
    manufacturing plant. The concentration of  anti-12-hydroxyendrin in
    urine decreased more slowly than the concentrations of endrin in
    blood, with a half-life of 55-75 h (Van Sittert, 1985).

    5.3.2  Application

         Endrin is applied in agriculture by high-pressure spraying with
    a hand gun, spraying orchards with a power air blast or boom to
    control mice, dusting potatoes, spraying row crops, or application
    from aircraft. These methods of application result in dermal and
    respiratory exposures.

         The potential dermal and respiratory exposure of workers applying
    endrin formulations in the field has been quantified in a few studies.
    Respiratory exposure to endrin during spraying of orchards,
    high-pressure spraying of crops, and piloting of aircraft varied from
    0.01 to 0.14 mg/h; dermal exposure during such activities was
    0.01-1.64 mg/h. The activity that caused the most exposure was dusting
    potatoes, which was associated with a respiratory exposure of 0.41

    mg/h and a dermal exposure of 18.7 mg/h. Total exposure, calculated as
    a percentage of a toxic dose/h = {dermal exposure (mg/h) +
    [respiratory exposure (mg/h) x 10]} ‰ [dermal LD50 (mg/kg) x 70] x
    100, was 0.21-1.5% (Durham & Wolfe, 1962) (see Table 11). These
    figures show that although endrin is acutely highly toxic it can be
    used safely when reasonable precautions are taken (Wolfe et al., 1963;
    Jegier, 1964; Wolfe et al., 1967; Hayes, 1975).

         Endrin was not found in the blood of 20 pesticide sprayers or in
    19 controls in Choluteca, southern Honduras (Steinberg et al., 1989).

    5.3.3  Appraisal of occupational exposure

         No residues were found in healthy workers. The range of threshold
    levels of endrin in blood below which no sign or symptom of
    intoxication occurs has been estimated to be 50-100 µg/litre. The
    half-life of endrin in blood may be in the order of 24 h following
    occupational exposure. The concentration of  anti-12-hydroxyendrin in
    the urine decreased more slowly than the concentration of endrin in
    blood, with a half-life of 55-75 h.

    
    Table 11.  Studies on potential exposure of agricultural workers to endrin, using direct methods
                                                                                                                          
    Activity                                         Exposure
                                                                                                   

                                                     Respiratory         Dermal   Totala (%) toxic    Reference
                                                                         (mg/h)   dose/h

                                                     mg/m3      mg/h
                                                                                                                          

    Spraying orchard cover crops for mouse                      0.01b      2.6    0.21              Wolfe et al. (1963)
                                                     control

    High-pressure hand-gun spraying orchard                     0.01b      3      0.25              Wolfe et al. (1967)
    cover crops for mouse control

    Operating air-blast or boom sprayers treating               0.01b      2.5    0.21              Wolfe et al. (1967)
    orchard cover crops for mouse control

    Dusting potatoes                                            0.41b     18.7    1.5               Wolfe et al. (1963)

    Spraying row crops                                          NDb,c      0.15   (0.01)d           Jegier (1964)

    Piloting during air application of spray         0.05       0.08b      1.18   0.29 (0.16)e      Jegier (1964)
                                                                                                                          
    aFor a 70-kg man on the basis of dermal LD50 for male rats (18 mg/kg body weight) using the formula given
     by Durham & Wolfe (1962)
    bMeasured by respirator pad
    cNot detected
    dOriginal values calculated on the basis of maximal exposure; recalculated values shown in parentheses are
     based on mean exposure.
    eCalculation based on published data on dermal and respiratory exposure (note in Wolfe et al., 1967)
    
    6.  KINETICS AND METABOLISM

    6.1  Absorption, distribution, and elimination

    6.1.1  Laboratory animals

    6.1.1.1  Oral administration

          Rat: One male rat was fed 14C-endrin at a level of 30 mg/kg
    of diet for 8 days. About 60-70% was excreted on the first day; after
    three days, the faeces contained more then 80% of the administered
    radiolabel; by day 9, 84% had been excreted; and there appeared to be
    a level of saturation after 6-7 days of feeding. Only 0.5% was found
    in the urine. About 75-80% of the label in the faeces was in at least
    two different metabolites. The adipose tissue stored 3-4 mg/kg, giving
    a storage rate of about 10 (FAO/WHO, 1971).

         After female rats were given a single oral dose of 14C-endrin
    at 16, 64, or 128 µg/kg body weight, excretion was rapid. The
    biological half-life of the doses of 16 and 64 µg/kg was 1-2 days;
    however, that of 128 µg/kg was approximately 6 days, showing that
    excretion of higher doses is slower (Korte et al., 1970).

         Six CFE rats of each sex were treated with a single oral dose of
    0.5 mg 14C-endrin in arachis oil (approximately equivalent to
    2.5-3.0 mg/kg body weight), and the radiolabel excreted in urine and
    faeces was measured over 3 days. The animals were then killed and the
    radiolabel measured in tissues. A sex difference was noted in the rate
    of elimination in faeces: 66% of the dose was excreted in 3 days by
    males and 37% by females; excretion was slower in females but tended
    to increase daily between days 1 and 3. Small quantities of radiolabel
    were excreted in the urine, females excreting three times more than
    males. No radiolabel was found in exhaled air (Hutson et al., 1975).
    The results are summarized in Tables 12 and 13.

         Three rats of each sex were each given a single oral dose of 8 µg
    14C-endrin in peanut oil (by gavage) daily for 12 days. A steady
    state (at which the excreted amount equalled the daily intake) was
    reached after about 6 days. Females stored about twice as much (27%)
    as males (14%). The radiolabel was excreted mainly in the faeces:
    after the first 24 h, 70-75% of the radiolabel was found in faeces as
    hydrophilic metabolites; subsequently, only metabolites were present.
    Four days after the last dose, males retained only 5% and females 15%
    of the administered radiolabel (Klein et al., 1968; Korte et al.,
    1970).

    Table 12.  Rates of excretion of radiolabel by rats treated with a
               single oral dose of 14C-endrin (percentage of
               radioactivity administered)

                                                                        
    Sex            Urine                           Faeces
                                                                        
                   Day 1   Day 2    Day 3          Day 1    Day 2   Day 3
                                                                        
    Male            1.3     0.6      0.6            30.6     14.4    21.2
    Female          1.8     2.5      2.9             2.3     10.7    24.2
                                                                        

    Table 13.  Recovery of radiolabel in rat tissues 3 days after a single
               oral dose of 14C-endrin (percentage of radioactivity
               administered)
                                                                        
    Sex       Urine  Faeces  Liver  Kidneys  Fat   Skin  Remaining  Total
                                                         carcass
                                                                        
    Males      2.7    66.2    1.2     0.6    1.7    2.3     12.2     86.9
    Females    7.5    37.2    2.0     0.4    8.0    4.0     28.1     87.2
                                                                        

          Rabbit: A Dutch strain male rabbit was given two oral doses of
    4.7 mg 14C-endrin in olive oil at an interval of 14 days. Between
    days 1 and 13, 37% of the first dose was excreted in the urine and 49%
    in the faeces; the second dose was eliminated similarly. By day 49,
    50% had been excreted in urine and 47% in faeces. Faecal excretion was
    rapid, being almost complete within 24 h, and consisted virtually
    entirely of unchanged endrin. The urine contained only metabolites
    (Bedford et al., 1975a). The excretion of metabolites in rabbits thus
    appears to differ considerably from that in rats: approximately half
    of a dose of 14C-endrin is excreted in the urine of rabbits and
    approximately 2% in rats; endrin metabolites are excreted in rat
    faeces over several days (after a single oral dose), whereas in
    rabbits faecal excretion is rapid, being almost complete within 24 h,
    and consists virtually entirely of unchanged endrin. The probable
    explanation is that the molecular weight threshold for biliary
    secretion of anions is 325 ± 50 in rats and 475 ± 50 in rabbits (Hirom
    et al., 1972). The glucuronide and sulfate conjugates of
    monohydroxyendrin have molecular weights of 572 and 470, respectively.
    Therefore, conjugates of the endrin metabolites are eliminated in the
    bile and faeces of rats and in the urine in rabbits.

          Dog: Three beagles were fed a diet containing endrin at a
    concentration equivalent to 0.1 mg/kg body weight for 128 days; two
    other animals were used as controls. The concentration of endrin in
    blood was determined at weekly intervals. The time to reach a plateau
    in blood was less than 1 week, and no significant increase in the
    concentration of endrin in blood was found during this period. The

    average concentration between day 9 and day 128 was 4 µg/litre. The
    concentration of endrin in eight organs and tissues of dogs killed 7
    days after termination of exposure was < 0.2 mg/kg of tissue; except
    that the spleen of one dog contained 2.6 mg/kg, and adipose tissue
    contained 0.2-0.8 mg/kg (Richardson et al., 1967).

    6.1.1.2  Intravenous administration

          Mouse: The concentrations of endrin were determined in tissues
    from groups of five adult male CFI mice given endrin intravenously at
    5 mg/kg body weight (LD90) in dimethyl sulfoxide. The concentrations
    prior to convulsions (about 10 min after injection) were approximately
    60 mg/kg in liver, 20 mg/kg in brain and omental fat, and
    approximately 5 mg/litre in blood. The concentration in whole brain 15
    min after an intravenous dose of 1.5 mg/kg body weight (the dose that
    caused ataxia in 90% of animals; TD90) was 9.4 mg/kg. No endrin was
    detected in the bile of animals with a bile fistula dosed
    intravenously with the TD90 in samples collected after 0.5, 1, or 2
    h (Walsh & Fink, 1972).

          Rat: Male Holtzman rats with or without a bile fistula were
    given a single intravenous dose of 14C-endrin at 0.25 m/kg body
    weight. More than 90% of the excreted radiolabel was found in the
    faeces of intact animals over the 7-day period after dosing or in the
    bile of animals with fistulas over 4 days. The mean total percentage
    recovery of administered radiolabel in faeces, urine, and carcasses
    was 97% from intact animals 7 days after dosing, and 94% from animals
    with a bile fistula 4 days after dosing (Cole et al., 1970). No
    unchanged endrin was found in bile; the major metabolite was
     anti-12-hydroxyendrin (see section 6.2.1).

         Rapid excretion was observed in rats given two intravenous
    injections of 14C-endrin at 0.1 mg/kg body weight at an interval of
    4 days. Excretion of the radiolabel was exponential and occurred
    mainly with faeces; only hydrophilic metabolites were present. With a
    dose of 200 µg/kg body weight, male rats retained 5.2% and females
    12.1% of the administered dose 20 days after the second injection. The
    biological half-life of endrin after a single intravenous dose of 200
    µg/kg body weight was 2.5-3 days in male rats and 4 days in females
    (Klein et al., 1968; Korte et al., 1970; Brooks, 1974).

          Rabbit: When rabbits were given 14C-endrin intravenously, the
    radiolabel was excreted mainly in the urine and only as metabolites.
    A probable explanation for the difference in excretion pattern after
    oral and intravenous administration is that much lower doses
    (micrograms compared with milligrams) were given intravenously (Korte
    et al., 1970).

    6.1.2  Domestic animals

         Twelve cows were fed hay from endrin-sprayed alfalfa containing
    an average of 1.9, 2.8, or 3.7 mg/kg endrin; the average daily intake
    of individual animals ranged from 0.04 to 0.11 mg/kg body weight. The
    average concentrations of endrin in the milk were < 0.05, 0.14, and
    0.15 mg/litre, respectively. When endrin dissolved in soya bean oil
    was fed to 11 dairy cows, levels > 1 mg/kg body weight were required
    in order for significant quantities of endrin to be detected in milk
    (Ely et al., 1957).

         Dairy cows (eight Jerseys and six Guernseys) were fed diets
    containing endrin at 0, 0.1, 0.25, 0.75, or 2.0 mg/kg of diet for 12
    weeks. No residues were found (limit of detection, 0.01 mg/litre) in
    the milk of animals that received 0.1 mg/kg, but up to 0.02 mg/litre
    was found in milk of animals fed 0.25 mg/kg and up to 0.04 mg/litre
    with 0.75 mg/kg of diet; the highest dose resulted in residues in milk
    of 0.1 mg/litre. The endrin content of brain, heart, liver, kidneys,
    body fat, and muscles was < 0.1 mg/kg, but renal fat contained up to
    0.8 mg/kg (Kiigemagi et al., 1958).

         The concentrations of endrin in milk of cows given feed
    containing endrin at approximately 0.05, 0.14, and 0.30 mg/kg of whole
    feed for 5 weeks were 0.004, 0.01, and 0.018 mg/litre, respectively
    (Williams et al., 1964). A steady (plateau) level in milk was reached
    after about 15 days.

         The concentration of endrin in the milk of dairy cows given feed
    contaminated with relatively low levels of endrin rose rapidly within
    a few hours to days and levelled off at a plateau characteristic for
    each concentration in the feed. The average milk:diet ratio for endrin
    was 0.07 for feed levels of 0.05-0.3 mg/kg of diet (Biehl & Buck,
    1987).

         Two lactating cows were fed 14C-endrin for 21 days at an
    overall dietary concentration of 0.1 mg/kg of diet, which was
    considered to be comparable to the highest dose that cows are likely
    to receive in cottonseed cake. Excretion of radiolabel in milk, urine,
    and faeces reached a plateau 4-9 days after start of treatment.
    Approximately 3% of the radiolabel was excreted in milk, 65% in urine,
    and 20% in faeces. Unchanged endrin was not found in urine, but about
    30% of the radiolabel in faeces and all of the 0.003-0.006 mg/litre
    found in milk was endrin. The concentration of endrin equivalent
    residues was 0.001-0.002 mg/kg in meat and 0.02-0.10 mg/kg in fat;
    most of the radiolabel in fat consisted of endrin (Baldwin et al.,
    1976).

         Steers, hogs, and lambs fed diets containing endrin at 0, 0.1,
    0.25, or 0.75 mg/kg of diet for 12 weeks had residues of < 0.1 mg/kg
    in red meat, liver, and kidneys and of 0.02-0.2 mg/kg in body fat.
    Feeding endrin at 2 mg/kg of diet to steers for 12 weeks resulted in

    residues of 0.9 mg/kg in fat and 0.2-0.3 mg/kg in red meat, liver and
    kidneys (Terriere et al., 1958). The biotransfer factors for endrin in
    beef and milk were directly proportional to the octanol-water
    partition coefficients, while the bioconcentration factor for endrin
    in vegetation was inversely proportional to the square root of the
    octanol-water partition coefficient (Travis & Arms, 1988).

         Six weeks after the start of feeding seven Delaware X New
    Hampshire male chicks and eight weeks after the start of feeding seven
    White Leghorn pullets a diet containing endrin at 0.1 mg/kg, the
    residues in eggs and meat were < 0.1 mg/kg and that in fat, 0.6
    mg/kg. At a dietary level of 0.25 mg/kg, the residue levels were
    0.2-0.3 mg/kg in eggs, 0.1 mg/kg in breast meat, and about 1 mg/kg in
    fat. With 0.75 mg/kg of diet, the levels were 0.4 mg/kg in eggs, 0.24
    mg/kg in breast meat, and 3.1 mg/kg in fat (Terriere et al., 1959).

         14C-Endrin was administered daily in corn oil in gelatin
    capsules to six laying hens at a concentration equivalent to 0.13
    mg/kg of total diet for 21 weeks. Ingestion and elimination in eggs
    and excreta were almost balanced after about 16 weeks. The residue
    levels in eggs were 0.11-0.18 mg/kg and were found in the yolk; none
    of the known metabolites was detected. The levels of endrin equivalent
    were about 0.01 mg/kg in breast meat and 0.1 mg/kg in leg meat; higher
    levels were found in the liver (0.47 mg/kg), kidneys (0.17 mg/kg), and
    fat (1 mg/kg). The residues were accounted for by unchanged endrin,
    except in the liver and kidneys, where part probably consisted of
    polar metabolites. About 50% of the administered radiolabel was
    excreted in the faeces, 10% of which was in unchanged endrin (Baldwin
    et al., 1976).

    6.1.3  Human beings

         The concentrations of endrin in the blood of workmen exposed to
    endrin were generally below the level of detection: endrin was not
    found in plasma (< 3 µg/litre) or fat (< 0.03 mg/kg) of workers
    exposed to endrin for an average of 88 days (Hayes & Curley, 1968). No
    endrin was found in the blood of healthy people working in an endrin
    manufacturing plant between 1964 and 1970, at an initial limit of
    detection of 10 µg/litre, improved after 1965 to 5 µg/litre (Jager,
    1970).

         Residues of endrin have been found in blood only in individuals
    with signs of recent intoxication or who have recently had excessive
    exposure (see section 9.2.2). Endrin appears to be eliminated rapidly
    from the human body.

    6.1.4  Systems in vitro

         Isolated liver preparations from Holtzman rats were perfused with
    a solution containing 14C-endrin at 0.003 mg/ml. Within 1 h, 50% of
    the radiolabel appeared in the bile; and in 6 h, more than 90% of the

    total label was found (Cole et al., 1970). With the same dose,
    radiolabel appeared 2-12 times faster in the bile of livers isolated
    from male rats as in that of livers from females, which may account
    for the lower toxicity and lower storage of endrin in adipose tissue
    in male rats (Klevay, 1971). After perfusion of albino rat liver with
    a physiological solution containing 40 µg of 14C-endrin, both endrin
    and hydrophilic metabolites were found (Altmeier & Korte, 1969).

    6.2  Biotransformation

         Information on the metabolism of endrin up to 1967 was reviewed
    (Soto & Deichmann, 1967; Brooks, 1969).

    6.2.1  Experimental animals

         A number of investigations have been carried out since 1970 to
    elucidate the identity of several metabolites of endrin in rats
    (Baldwin et al., 1970; Richardson et al., 1970; Hutson et al., 1975;
    Bedford & Hutson, 1976), rabbits (Bedford et al., 1975a; Hutson,
    1981), cows and chickens (Baldwin et al., 1976). The 12-hydroxy
    derivative was reported to be present in the faeces of rats (Baldwin
    et al., 1970), and the hydroxyl group was assigned tentatively as  syn
    to the epoxide ring. The stereochemical configuration was subsequently
    shown to be  anti to the epoxide group (Baldwin et al., 1973), and
    this configuration was confirmed by the synthesis of  anti-12-
    hydroxyendrin (also called 9- anti-hydroxyendrin) (Bedford & Harrod,
    1973; Bedford et al., 1986a). The chemical structures of these
    compounds are shown in Figure 2; the chemical names are given in Annex
    I.

         Formation of anti-12-hydroxyendrin ( III), together with its
    sulfate and glucuronide conjugates, is considered to be the major
    route of metabolism of endrin. Four other metabolites have been
    reported, but their concentrations are generally smaller than that of
     anti-12-hydroxyendrin and its conjugates. These four metabolites are
     syn-12-hydroxyendrin ( II; tentative identification),
    3-hydroxyendrin ( IV; synthesized and structure confirmed by Bedford
    et al., 1986b), 12-ketoendrin ( V), and the product of formal
    hydroxylation of endrin, the 4,5- trans-dihydroisodrindiol ( VI;
    tentative structure). The  trans-diol ( VI) is a minor metabolite in
    both rats and rabbits; it may be formed via an oxidation-reduction
    pathway involving intermediates of the corresponding ketol ( VII).
    Each of the hydroxy compounds is also excreted partly as its sulfate
    or glucuronide in the urine of animals (Bedford et al., 1975a,b;
    Hutson et al., 1975).

         The three monohydroxylated derivatives of endrin,  syn- and
     anti-12-hydroxyendrin ( II and  III) and 3-hydroxyendrin ( IV),
    are the products of the action of liver microsomal monooxygenases on
    endrin (Bedford & Hutson, 1976). These alcohols are also conjugated to
    glucuronides and sulfates to some extent in the liver. Comparative

    metabolic studies with rat liver microsome preparations have shown
    that free  syn-12-hydroxyendrin, but not its free  anti-isomer, is
    the precursor of 12-ketoendrin ( V) (Hutson & Hoadley, 1974).

         Rats exhibit a sex difference in the rate of metabolism. The
    major metabolite in animals of each sex is  anti-12-hydroxyendrin,
    which is excreted via the bile as the glucuronide; this undergoes
    enterohepatic circulation and is eliminated as the aglycone in the
    faeces, together with two minor metabolites, 3-hydroxyendrin and
    4,5- trans-dihydroisodrindiol. Male rats produce the metabolite at a
    higher rate than do females. The major urinary metabolite in male CFE
    rats was 12-ketoendrin, while females excreted mainly
     anti-12-hydroxyendrin O-sulfate. Endrin and the lipophilic
    metabolite 12-ketoendrin were the major compounds found in the organs
    and tissues of male and female CFE rats 3 days after a single oral
    dose of endrin, but the ratio of endrin:12-ketoendrin was 2/1 in
    females and 1/8 in males. Thus, 12-ketoendrin constituted most of the
    radiolabel in the liver and kidneys of males and endrin that in the
    kidneys of females (Hutson et al., 1975; Hutson, 1981).

         The metabolism of endrin in rabbits is superficially different
    from that in rats. The major metabolite is still
     anti-12-hydroxyendrin, but it is conjugated with sulfate and
    eliminated in the urine. Some  syn-12-hydroxyendrin was also detected
    as its sulfate in urine, and perhaps conjugation and elimination
    prevented further oxidation to 12-ketoendrin. The respective
    glucuronide conjugates were also eliminated in the urine, as were the
    glucuronides of 3-hydroxyendrin and the 4,5- trans-diol ( VI)
    (Bedford et al., 1975b; Hutson, 1981).

         Studies with 14C-endrin in lactating cows showed that the
    residues in milk and body fat consisted of unchanged endrin, although
    traces of 12-ketoendrin were consistently found in fat. As in rats,
     anti-12-hydroxyendrin was the major metabolite in urine and faeces,
    the urine being the major excretory route, as in rabbits.
    12-Ketoendrin and  syn-12-hydroxyendrin were minor metabolites in cow
    urine (Baldwin et al., 1976). Thus, although the metabolic pathways of
    endrin in cows are qualitatively similar to those in rats and rabbits,
    quantitative differences are seen in faecal and urinary excretion.

         In hens, only endrin was found as a residue in meat, fat, and
    eggs. Unchanged endrin accounted for about 10% of the radiolabel in
    excreta, and the major metabolite was  anti-12-hydroxyendrin and its
    sulfate conjugate. No 12-ketoendrin was detected in tissues, eggs, or
    excreta. The metabolism of endrin in hens is fundamentally similar to
    that in rats, rabbits, and cows, except that they produce neither
     syn-12-hydroxyendrin nor the related 12-ketoendrin. The rate of
    metabolism, however, was much lower than in cows (Baldwin et al.,
    1976). The absence of 12-ketoendrin in birds was confirmed in a study
    of four species killed by endrin (Stickel et al., 1979). Hutson et al.

    FIGURE 2

    (1975) suggested that the acute toxicity of endrin in birds is not
    associated with the formation of 12-ketoendrin.

    6.2.2  Human beings

         No endrin was found (limit of detection, 0.0016 mg/litre) in 14
    samples of urine from workers exposed to aldrin, dieldrin, and endrin,
    even though workers with a complete work history had been exposed to
    endrin for an average of 2160 h (Hayes & Curley, 1968). Endrin was not
    detected in urine from five men and five women (Cueto & Hayes, 1962;
    Cueto & Biros, 1967). No unchanged endrin was found in the urine of
    Dutch workers exposed to endrin, but it occurred in the faeces (Jager,
    1970; Baldwin & Hutson, 1980).

         Neither 3-hydroxyendrin nor the diol was detected in urine or
    faeces (Hutson, 1981).  anti-12-Hydroxyendrin was present in the
    urine of workers exposed to endrin, and the glucuronide was found in
    the faeces. Concentrations of up to 0.36 mg/g of creatinine were found
    in urine after 7 days, accompanied by a sharp rise in the level of
    D-glutaric acid (excreted in the urine of mammals as a metabolite of
    D-glucuronolactone [Marsh, 1963]), indicating that liver enzyme
    induction may have occurred. The levels tended to decrease over the
    weekend (Ottevanger & Van Sittert, 1979). Endrin,
     anti-12-hydroxyendrin, 12-ketoendrin, and the beta-glucuronide of
     anti-12-hydroxyendrin were not found in the blood of workers at a
    Dutch plant for the manufacture of endrin (limit of detection, 2
    µg/litre). Both endrin and  anti-12-hydroxyendrin were found in the
    faeces, and all urine samples contained the beta-glucuronide of
     anti-12-hydroxyendrin up to a concentration of 0.14 mg/litre as
     anti-12-hydroxyendrin (Baldwin & Hutson, 1980).

         Hydroxylation at  anti-C-12 is relatively rapid and accounts for
    the rapid metabolism of endrin. Even  syn-12-hydroxyendrin is
    hydroxylated rapidly at its  anti-C-12 position, affording
    12-ketoendrin (Hutson, 1981).

         As neither endrin nor its metabolites were found in the blood of
    exposed, healthy workers, exposure can be measured by determining
     anti-12-hydroxyendrin in urine. A quantitative relationship between
    exposure to endrin and the concentration of this metabolite cannot be
    established, however, owing to lack of data.

    6.2.3  Microorganisms

         In mixed anaerobic microbial populations developed using inocula
    from soil, freshwater mud, sheep rumen, and chicken litter, endrin
    (like other cyclodiene compounds) was monodechlorinated at the
    methylene bridge carbon atom. Neither endrin nor any other compound
    was further metabolized. The 10 obligate anaerobic bacteria that made
    up the mixed population were subsequently isolated in pure culture. Of
    these, only  Clostridium bifermentans, C. glycolium, and other

     Clostridium species were capable of dehalogenation, but at a rate
    that was much slower than that of the mixed population (Maule et al.,
    1987).

    6.2.4  Plants

         Three experiments were carried out on tobacco plants. In the
    first experiment, 2.08 mg of 14C-endrin were applied to the leaves
    with free aeration during the experimental period. In the second test,
    the same dose was applied but with little aeration; and in the third,
    plants were exposed to 1.04 mg of 14C-endrin with little aeration.
    An initial residue level of 50-100 mg/kg was found on leaves in all
    three experiments, but, subsequently, less residue was found on plants
    with free aeration. Six weeks after treatment, 30-47% of radiolabel
    was recovered in residues, which consisted of endrin and hydrophilic
    substances (Weisgerber et al., 1969; Donoso et al., 1979).

         The leaves of cotton plants were treated with 4.2 mg of
    14C-endrin, and the application was repeated after 2 and again after
    6 weeks, at which time parathion was also applied. At harvest,
    two-thirds of the radiolabel had evaporated, and the total residue in
    cotton seed was 0.333 mg/kg. Endrin and two groups of degradation
    products were found in the plants; one of these products (possibly
    delta-ketoendrin) was only slightly more hydrophilic than endrin, and
    the other was very hydrophilic. Most of the metabolites were found on
    the surface of the leaves. When delta-ketoendrin was applied to white
    cabbage, it disappeared more slowly than endrin, with the formation of
    hydrophilic metabolites (Korte, 1969).

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1  Microorganisms

         The interactions of halogenated pesticides and microorganisms
    have been reviewed extensively (Pfister, 1972).

         In three Willamette valley soils (USA) treated with endrin at 0,
    1 or 10 mg/kg, no effect was found 30 days after application on the
    function and activity of the microbial population, the decomposition
    of native organic matter, the transformation of native soil nitrogen,
    ammonification of peptone, or nitrification of ammonium sulphate
    (Bollen & Tu, 1971). Even at an annual application rate of 5 lb/acre
    (5.6 kg/ha) for 5 years, no effect was seen on the numbers or kinds of
    soil fungi, the numbers of bacteria, the decomposition rate of organic
    matter (measured by CO2 production), or the oxidation of ammonium to
    nitrate (Martin et al., 1959).

         Endrin at a concentration of 100 mg/kg of soil had no effect on
    denitrification in soil under anaerobic incubation for 5 days at 30 °C
    or in an isolated denitrifying bacterium (Bollag & Henninger, 1976).
    A concentration of 1000 mg/kg had no effect on methanogenesis, sulfate
    reduction, or carbon dioxide evolution in anaerobic salt-marsh
    sediments (Kiene & Capone, 1984).

         The growth rates of two strains of blue-green algae were
    decreased in the presence of endrin at a concentration of 0.29
    µg/litre (Batterton et al., 1971), and the productivity of many forms
    of natural phytoplankton in estuarine waters was decreased by 46% when
    they were exposed to 1 mg/litre (Butler, 1963).

    7.2  Aquatic organisms

    7.2.1  Invertebrates

         Acute toxicity of endrin to invertebrates is given in Tables 14
    and 15.

         A static system was used to study the toxicity of endrin to a
    polychaete worm  (Nereis virens) in water and sediment, in which sea
    water or sediment (containing 17% sand, 83% clay, and 2% organic
    carbon) was present at a temperature of 9-10 °C for 12 days. None of
    the worms in sea water died after exposure to endrin at 0.11 mg/litre
    for 12 days, but two of five worms exposed to 28 mg/kg in sediment
    died in this period (McLeese et al., 1982).

        Table 14.  Acute toxicity of endrin to freshwater invertebrates
                                                                                                                                    
    Organism                   Size/       Static/   Temp.   Hardness      pH     Parameter   Concentration    Reference
                               age         flowa     (°C)    (mg CaCO3/l)                     (mg/l)
                                                                                                                                    
    Red snail                              Static                                 48-h LC50   7200          Hashimoto & Nishiuchi
     Indoplanorbis exustus                                                                                   (1981)

    Marsh snail                            Static                                 48-h LC50   9500          Hashimoto & Nishiuchi
     Semisulcospira libertina                                                                                (1981)

    Snail                                  Static                                 48-h LC50   12 000        Hashimoto & Nishiuchi
     Physa acuta                                                                                             (1981)

    Water flea                             Static    18-23                        48-h LC50   160           Thurston et al.(1985)
     Daphnia magna                           Static    21          44        7.1    48-h LC50   4.2           Mayer & Ellersieck (1986)
                                           Static    18          48        7.4    48-h LC50   41-74         Mayer & Ellersieck (1986)
                                           Static    22-24      240        8.0    96-h LC50   59            Elnabarawy et al. (1986)

    Water flea                             Static    15          44        7.1    48-h LC50   20            Mayer & Ellersieck (1986)
     Daphnia pulex                           Static    22-24      240        8.0    96-h LC50   30            Elnabarawy et al. (1986)

    Water flea                             Static    22-24      240        8.0    96-h LC50   24            Elnabarawy et al. (1986)
     Daphnia reticulata

    Water flea                             Static    21          44        7.1    48-h LC50   45            Mayer & Ellersieck (1986)
     Simocephalus serrulatus                 Static    15          44        7.1    48-h LC50   26            Mayer & Ellersieck (1986)

    Water flea                 Adult       Static    21          44        7.1    48-h LC50   1.8           Mayer & Ellersieck (1986)
     Cypridopsis vidua

    Sow bug (isopod)           Adult       Static    15          44        7.1    96-h LC50   1.5           Mayer & Ellersieck (1986)
     Asellus brevicaudus

    Scud                       Adult       Static    21          44        7.1    96-h LC50   4.3           Mayer & Ellersieck (1986)
     Gammarus fasciatus          Adult       Static    15         272        7.4    96-h LC50   1.3           Mayer & Ellersieck (1986)
                                                                                                                                    

    Table 14. (contd)
                                                                                                                                    
    Organism                   Size/       Static/   Temp.   Hardness      pH     Parameter   Concentration    Reference
                               age         flowa     (°C)    (mg CaCO3/l)                     (mg/l)
                                                                                                                                    
    Scud                       Adult       Static    21          44        7.1    96-h LC50   3.0           Mayer & Ellersieck (1986)
     Gammarus lacustris

    Crayfish                   3-5         Static    21         272        7.4    96-h LC50   3.2           Mayer & Ellersieck (1986)
     Orconectes nais             weeks
                               Adult       Static    21         272        7.4    96-h LC50   320           Mayer & Ellersieck (1986)

    Crayfish                   0.4-2.0 g   Flow      18-23                        96-h LC50   > 89          Thurston et al. (1985)
     Orconectes immunis

    Red crayfish                           Static                                 48-h LC50   300           Muncy & Oliver (1963)
     Procambarus clarki

    Tantytarsus                            Static    18-23                        48-h LC50   0.84          Thurston et al. (1985)
     Tantytarsus dissimilis

    Glass shrimp               Adult       Static    21         272        7.4    96-h LC50   3.2           Mayer & Ellersieck (1986)
     Palaemonetes                Adult       Flow      21         272        7.4    96-h LC50   0.5           Mayer & Ellersieck (1986)
     kadiakensis

    Stonefly                   Larvae      Static    15          44        7.1    96-h LC50   > 0.18        Mayer & Ellersieck (1986)
     Acroneuria sp.

    Stonefly                   Larvae      Static    15          44        7.1    96-h LC50   0.076         Mayer & Ellersieck (1986)
     Claasenia sabulosa

    Stonefly                   Larvae      Static    15          44        7.1    96-h LC50   0.54          Mayer & Ellersieck (1986)
     Pteronarcella badia

    Stonefly                   Larvae      Static    15          44        7.1    96-h LC50   0.25          Mayer & Ellersieck (1986)
     Pteronarcys californica
                                                                                                                                    

    Table 14. (contd)
                                                                                                                                    
    Organism                   Size/       Static/   Temp.   Hardness      pH     Parameter   Concentration    Reference
                               age         flowa     (°C)    (mg CaCO3/l)                     (mg/l)
                                                                                                                                    
    Mayfly                     Larvae      Static    15          44        7.1    96-h LC50   0.9           Mayer & Ellersieck (1986)
     Baetis sp.

    Mayfly                     Larvae      Static    15          44        7.1    96-h LC50   62            Mayer & Ellersieck (1986)
     Hexagenia bilineata

    Damselfly                  Larvae      Static    21          44        7.1    96-h LC50   2.4           Mayer & Ellersieck (1986)
     Ischnura verticalis         Larvae      Static    21         272        7.4    96-h LC50   2.1

    Snipe fly                  Larvae      Static    15          44        7.1    96-h LC50   4.6           Mayer & Ellersieck (1986)
     Atherix variegata
                                                                                                                                    
    aStatic, static conditions (water unchanged for duration of test); flow, flow-through conditions; endrin
     concentration in water maintained continuously

    Table 15.  Acute toxicity of endrin to estuarine and marine invertebrates
                                                                                                                                    
    Organism                   Size/         Static/  Temp.    Salinity     Parameter     Concentration     Reference
                               age           flowa    (°C)     (%)                        (µg/l)
                                                                                                                                    
    Sand shrimp                              Static                         96-h LC50       1.7             Eisler (1970a)
     Crangon septemspinosa                     Static                         96-h LC50       0.2-2.0         McLeese & Metcalfe (1980)
                                             Static                         96-h LC50       4-120           McLeese & Metcalfe (1980)

    Brown shrimp               Juvenile      Flow     15       26           48-h LC50       0.2             Mayer (1987)
     Penaeus aztecus

    Pink shrimp                Juvenile      Flow     17       30           48-h LC50       0.2             Mayer (1987)
     Penaeus duorarum            Adult         Flow     17       28           96-h LC50       0.037

    Grass shrimp               Larvae        Flow     25       13           96-h LC50       1.2             Mayer (1987)
     Palaemonetes pugio          Juvenile      Flow     25       23           96-h LC50       0.35
                               Adult         Flow     25       21           96-h LC50       0.69

    Blue crab                  Juvenile      Flow     11       16           48-h LC50       15              Mayer (1987)
     Callinectes sapidus

    Hermit crab                                                             96-h LC50       1.2             Eisler (1970a)
     Pagurus longicarpus
                                                                                                                                    
    aStatic, static conditions (water unchanged for duration of test); flow, flow-through conditions; endrin
     concentration in water maintained continuously
    

         The mean 96-h LC50 for the oligochaetes  Stylodrilus
     heringianus and  Limnodrilus hoffmeisteri exposed to sediment from
    Lake Michigan contaminated with 14C-endrin was 2588 ± 1974 mg/kg dry
    weight of sediment in four assays and 2725 ± 955 mg/kg in two assays.
    The toxicity to  L. hoffmeisteri appeared to be reduced in the
    presence of  S. heringianus. The 96-h EC50 burrowing avoidance
    values were 15.3-19 mg/kg for  S. heringianus and 59 mg/kg of
    sediment for  L. hoffmeisteri (Keilty et al., 1988a).

         Sediment reworking by  L. hoffmeisteri alone and with
     S. heringianus was measured by monitoring the burial of a 137Cs
    marker layer in sediments dosed with 12C- and 14C-endrin at
    concentrations of 5.5-81 400 µg/kg of dry sediment. With low endrin
    concentrations, the marker layer burial rate did not suggest
    stimulation of reworking by either  L. hoffmeisteri or
     S. heringianus. At higher concentrations, the reworking rates were
    equal to or slower than control rates at the beginning of the
    experiment but decreased thereafter. The presence of S. heringianus
    appeared to enhance the reworking response of  L. hoffmeisteri. A
    reduction in the post-experimental mortality and an increase in the
    dry weight of  L. hoffmeisteri in tests with the two species implies
    that  L. hoffmeisteri benefits from the presence of  S. heringianus,
    although the reverse was not observed. High concentrations of endrin
    in the upper 3 cm of the final sediment showed that the worms had
    transported the contaminant upward. The bioaccumulation factor for
     S. heringianus ranged from 9.7 to 43.8 and was consistently three to
    four times greater than that for  L. hoffmeisteri (1.7-13.6) (Keilty
    et al., 1988b).

         The reworking rates of  S. heringianus in microcosms containing
    sediments dosed with 14C-endrin at 3.1-42 000 µg/kg of dry matter
    were measured at 10 °C by monitoring a 137Cs marker layer buried in
    contaminated and uncontaminated microcosms. Alterations in reworking
    rates were observed at endrin concentrations 5.5 orders of magnitude
    below the LC50 of 1650 mg/kg. At the lower concentrations, a
    possible stimulatory effect on the marker layer burial rate in the
    first 300-600 h was followed by a significant decrease relative to the
    controls. At the higher concentrations, the rates were equal or slower
    during the first 600 h and decreased dramatically in the last 600 h.
    Mortality was 9.3-28% at 11 500 and 42 000 µg/kg and 0-6.7% at all the
    other concentrations tested, including controls. The dry weights of
    the worms at the end of the experiment were inversely related to the
    high concentrations. The bioaccumulation factors ranged from 34 to 67
    on the basis of grams of dry organism to grams of dry sediment (Keilty
    et al., 1988c).

         The effect of addition of endrin at 50 mg/kg dry weight of
    sediment on protein utilization by  S. heringianus was examined on
    days 4, 8, 20, 28, 39, and 69. A slight increase in the relative
    percentage of protein to total body weight was observed, but the
    authors concluded that estimation of total protein is not a useful
    measure of sublethal responses (Keilty & Stehly, 1989).

         The total organic carbon content of sediment had little apparent
    effect on the toxicity of endrin in the freshwater amphipod  Hyalella
     azteca. The 10-day LC50 for endrin in sediment (dry-weight basis)
    was 4.4 µg/litre at 3.0% total organic carbon and 6.0 µg/litre at
    11.2% carbon (Nebeker et al., 1989).

         The EC50s in the green sea urchin  (Strongylocentrotus
     droebachiensis), the purple sea urchin  (S. purpuratus), the red
    sea urchin  (S. franciscanus), and the sand dollar  (Dendraster
     excentricus) were 103-441 µg/litre for sperm in a static system and
    221-> 362 µg/litre for embryos in a continuous flow of sea water
    (temperature, 8.2-8.4 °C; salinity, 30.0 parts per thousand; pH
    7.8-8.1 for the sea urchins and 12.5-13.0 °C, 30.0 parts per thousand,
    and pH 8.0-8.1 for sand dollar embryos), both with an exposure time of
    120 h. In a larval test of static exposure of Dungeness crab  (Cancer
     magister), the EC50 was 2.0 µg/litre (Dinnel et al., 1989).

         Endrin was tested at 0, 0.025, 0.05, 0.1, 0.25, 0.5, 1.0, 2.5,
    5.0, and 10 mg/litre for its effects on embryos of the American oyster
     (Crassostrea virginica) and their larvae. Fertilized eggs were
    studied after 48 h, and survival and growth of veliger larvae were
    studied in 2-day old larvae and in larvae kept for a further 12 days
    at 24 °C. The results varied considerably. The estimated concentration
    that would cause an approximately 50% reduction in the number of eggs
    that develop into normal straight-hinge larvae, calculated by
    interpolation from the data, was 0.79 µg/litre and that at which 50%
    of the larvae survived was > 10.0 mg/litre (Davis & Hidu, 1969).

         In the mysid shrimp  Mysidopsis bahia, exposed for the complete
    life cycle, acute lethality (over 96 h) was observed with endrin at
    120 ng/litre; increased oxygen consumption was measurable within 24 h
    of exposure. The lowest-observed-effect level for chronic lethality
    was 60 ng/litre; sub-lethal effects on growth (reduced by day 4 of
    exposure) and oxygen consumption (increased by day 10 of exposure)
    were observed before death (over 20 days). Reduced reproductive
    capacity (assessed as production of young) was observed at 30 ng/litre
    over 20 days--the time to full maturity (McKenney, 1986).

         Behavioural changes were observed in stoneflies  (Pteronarcys
     dorsata) within 4 days of exposure to 96.1% endrin at 0.07 µg/litre
    and in caddis flies  (Brachycentrus americanus) at 0.15 µg/litre. The
    28-day LC50 was < 0.03 µg/litre for caddis flies and 0.07 µg/litre
    for stoneflies (Anderson & DeFoe, 1980).

    7.2.2  Fish

    7.2.2.1  Acute toxicity

         Endrin is highly toxic for both freshwater and marine fish. The
    available data are summarized in Tables 16 and 17.

    7.2.2.2  Short-term toxicity

         Channel catfish  (Ictalurus punctatus) were exposed continuously
    to renewed solutions of endrin in water at 15 and 22 °C. Measured
    endrin concentrations of 0.25-0.30 µg/litre were found to be acutely
    toxic to the fish within 10 days or less. None of the fish survived
    blood concentrations exceeding 0.28 mg/litre, a well-defined threshold
    concentration of endrin in blood, and none died at less than 0.23
    mg/litre. The concentration of endrin in the blood of fish exposed to
    lethal concentrations in water for periods insufficient to cause death
    were markedly lower than that in fish that died from exposure to the
    same water (Mount et al., 1966).

         The 28-day LC50 for 96.1% eldrin in bullheads  (Ictalurus
     melas) was 0.10 µg/litre (Anderson & DeFoe, 1980).

         In larval fathead minnows (< 24 h old) exposed continuously to
    endrin (98%) for 28-30 days in a flow-through system, growth was the
    most sensitive parameter. A 48-h exposure to 0.62 µg/litre caused
    significant reduction in growth, and survival was reduced at 1.21
    µg/litre; with a 72-h exposure, growth was reduced at 0.63 µg/litre,
    and all fish died at 1.15 µg/litre. Continuous exposure to 0.38
    µg/litre for 30 days significantly reduced growth, and all fish died
    at 0.73 µg/litre (Jarvinen et al., 1988).

         Sheephead minnows  (Cyprinodon variegatus) were exposed
    continuously for 23 weeks to endrin from the embryonic stage through
    hatching, until adulthood and spawning. The average exposure
    concentrations were 0 (control), 0.027, 0.077, 0.12, 0.31, and 0.72
    µg/litre. The resultant progeny were monitored to determine effects on
    their survival, growth, and reproduction. Embryos exposed to 0.31 and
    0.72 µg/litre hatched early; all fry exposed to 0.72 µg/litre died by
    day 9 of exposure. At 0.31 µg/litre, fry were initially stunted and
    some died. Survivors seemed unaffected until maturity, when some
    females died during spawning; fewer eggs were fertile, and survival of
    exposed progeny was decreased. No significant effect was observed
    throughout the life cycle at an exposure concentration of 0.12
    µg/litre (Hansen et al., 1977).

         Endrin was tested in flagfish  (Jordanella floridae) at 0.21,
    0.29, and 0.39 µg/litre for 30 days. Only the highest concentration
    decreased survival, and the two highest dose levels affected the mean
    number of eggs produced (Hermanutz et al., 1985).

        Table 16.  Acute toxicity of endrin to freshwater fish
                                                                                                                                    
    Organism                   Size/      Static/   Temp.   Hardness     pH       Parameter   Concentration     Reference
                               age        flowa     (°C)    (mg CaCO3/l)                      (µ g/l)
                                                                                                                                    
    Tilupa sp.                             Static    15         44       7.1      96-h LC50   12            Mayer & Ellersieck (1986)

    Coho salmon                            Static    16         44       7.1      96-h LC50   0.089         Mayer & Ellersieck (1986)
     Oncorhynchus kisutch        1.9 g       Static    20                           96-h LC50   0.27          Katz & Chadwick (1961)

    Chinook salmon             6-8 g       Static    20                           96-h LC50   0.92          Katz & Chadwick (1961)
     Oncorhynchus
     tshawytscha

    Cutthroat trout            1.0 g       Static    13         44       7.1      96-h LC50   > 1.0         Mayer & Ellersieck (1986)
     Salmo clarki

    Rainbow trout              1.0 g       Static    13         44       7.1      96-h LC50   0.75          Mayer & Ellersieck (1986)
     Oncorhynchus mykiss         1.0 g       Static    13        272       7.4      96-h LC50  0.74
                               1.4 g       Static    2          44       7.1      96-h LC50   2.4
                               1.4 g       Static    7          44       7.1      96-h LC50   1.4
                               1.4 g       Static    13         44       7.1      96-h LC50   1.11
                               1.4 g       Static    18         44       7.1      96-h LC50   0.75
                               0.6-8.0 g   Flow      18-23                        96-h LC50   0.3           Thurston et al. (1985)

    Goldfish                   1-4 g       Flow      12        314       7.6      96-h LC50   0.44          Mayer & Ellersieck (1986)
     Carrassius auratus                      Flow      18-23                        96-h LC50   0.95          Thurston et al. (1985)
                                           Static                                 48-h LC50   1.0           Hashimoto & Nishiuchi
                                                                                                            (1981)

    Carp                                   Flow      12        314       7.6      96-h LC50   0.32          Mayer & Ellersieck (1986)
     Cyprinus carpio                         Static                                 48-h LC50   0.84          Hashimoto & Nishiuchi
                                                                                                            (1981)

    Medaka                                 Static                                 48-h LC50   1.4           Hashimoto & Nishiuchi
     Oryzias latipes                                                                                         (1981)
                                                                                                                                    

    Table 16. (contd)
                                                                                                                                    
    Organism                   Size/      Static/   Temp.   Hardness     pH       Parameter   Concentration     Reference
                               age        flowa     (°C)    (mg CaCO3/l)                      (µ g/l)
                                                                                                                                    
    Pond loach                            Static                                 48-h LC50   4.9           Hashimoto & Nishiuchi
     Misgurnus                                                                                                 (1981)
     anguilicaudatus

    Fathead minnow             1.2 g       Static    18         44       7.1      96-h LC50   1.8           Mayer & Ellersieck (1986)
     Pimephales promelas         0.9 g       Flow      12        314       7.6      96-h LC50   0.24
                                           Static                                 24-h LC50   12            Kagan et al. (1986)
                               Larvae      Static    25-26      46       7.1-8.3  96-h LC50   0.7           Jarvinen et al. (1988)
                               0.2-1.0 g   Flow      18-23                        96-h LC50   0.65          Thurston et al. (1985)

    Bluntnose minnow                       Static                                 96-h LC50   0.29          Johnson (1968)
     Pimephales notatus

    Black bullhead             1.5 g       Static    24         44       7.1      96-h LC50   1.13          Mayer & Ellersieck (1986)
     Ictalurus melas

    Channel catfish            5.2 g       Static    18         44       7.1      96-h LC50   1.9           Mayer & Ellersieck (1986)
     Ictalurus punctatus         1.4 g       Static    24         44       7.1      96-h LC50   0.32

    Mosquito fish              0.6 g       Static    17         44       7.1      96-h LC50   1.1           Mayer & Ellersieck (1986)
     Gambusia affinis            0.222 g     Static    25                           96-h LC50   5.27          El-Sebae (1987)

    Bluegill                   1.5 g       Static    18         44       7.1      96-h LC50   0.61          Mayer & Ellersieck (1986)
     Lepomis macrochirus         0.5 g       Static    18        272       7.4      96-h LC50   0.53
                               1.3 g       Static    7          44       7.1      96-h LC50   0.73
                               1.3 g       Static    13         44       7.1      96-h LC50   0.68
                               1.3 g       Static    18         44       7.1      96-h LC50   0.41
                               1.3 g       Static    24         44       7.1      96-h LC50   0.37
                               1.3 g       Static    29         44       7.1      96-h LC50   0.19
                                                                                                                                    

    Table 16. (contd)
                                                                                                                                    
    Organism                   Size/      Static/   Temp.   Hardness     pH       Parameter   Concentration     Reference
                               age        flowa     (°C)    (mg CaCO3/l)                      (µ g/l)
                                                                                                                                    
    Largemouth bass            2.5 g       Static    18        272       7.4      96-h LC50   0.31          Mayer & Ellersieck (1986)
     Micropterus salmoides

    Yellow perch                           Flow      12        314       7.6      96-h LC50   0.15          Mayer & Ellersieck (1986)
     Perca flavescens

    Tilapia                    1.1 g       Static    24         44       7.1      96-h LC50   < 5.6         Mayer & Ellersieck (1986)
     Tilapia mossambica

    Tilapia (Behera strain)    0.825 g     Static    25                           96-h LC50   10.09         El-Sebae (1987)
     Tilapia zilli

    Tilapia (Alexandria
     strain)                   0.825 g     Static    25                           96-h LC50   0.26          El-Sebae (1987)
     Tilapia zilli

    Guppy                                  Static    20                           96-h LC50   0.9           Katz & Chadwick (1961)
     Poecilia reticulata

    Flagfish                   2-3 days    Static    24-26   43-48       6.9-7.8  96-h LC50   0.85          Hermanutz et al. (1985)
     Jordanella floridae
                                                                                                                                    
    aStatic, static condition (water unchanged for the duration of the test); flow, flow-through conditions; endrin
     concentration in water maintained continuously.

    Table 17.  Acute toxicity of endrin to estuarine and marine fish
                                                                                                                                    
    Organism                   Size/        Static/   Temp.    Salinity   Parameter       Concentration       Reference
                               age          flowa     (°C)     (%)                        (µg/l)
                                                                                                                                    
    American eel               57 mm        Static      20     24         96-h LC50       0.6             Eisler (1970b)
     Anguilla rostrata

    Atlantic riverside         54 mm        Static      20     24         96-h LC50       0.05            Eisler (1970b)
     Menidia menidia

    Blue head                  90 mm        Static      20     24         96-h LC50       0.1             Eisler (1970b)
     Thalassoma bifasciatum

    Gulf menhaden              Juvenile     Flow        27     29         24-h LC50       0.8             Mayer (1987)
     Brevoortia patronus

    Sheepshead minnow          Juvenile     Flow        14     30         48-h LC50       1.0             Mayer (1987)
     Cyprinodon variegatus       Juvenile     Flow        30     24         96-h LC50       0.34
                               Adult        Flow        18     18         96-h LC50       0.38
                               Adult        Flow        30     16         96-h LC50       0.36

    Longnose killifish         Juvenile     Flow        25     19         24-h LC50       0.23            Mayer (1987)
     Fundulus similis

    Striped killifish          40 mm        Static      20     24         96-h LC50       0.3             Eisler (1970b)
     Fundulus majalis

    Mummichog                  51 mm        Static      20     24         96-h LC50       0.6             Eisler (1970b)
     Fundulus heteroclitus

    Sailfin molly              Adult        Flow        20     27         96-h LC50       0.63            Mayer (1987)
     Poecilia latipinna

    Spot                       Juvenile     Flow        12     24         48-h LC50       0.3             Mayer (1987)
     Leiostomus xanthurus
                                                                                                                                    

    Table 17. (contd)
                                                                                                                                    
    Organism                   Size/        Static/   Temp.    Salinity   Parameter       Concentration       Reference
                               age          flowa     (°C)     (%)                        (µg/l)
                                                                                                                                    
    Striped mullet             Juvenile     Flow        14     30         48-h LC50       0.4             Mayer (1987)
     Mugil cephalus              83 mm        Static      20     24         96-h LC50       0.3             Eisler (1970b)

    White mullet               Juvenile     Flow        29                48-h LC50       2.6             Butler (1963)
     Mugil curema

    Northern puffer            131 mm       Static      20     24         96-h LC50       3.1             Eisler (1970b)
     Sphaeroidus maculatus

    Striped bass               2.7 g        Static      16-18  28         96-h LC50       0.09            Korn & Earnest (1974)
     Morone saxatilis

    Shiner perch               1.2-11 g     Static      13     26         96-h LC50       0.8             Earnest & Benville (1972)
     Cymatogaster aggregata      1.2-11 g     Int. flow   13     26         96-h LC50       0.12

    Dwarf perch                1.2-11 g     Static      13     18         96-h LC50       0.6             Earnest & Benville (1972)
     Micrometrus minimus         1.2-11 g     Int. flow   13     28         96-h LC50       0.13

    Threespine stickleback     0.3 g        Static      20     25         96-h LC50       1.5             Katz & Chadwick (1961)
     Gasterosteus aculeatus
                                                                                                                                    
    aStatic, static conditions (water unchanged for duration of test); flow, flow-through conditions; int. flow,
     intermittent flow-through conditions; endrin concentration in water maintained continuously
    
    7.2.2.3  Studies of resistance

         Populations of mosquito fish  (Gambusia affinis) developed high
    levels of resistance to endrin and other cyclodiene insecticides as a
    result of inadvertent exposure to agricultural sprays. Susceptible
    fish (male) showed a LC50 of 8.3 mg/litre and resistant fish, 161
    mg/litre. Genetic crossing studies show that endrin resistance is
    inherited as a single, autosomal, intermediate gene (Yarbrough et al.,
    1986).

         Pesticide-susceptible and -resistant mosquito fish were exposed
    to 14C-endrin at 20 or 1000 µg/litre, and liver and brain were
    assayed to determine any difference in distribution, uptake, and nerve
    binding patterns (Fabacher & Chambers, 1976). The results are
    summarized in Table 18. Endrin was taken up faster by brain and liver
    from susceptible fish than resistant fish. In resistant fish, at least
    at a high lethal concentration (1000 µg/litre), endrin entered the
    brain slowly and accumulated in the liver, suggesting a more efficient
    blood-brain barrier in resistant than in susceptible fish. Extraction
    studies provided some evidence that endrin binds more readily to
    nonessential protein complexes in the nervous tissue of resistant
    fish, consequently decreasing the amount of endrin available to
    produce a toxic effect.

    
    Table 18.  Mean quantities of endrin (in mg/kg tissue) in brain and
               liver of susceptible and resistant mosquito fish
                                                                                 
    Genotype         At 20 µg/litre                   At 1000 µg/litre
                                                                                 
                     Brain   Liver   Brain:liver      Brain    Liver   Brain:liver
                                                                                 
    Susceptible      16.98   33.28      0.51          149.31   160.27     0.93

    Resistant         8.83   16.84      0.52           57.52   353.42     0.16

    Susceptible:      1.90    1.90      1.00            2.60     0.45     5.80
    resistant
                                                                                 
    
         Cell membrane fractions from resistant mosquito fish bound more
    endrin than those from susceptible fish, and mitochondria from the
    liver of the resistant genotype bound less endrin than those from
    susceptible fish. Differences in endrin uptake, retention of endrin by
    brain cell membranes, a blood-brain barrier, and a structural
    difference in myelin mayaccount for the resistance of some mosquito
    fish to endrin (Wells & Yarbrough, 1972).

         In resistant and non-resistant populations of golden shiner
     (Notemigonus crysoleucas), blue gill sunfish  (Lepomis macrochirus),
    and green sunfish  (Lepomis cyanellus), the median tolerated limit at
    36 h was 3.0, 1.5, and 3.4 µg/litre for non-resistant strains and 310,
    300, and 160 µg/litre for resistant fish, respectively (Ferguson et
    al., 1964).

    7.2.2.4  Interaction with other chemicals

         The joint action of endrin with malathion on mortality in
    flagfish  (Jordanella floridae) consisted of enhanced effects at
    concentrations that had no effect when the substances were tested
    individually. The effects of the mixture on growth followed a simple
    additive model. Malathion did not modify the effect of endrin on egg
    production. In a separate test, malathion did not affect the uptake or
    elimination of endrin (Hermanutz et al., 1985).

         In a study of the interaction between the accumulation and
    elimination of 14C-endrin and 14C-DDT in mosquito fish  (Gambusia
     affinis), fish about 4 cm long were exposed to a nominal
    concentration of 3.94 nM endrin or DDT, or to a mixture of the
    compounds. Prior exposure to DDT for 4 h generally reduced the
    accumulation of endrin in serum, gall-bladder, and whole bodies,
    whereas prior exposure to endrin for 4 h had little effect on DDT
    accumulation. Simultaneous exposure to DDT and endrin reduced the
    accumulation of DDT in the gall-bladder over the 4 h of exposure and
    in the whole bodies during the first hours, and it reduced the
    accumulation of endrin in gall-bladder and in the whole body. Endrin
    levels in fish exposed subsequently only to DDT or DDE were
    significantly higher in gall-bladder and were reduced in the whole
    body over 4 h. The interactions observed may be the result of
    competition for and/or displacement of insecticides from mutual
    binding sites (Denison et al., 1985).

         In a study of the relative binding and competition between
    organochlorine pesticides for serum binding sites, incubation with
    serum from mosquito fish led to their association primarily with the
    vitellogenin/lipoprotein and albumin fractions. Preincubation of serum
    with endrin significantly reduced the quantity of 3H-DDT that was
    bound subsequently, while the reverse was not observed. Although the
    reason for the apparent quantitative decrease in binding is unknown,
    this phenomenon may be of toxicological importance (Denison &
    Yarbrough, 1985).

    7.2.2.5  Special studies

         Fingerlings of carp  (Cyprinus carpio) exposed to endrin at the
    LC50 (0.0065 mg/kg) for 24 h showed clear inhibition of ý-amylase
    activity in the liver (Datta & Ghose, 1985).

         A group of 240 rainbow trout  (Salmo gairdneri) were exposed to
    endrin at 0.12-0.15 µg/litre for 30 days; one untreated and one
    solvent control group were used. On day 30, 10 fish from each group
    were sacrificed and examined for the ability of peritoneal macrophages
    to phagocytize latex beads. The remaining fish were immunized with 10
    µg of  Yersinia ruckeri O-antigen and exposure to endrin continued.
    Assays for migration inhibition factor, plaque forming cells, and
    serum agglutination titre were performed 2, 14, and 30 days after
    inoculation, and serum was collected from all fish to determine the
    cortisol concentration. Exposure to endrin had no effect on the
    phagocytic ability of peritoneal macrophages, but the responses in the
    three assays were significantly reduced in comparison with the control
    values. Serum cortisol concentrations were significantly elevated in
    the endrin-treated fish. The study did not, however, elucidate the
    mechanism of immune suppression, other than showing that a stress
    response had occurred (Bennett & Wolke, 1987a). In another study,
    therefore, control fish were fed cortisol at 20 mg/kg and metyrapone
    at 35 mg/kg body weight, and endrin-exposed fish received metyrapone
    at 35 mg/kg body weight per day in the diet. The fish that received
    cortisol had significantly reduced responses in all three assays; but
    in the endrin-exposed fish that received metyrapone, the migration
    inhibition factor response was completely restored, the plaque forming
    cell response was restored to 61%, and serum agglutination titres to
    69%. These results indicate that elevated serum cortisol concentration
    plays a central role in repressing the immune response (Bennett &
    Wolke, 1987b).

         The concentrations of serum glucose, liver and muscle glycogen,
    cortisol, protein, and cholesterol were determined in carp  (Cyprinus
     carpio) exposed to endrin at 2 µg/litre for 6, 24, and 72 h. Only
    the concentration of cortisol in serum was clearly decreased (Gluth &
    Hanke, 1985).

    7.2.3  Amphibia

         The acute toxicity of endrin to amphibians is summarized in
    Table 19.

    7.3  Terrestrial organisms

         The acute oral toxicity of endrin for terrestrial animals is
    high. The available LD50 values are summarized in Table 20.

    7.3.1  Honey bees

         The 48-h LD50 of endrin in worker honey bees  (Apis mellifera)
    using a dusting technique was 2.02 µg/bee (Atkins et al., 1973). The
    LD50 for bees after contact was 0.65 µg/bee, and the acute oral
    LD50 was 0.46 µg/bee (Oomen, 1986).

    
    Table 19.  Acute toxicity of endrin to amphibians
                                                                                                                                   
    Organism                 Size/      Static/  Temp.  Hardness      pH        Parameter    Concentration       Reference
                             age        flowa    (°C)   (mg CaCo3/l)            (mg/1)       (mg/l)
                                                                                                                                   
    Bullfrog                 2-5 g      Flow     18-23                          96-h LC50    2.5          Thurston et al. (1985)
     Rana catesbiana

    Leopard frog             Eggs       Flow     20     100           7.2-7.5   24-h LC50    2.5          Hall & Swineford (1980)
     Rana spenocephala         Larvae     Flow     20     100           7.2-7.5   96-h LC50    6
                             Subadult   Flow     20     100           7.2-7.5   96-h LC50    5

    Frog                     0.5 g      Static   14     20            6.2       96-h LC50    0.21         Khangarot et al. (1985)
     Rana hexadactyla

    Western chorus frog      Tadpole    Static   15     44            7.1       96-h LC50    120          Mayer & Ellersieck (1986)
     Pseudacris triseriata

    Fowlers toad             Tadpole    Static   15     44            7.1       96-h LC50    180          Mayer & Ellersieck (1986)
     Bufo woodhousei
     fowleri
                                                                                                                                   
    aStatic,static conditions (water unchanged for duration of test); flow, flow-through conditions; endrin concentration in water
     maintained continuously
    
        Table 20.  Acute oral LD50s of endrin for terrestrial species
                                                                        
    Species                 LD50                 Reference
                            (mg/kg body weight)
                                                                        
    Birds

    Mallard                 5.6 (2.7-11.7)       Hudson et al. (1984)
     (Anas platyrhynchos)

    Pigeon                  2.0-5.0
     (Columbia livia)

    Pheasant                1.8 (1.1-2.8)
     (Phasianus colchicus)

    Sharp-tailed grouse     1.06 (0.552-2.04)
     (Pedioecetes phasia
     nellus)

    California quail        1.19 (0.857-1.65)

    Redwinged blackbird     2.37                 Schafer et al. (1983)
     (Agelaius phoeniceus)

    Starling                2.37-3.16
     (Sturnus vulgaris)

    Quail                   4.22
     (Coturnix coturnix)

    Mammals

    Big brown bat           5-8                  Luckens & Davis (1965)
     (Eptesicus fuscus)

    Pine mouse  (Microtus    2.6/19.0             Petrella et al. (1975)
     pitymys pinetorum)      1.3/36.4             Webb et al. (1973)
                            (susceptible/
                            resistant)
                                                                        
    
    7.3.2  Birds

    7.3.2.1  Acute toxicity

         The LD50s of endrin for some bird species are given in Table
    20.

    7.3.2.2  Short-term toxicity

         Groups of 40 one-day-old quail were fed endrin at dietary levels
    of 0, 0.5, 1, 5, 10, 20, or 50 mg/kg of diet. Survival was adversely
    affected in all test groups, and there were no survivors beyond two
    weeks among birds fed 10 mg/kg or more. Food consumption was
    abnormally low, and symptoms involved lack of muscular coordination,
    tremors, and occasional convulsive movements. Similar results were
    obtained in 40 one-day-old pheasants fed endrin at dietary levels of
    5 or 20 mg/kg, none of which survived beyond 8 days (Dewitt, 1965).

         Groups of 20 seven-day-old chicks were unaffected by diets
    containing endrin at 0, 1.5, or 3 mg/kg. When the concentration was
    increased to 6 or 12 mg/kg, the birds became highly excitable and
    failed to gain weight in comparison with controls. The survival rates
    over a 12-week period were 85 and 5%, respectively, compared with 100%
    in the controls (Sherman & Rosenberg, 1954).

         The LC50 values for 2-3-week-old bobwhite quail (Colinus
    virginianus), Japanese quail  (Coturnix coturnix japonica),
    ring-necked pheasants  (Phasianus colchicus), and mallards  (Anas
     platyrhynchos) (8-13 birds per group) fed endrin in their diet for
    5 days followed by 3 days of untreated diet, were 14-22 mg/kg diet
    (Hill et al., 1975; Hill & Camardese, 1986).

    7.3.2.3  Studies of reproduction

         In a study of reproduction in pheasants, a diet containing endrin
    at 10 mg/kg reduced egg production and chick survival; diets
    containing up to 2 mg/kg did not affect egg production, fertility,
    hatchability, or chick survival (Dewitt, 1965).

         Groups of five female and two male mallard ducks  (Anas
     platyrhynchos) were administered diets containing endrin at 0, 0.5,
    or 3.0 mg/kg for a 12-week oviposition period. Egg production was not
    affected. The eggs were incubated, and infertile eggs, embryo
    survival, and hatchability were measured. Fertility and hatchability
    were not affected, although a 9.6% drop in embryo survival was
    observed in the group that had received the highest dose. Endrin
    residues in body fat were 3.4 mg/kg of tissue in the group that
    received 0.5 mg/kg and 19.3 mg/kg in the group that received 3.0
    mg/kg. The concentrations were higher in females than in males. The
    endrin residue levels in eggs were none detected in the controls, 0.43
    mg/kg in the group fed 0.5 mg/kg, and 2.75 mg/kg in the group fed 3.0
    mg/kg (Roylance et al., 1985).

          Three groups of 27 pairs of mallards were fed endrin at 0, 1, or
    3 mg/kg of dry duck mash from December to the summer to investigate
    the influence on reproduction and health. Birds fed 1 mg/kg reproduced
    as well as the controls; they had significantly greater success in
    hatching fertile eggs than did those fed 0 or 3 mg/kg and their

    clutches hatched earlier (not significantly) than those of birds fed
    3 mg/kg. Endrin accumulated in eggs to a mean level of 1.1 mg/kg (wet
    weight) in the group fed 1 mg/kg and 2.9 mg/kg in the group fed 3
    mg/kg. The concentration of endrin in adipose tissue was four to seven
    times higher than that in eggs (Spann et al., 1986).

    7.3.2.4  Interaction with other chemicals

         The toxicity of combinations of chlordane and endrin was studied
    in   14-week-old male and female bobwhite quail. Eight birds received
    10 mg/kg chlordane in the diet for 10 weeks; 20 quail were treated
    with 10 mg/kg chlordane for 10 weeks followed immediately by 10 mg/kg
    endrin (98%) in the diet; a fourth group of 20 birds received only 10
    mg/kg endrin in the diet. The pesticides were dissolved in propylene
    glycol. After 9-10 days on a control diet, survivors were sacrificed
    and their brains dissected. No deaths occurred among the birds fed the
    control diet or 10 mg/kg chlordane. With endrin alone, 15 birds died,
    and with the combination 14 birds died. In birds that received endrin
    alone, the residue levels in the brain were 0.34-1.84 mg/kg in those
    that died and 0.28-0.62 mg/kg in the survivors. In the birds fed
    chlordane and endrin, the residue levels were 0.17-1.25 mg/kg in birds
    that died and 0.14-0.56 mg/kg in survivors. Birds treated with the
    combination had considerably more chlordane residues in their brains
    than did those fed chlordane alone. The main conclusion of this study
    was that the additive toxicity of closely related chemicals should be
    taken into account in diagnosing cause of death (Ludke, 1976).

    7.3.2.5  Special studies

          The influence of endrin at 5 and 10 mg/kg of feed on the
    activity of various enzymes in the serum of juvenile cockerels was
    studied. The greatest increases in activity were measured for
    glutamate oxalacetate transaminase, cholinesterase, and alkaline
    phosphatase. Smaller increases were observed for creatine kinase,
    glutamate dehydrogenase, ý-hydroxybutyrate dehydrogenase, and
    phosphohexose isomerase (Horn et al., 1987).

    7.3.2.6  Behavioural studies

         The effect of a sub-lethal dose of endrin (2 mg/kg diet) on
    avoidance responseswas studied in eight pens of 25 seven-day-old
    Coturnix quail chicks for 14 days. The stimulus used to elicit
    avoidance was a moving silhouette, and the response was measured
    daily. Group avoidance response was significantly suppressed by
    exposure to endrin, but the behaviour returned to normal after 2 days
    on untreated diet (Kreitzer & Heinz, 1974).

         Adult male bobwhite quail  (Colinus virginianus) were fed a diet
    containing endrin at 0.1 or 1.0 mg/kg for 138 days (beginning at 3
    days of age), and then their performance in five non-spatial
    discrimination reversal tasks was studied. Treated birds made 36-139%

    more errors than controls, and birds fed the lower dose made
    significantly more errors than those given the higher dose after
    reversal 3 or 4 in the first three tests. The effects of endrin were
    reversed after 50 days on untreated feed. The principal effect of
    endrin was to impair the birds' ability to solve a novel problem. The
    mean levels of endrin residues in the brain were 0.075 mg/kg wet
    weight in those given the lower dose and 0.35 mg/kg for those on the
    higher dose (Kreitzer, 1980).

    7.3.3  Mammals

    7.3.3.1  Toxicity

         The LC50 values for short-tailed male and female shrews
     (Blarina brevicauda) aged 180, 105-150, and 30-75 days were 87-174
    mg/kg diet for 14 days (Blus, 1978).

         Five groups each of 13-14 pairs of Saskatchewan deer mice
     (Peromyscus maniculatus) of various ages were fed endrin at 0, 1, 2,
    4, or 7 mg/kg of diet for intermittent periods, between which the
    animals were either fed a normal diet or were subjected to 48-h
    starvation. The animals were sacrificed by exposing them to cold
    stress at -16 °C and the time of death recorded. No influence was
    found on litter production, frequency, or mean litter size. At the
    higher levels of feeding, postnatal mortality before weaning was
    increased. Significant parental mortality occurred at 4 mg/kg and
    higher and appeared to be dose-dependent (Morris, 1968). (Remark:
    Since the animals in this study were captured in the field and the
    periods of feeding alternated with short periods of starvation in an
    effort to simulate possible conditions in the field, this study is of
    only limited value).

         The effects of endrin at 8.0 oz/acre (0.56 kg/ha) on unenclosed
    field populations of meadow voles  (Microtus pennsylvanicus) and deer
    mice  (Peromyscus maniculatus) were investigated in 1966-68. Animals
    were trapped live on adjacent 7-acre (2.8 ha) plots each summer at
    regular intervals, before and after a single application of endrin.
    Immediate, significant declines in the number of voles were seen on
    the experimental plot, but no long-term toxicological effects were
    observed. The population rapidly recovered, exceeding the initial and
    control numbers in all three years. The experimental vole population
    thus appears to have responded to endrin as it would to a local
    depopulation by trapping. The mouse population decreased significantly
    after the application of endrin in 1966 and did not recover, and the
    highly unstable, transitory population on the experimental plot
    indicated a long-term toxicological effect (Morris, 1970, 1972).

    7.3.3.2  Studies of resistance

         14C-Endrin in corn oil was administered to a resistant and a
    susceptible strain of pine mice  (Microtus pitymus pinetorum) orally

    at 0.5 mg/kg body weight, as follows: days 1-5, unlabelled endrin;
    days 6-14, 14C-endrin; and day 15 unlabelled endrin. Total recovery
    of 14C in both faeces and urine was 76% for the resistant strain and
    53% for the susceptible strain. The two strains produced the same
    major faecal and urine metabolite, but the resistant strain produced
    about twice the quantity as the susceptible strain. The quantitative
    differences in the excretion of more polar endrin metabolites may
    indicate metabolic differences between the two strains and,
    consequently, the greater tolerance of the resistant strain to toxic
    effects (Petrella et al., 1975). The major metabolite was identified
    as  anti-12-hydroxyendrin; one of the other more polar metabolites,
    found in minor quantities, was suggested to be a tertiary alcohol of
    endrin (Petrella et al., 1977).

         The degree of toxicity of endrin in first-generation progeny of
    susceptible and resistant strains and a cross of the two strains of
    pine mice was studied by Webb et al. (1973). The LD50 for offspring
    of susceptible x susceptible parentage was 5.0 mg/kg body weight; that
    for resistant x resistant, 21.1 mg/kg; and that for susceptible x
    resistant, 8.6 mg/kg. These results offer preliminary support for a
    genetic mechanism with intermediate dominance. An increase in
    resistance against the toxic effects of endrin was demonstrated in
    wild pine mice trapped in orchards where endrin had been used for
    years. The oral LD50 in susceptible mice was about 3 mg/kg body
    weight and that in resistant mice, an average of 36 mg/kg body weight.
    The increased resistance appeared to be heritable in the first
    generation (Webb & Horsfall, 1967; Webb et al., 1973). Although
    differences in the rate of metabolism of endrin could be demonstrated,
    especially in the activity of mixed-function oxidase, these did not
    appear to be sufficiently large to explain the resistance (Hartgrove
    et al., 1977).

    7.4  Effects in the field

         Episodes have been reported in which endrin was concluded to be
    the cause of death in fish and birds. Numerous fish kills were
    reported from the sugar-cane growing areas of Louisiana in 1960-63. No
    association with variables such as dissolved oxygen, pH, or
    temperature was found, but following the development of sensitive
    analytical techniques it was concluded that the fish had been killed
    by endrin (Mount & Putnicki, 1966). Surface runoff from fields was
    reported to be the main source of the endrin that contaminated the
    rivers (Lauer et al., 1966), although effluent from an insecticide
    plant may have contributed since the fish contained two chemicals
    involved in endrin manufacture (Mount & Putnicki, 1966). Levels of
    endrin found in studies of fish in the wild are given in section
    5.1.4.2.

         Declines in the population of brown pelicans in Louisiana were
    attributed to endrin, although at least six other organochlorine
    pesticides and polychlorinated biphenyls were found in the animals

    (Blus et al., 1975; King et al., 1977). The eggs of brown pelicans
     (Pelecanus occidentalis) in Texas, USA, were examined for endrin
    residues in 1975-81. The compound was recovered only in 1975, in 15 of
    18 eggs, at levels of 0.1-0.3 mg/kg. In the same year, the highest
    levels of endrin were found in pelican eggs in Louisiana, and this
    maximum coincided with the deaths of large numbers of brown and white
    pelicans  (P. erhyrorhyncos) (King et al., 1985).

         Endrin was found in one of ten eggs of the American white pelican
     (Pelecanus erythrorhynchos) collected in 1969, at 0.20 mg/kg, and in
    two of 35 samples collected in 1981, at up to 0.18 mg/kg wet weight.
    Brains of pelicans found dead in the period 1975-81 had levels up to
    0.80 mg/kg. No endrin was found in eggs of the western grebe
     (Aechmophorus accidentalis) collected in 1981. It was concluded that
    endrin had caused some of the deaths among pelicans in California
    (Boellstorff et al., 1985).

         The death of sandwich terns in The Netherlands was attributed to
    the discharge of a combination of endrin and related pesticides into
    an estuary from a manufacturing plant (Koeman et al., 1967, 1969;
    Koeman, 1971).

         On several occasions in Victoria, Australia, large numbers of
    wild birds, in particular pigeons  (Columba livia), sparrows  (Passer
     domesticus) and Indian mynahs  (Gracula religiosa), were observed
    to be paralysed or in convulsions (Reece et al., 1985). The crops and
    livers contained endrin at levels of up to 1.2 mg/kg.

         Fulvous whistling ducks  (Dendrocygna bicolor), which nest in
    rice fields along the south-eastern coast of Texas, USA, suffered a
    major decline in population in the late 1960s, which was attributed to
    exposure to dieldrin or aldrin. Organochlorine pesticides were
    determined in 1983 in the carcasses of 15 adult ducks immediately
    after their arrival in Texas from Mexico in the spring and before
    departure from Mexico in the autumn. Four of the ducks with high
    levels of dieldrin residues also had residues of endrin; and four
    other ducks, collected in 1967 and 1969, had endrin residues. The
    geometric mean levels in the different years were 0.03-0.08 mg/kg wet
    weight; in juveniles in 1960-69, the geometric mean level was 0.16
    mg/kg (Flickinger et al., 1986).

         The effects of endrin on wildlife were studied in 1981-83 in
    fruit orchards in Washington, USA. A single application of endrin
    after harvest resulted in acute and chronic toxicity to a variety of
    avian species; most deaths occurred soon after the application, but
    several raptors died during the spring and summer. The brains of 73 of
    125 birds contained endrin at < 0.10-0.80 mg/kg; detectable levels
    occurred most frequently in the brains of galliforms and falconiforms.
    The species in which the greatest numbers of deaths attributed to
    endrin occurred include California quail  (Callipepta california),
    chukars  (Alectoris chukar), and common barn owls  (Tyto alba). Of

    the 97 eggs analysed, 68 contained detectable endrin residues: 51 had
    levels of < 0.10 mg/kg, and the eggs of 10 species contained
    0.01-0.17 mg/kg wet weight (range, none detected to 1.67). The authors
    concluded that endrin was toxic to wildlife, although there was no
    evidence that it affected reproductive success or population level
    (Blus et al., 1989).

         Levels found in birds in the wild are also given in section
    5.1.4.1.

    7.5  Appraisal of effects on organisms in the environment

         Use of endrin in agriculture is the major source of its presence
    in the environment, but discharge of waste material from manufacturing
    and formulating plants has contributed to local contamination.
    World-wide monitoring surveys have shown that the concentrations of
    endrin in the biosphere are generally very low (Table 10), both
    absolutely and relatively: The levels of residues of other
    organochlorine compounds, particularly DDE and polychlorinated
    biphenyls, are generally 100 times or higher than those of endrin.

         Toxicologically significant levels of endrin residues have been
    found locally in fish and other organisms, particularly in cases in
    which endrin was applied near rivers and lakes and when runoff
    occurred into waterways. Residues may also occur when endrin is used
    as a seed dressing or in bait to control rodents.

         The most serious adverse ecological effects that have been
    reported were the fish kills (and associated adverse effects on brown
    pelican populations) in the Mississippi River system in the USA.
    Although the initial evidence for ascribing these effects to endrin
    was circumstantial, the results of analyses of dead fish were
    considered to confirm a causal relationship; there is little doubt
    that endrin was a contributory factor in at least some of these fish
    kills. The evidence that endrin was the primary cause of the decline
    in the brown pelican population is less convincing, since the harmful
    effects on reproductive success have been attributed to DDE and other
    factors (Blus et al., 1974, 1979).

         In summary, agricultural application of endrin should be such as
    to avoid or minimize contamination of waterways, either by
    overspraying or runoff or by leaching from dressed seed in
    rice-growing areas. The effects of the use of baits containing endrin
    for rodent control on non-target organisms should be assessed in the
    light of local circumstances. Finally, effluents from manufacturing
    and formulating plants must be treated adequately before being
    discharged into waterways.

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO

         The toxicology and risk assessment of endrin have been reviewed
    (US EPA, 1987a,b; Anon., 1988a,b).

    8.1  Acute toxicity of technical-grade endrin

    8.1.1  Oral administration

         Endrin is highly toxic when given by the oral route and is more
    acutely toxic to mammals than its stereoisomer dieldrin (WHO, 1989),
    with an acute oral LD50 of 7.5-17.8 mg/kg body weight (Table 21),
    compared with 50-60 mg/kg for dieldrin. There appears to be a
    sex-dependent sensitivity to the acute effects of endrin, female
    animals being more sensitive than males. A species-dependent
    sensitivity has also been reported, monkeys and cats being more
    susceptible than mice and rats.

         Signs of intoxication may include increased irritability and
    tremor, followed by tonic-clonic convulsions, ataxia, dyspnoea,
    gasping, and cyanosis. Convulsions usually occur 30-60 min after an
    oral dose, and death may occur within 24 h after the administration of
    a lethal dose (Speck & Maaske, 1958). Animals that survive poisoning
    recover completely with no delayed or persistent effect.

    8.1.2  Dermal administration

         The acute dermal LD50s for technical endrin in various animal
    species are given in Table 22. Endrin is highly toxic when applied as
    a solution in hydrocarbon solvents but moderately toxic when applied
    as a dry powder. The signs of poisoning are similar to those seen
    after oral administration.

    8.1.3  Parenteral administration

         The acute LD50s for technical-grade endrin given by parenteral
    routes of administration are shown in Table 23.

    8.1.4  Toxicity of metabolites and isomers

    8.1.4.1  Mammalian metabolites

         In a comparative study, the acute oral LD50s of endrin and
    three of its metabolites were determined in rats (Table 24). When the
    brains of some of the rats were analysed for the presence of endrin
    and its metabolites, the concentration of 12-ketoendrin in male rats
    given endrin at 60 mg/kg body weight was found to be higher (mean, 0.3
    mg/kg) than that of endrin (0.07 mg/kg) 22 h after dosing. In male
    rats intoxicated with  syn-12-hydroxyendrin or 12-ketoendrin (at 16
    mg/kg body weight each), the concentrations of 12-ketoendrin in the
    brain 30 min after dosing were much higher (mean values, 1.9 and 1.4

    
    Table 21.  Oral LD50s for technical-grade endrin
                                                                                                              
    Species (age)               Vehicle                  LD50(mg/kg body weight)    Reference
                                                                               
                                                         Males       Females
                                                                                                              
    Mouse                       Corn oil                  8.6             -       Spynu (1964)
    Mouse                       Unknown                    13            13       Gray et al. (1981)
    Rat (4-5 weeks)             Peanut oil               28.8          16.8       Treon et al.(1955)
    Rat (6 months)              Peanut oil               43.4           7.3       Treon et al. (1955)
    Rat (6 months)              Peanut oil               40.0             -       Speck & Maaske (1958)
    Rat (adult)                 Peanut oil               17.8           7.5       Gaines (1960)
    Rat (7 weeks)               Cottonseed oil             27             -       Boyd & Stefec (1969)
    Rat (12-14 weeks)           Dimethyl sulfoxide        5.6a          5.3a      Bedford et al. (1975b)
    Rat (12-13 weeks)           Corn oil                  8.9           4.0       Carter & Simpson (1978)
    Rat                         Corn oil                  9.0             -       Spynu (1964)
    Rat                         Unknown                     4             4       Gray et al. (1981)
    Rabbit                      Peanut oil                  -          7-10       Treon et al. (1955)
    Guinea- pig                 Peanut oil               36.0          16.0       Treon et al. (1955)
    Hamster (golden Syrian)     Corn oil                    -          18.6       Chernoff et al. (1979)
    Hamster (golden Syrian)
     (6 weeks)                  Unknown                    12          17.0       Cabral et al. (1979)
    Hamster                     Unknown                    18            18       Gray et al. (1981)

    Cat                         Cod liver oil          Lethal dose:               Ressang et al. (1958);
                                                          3-6                     Cook & Casteel (1985);
                                                                                  Casteel & Cook (1985)
    Monkey  (Macacus mulatta)     Peanut oil                  3                     Treon et al. (1955)
    Monkey  (Macacus speciosa)    Unknown                    12                     Barth (1967)
    Domestic goat               Unknown                               25-50       Tucker & Crabtree (1970)
    Mule deer                   Unknown                               6.25-12.5   Hudson et al. (1984)
                                                                                                              
    aEndrin of 99% purity

    Table 22.  Dermal LD50s for technical-grade endrin
                                                                                            
    Species (age)   Vehicle          LD50(mg/kg body weight)        Reference
                                                           
                                     Males         Females
                                                                                            
    Rat             Xylene           18            15               Gaines (1960,1969)

    Rat             Shellsol A       10-20         5-10             Carter & Simpson (1978)

    Rat             Toluene          approx. 10    approx. 10       Carter & Simpson (1978)

    Rat             Corn oil         12.5          -                Spynu (1964)

    Rabbit          None             -             Minimum lethal   Treon et al. (1955)
                                                   dose: 60-94

    Cat             Cod-liver oil    Lethal dose:                   Ressang et al. (1958)
                                     approx. 150
                                                                                            
    
        Table 23.  Parental LD50s for technical- grade endrin
                                                                        
    Species  Route            Vehicle    LD50 (mg/kg   Reference
                                         body weight)
                                                                        
    Mouse    Intraperitoneal  Corn oil       5.6       Graves & Bradley
                                                       (1965)

    Mouse     Intravenous     Dimethyl       2.3       Walsh & Fink
                              sulfoxide                (1970, 1972)

    Dog       Intravenous     Ethanol        3         Hinshaw et al.
                                                       (1966)
                                                                        

    Table 24.  Acute oral toxicity of mammalian metabolites of
               endrin in rats
                                                                        
    Compound                 Oral LD50 (mg/kg body weight)
                                                                         
                             Male                     Female
                                                                       
                             Mean      95% CI         Mean       95% CI
                                                                        
    Endrin                   5.6       3.0-7.9        5.3        3.6-7.4
     anti-12-Hydroxyendrin    2.4       2.0-3.0        5.5        4.2-7.2
     syn-12-Hydroxyendrin     1.2       0.6-1.7        2.8        0.8-4.0
    12-Ketoendrin            1.1       0.7-1.5        0.8        0.5-1.2
                                                                        
    a95% CI, 95% confidence interval
    
    mg/kg, respectively) than those in the brains of rats given a similar
    but non-toxic dose of  anti-12-hydroxyendrin (mean, 0.09 mg/kg) and
    killed at the same time. The signs of intoxication were similar to
    those of endrin (Bedford et al., 1975b).

         These results suggest that 12-ketoendrin may be the acute
    toxicant in rats. The production of 12-ketoendrin varies greatly from
    one mammalian species to another, however, and none has been detected
    in birds of various species that were killed by endrin (Stickel et
    al., 1979).

    8.1.4.2  Isomers

         As described in section 4.2, endrin is changed under the
    influence of sunlight into delta-ketoendrin. The acute toxicity of
    this isomer is given in Table 25. It is less toxic than endrin, and,
    like endrin, it is more toxic to female than to male rats. The signs
    of intoxication are similar to those seen with endrin.

         The acute tocixity of the endrin aldehyde has been reported to be
    > 500 mg/kg body weight in male mice (Phillips et al., 1962).

        Table 25.  Acute toxicity of delta-ketoendrin
                                                                        
    Sex and      Route            LD50 (mg/kg       Reference
    species                       body weight)
                                                                        
    Male rats    Oral             120-180           Soto & Deichmann
                                                    (1967)

    Female rats  Oral             10-36

    Male rats    Oral             62.1 (53.3-72.2)  Stanford Research
                                                    Institute (1954)

    Rats         Intravenous      5                 Soto & Deichmann
                                                    (1967)

    Male rats    Intraperitoneal  82                Stanford Research
                                                    Institute (1953)

    Male mice    Oral             23.6 (19.9-28.0)  Stanford Research
                                                    Institute (1954)

    Male mice    Intraperitoneal  16.7              Stanford Research
                                                    Institute (1953)
                                                                        
    
    8.1.5  Acute toxicity of formulated material

    8.1.5.1  Oral and dermal administration

         Oral and dermal LD50 values for formulated endrin in rats
    (Muir, 1970) are presented in Table 26. Dry formulations were
    administered orally as 1-2% aqueous suspensions and dermally in both
    dry form and as 2-5% aqueous suspensions. In general, the type of
    formulation did not significantly alter the acute oral toxicity of
    endrin. The dermal toxicity of the 50% wettable powder was similar to
    that of the 20% emulsifiable concentrate; the 2% field strength dust
    was the least toxic.

         Ten rabbits (body weight, 2.4-4.1 kg) were treated with an
    emulsifiable concentrate containing 19.4% endrin on clipped skin at a
    dose of 200 mg/kg body weight, and the material was allowed to remain
    in contact with the skin for 24 h. Four of the 10 animals died within
    48 h (Anderson et al., 1953). Two of 10 rabbits (body weight,
    2.0-2.5 kg) treated similarly with a 25% dust concentrate died within
    48 h (Hine et al., 1954).

        Table 26.  Oral and dermal LD50s for endrin formulations in rats
                                                                        
    Formulation        LD50 (mg/kg body weight)
                                                                        
                       Oral                    Dermal
                                                                        
                       Formulation   Active    Formulation       Active
                                     material                    material
                                                                        
    20% Emulsifiable       20         4.20     52.20 (undiluted)    10.90
    concentrate

    50% Wettable            7.6       3.80     21.80 (dry)          10.90
    powder                                     14.40 (aqueous)       7.20

    2% Field strength     275         5.50     5720 (dry)          114.40
    dust                                       1140 (aqueous)       22.80
                                                                        
    From Muir (1970)
    
    8.1.5.2  Inhalation

         Ten adult rats were exposed for 1 h to a mist of of an
    emulsifiable concentrate containing 19.4% by weight of endrin in
    xylene, at a concentration of endrin slightly exceeding 2000 mg/m3
    of air, and were observed for 48 h. The particle size of the mist and
    other details of exposure were not reported. Three of the animals died
    1-14 h after exposure (Anderson et al., 1953).

         Groups of 10 Long Evans rats were exposed for 1 h to 25% and 30%
    endrin dust concentrates at a concentration of 2000 mg/m3 of air.
    Particle size and other details of exposure were not provided. Five
    rats exposed to the 30% and three exposed to the 25% dust died within
    48 h after exposure (Hine et al., 1954).

    8.2  Short-term exposure

    8.2.1  Oral administration

    8.2.1.1  Mouse

         Feeding studies were conducted to estimate the maximum tolerated
    doses of endrin in B6C3F1 mice. Groups of five males and five females
    were given a normal diet or one containing endrin at 2.5-20 mg/kg for
    6 weeks, followed by observation for another 2 weeks. Three males and
    four females given 10 mg/kg died, but no mortality occurred at 5
    mg/kg. No data were provided on animals fed 20 mg/kg.
    Hyperexcitability was observed in male mice given doses > 5 mg/kg of
    diet. Mean body weight gains were comparable with those of controls.

    The maximum tolerated dose was calculated by extrapolation to be 5
    mg/kg of diet (NCI, 1978, 1979).

    8.2.1.2  Rat

         Groups of three male and two to three female Carworth rats,
    either 29 days or 6 months old, received daily doses of endrin at 1,
    2, or 5 mg/kg body weight in peanut oil by gavage, on five days per
    week for 67-72 days. All rats given 1 mg/kg survived; the increased
    mortality in the other groups was dose-related: 2/5 females at 2 mg/kg
    and 3/3 males at 5 mg/kg day died. Pathological findings at autopsy
    included diffuse degenerative changes in the liver, kidneys, and
    brain, while survivors showed no such changes. All treated animals
    lost weight and developed hypersensitivity to stimuli (Treon et al.,
    1955).

         Groups of five male and five female adult Sprague-Dawley rats
    were given diets containing technical-grade endrin at 0, 1, 5, 25, 50,
    or 100 mg/kg diet over a maximal period of 16 weeks and were observed
    for behaviour, weight gain, feed consumption, mortality rate, and
    symptoms of toxicity. Alkaline phosphatase levels, determined once a
    week, were higher in rats fed endrin than in the control group, and
    the total average feed consumption of treated rats was less than that
    of the control group. All rats fed 100 mg/kg of diet died during the
    first two weeks of the study, and only two female rats fed 50 mg/kg of
    diet survived the experiment. All male rats given 1 mg/kg and all
    female rats given 1 and 5 mg/kg of diet survived. Males appeared to be
    more susceptible than females to endrin in this study. The symptoms of
    intoxication were hypersensitivity to stimuli and convulsions:
    hypersensitivity was noted in all rats, and convulsions occurred among
    rats receiving 25, 50, and 100 mg/kg diet. Weight loss was
    dose-dependent and significant in all rats treated with endrin (Nelson
    et al., 1956).

         To estimate the maximum tolerated doses of endrin in
    Osborne-Mendel rats, groups of five males and five females were given
    diets with or without endrin for 6 weeks, followed by observation for
    another 2 weeks. Endrin was added to the diet in two-fold increasing
    concentrations of 2.5-80 mg/kg. Mortality was not increased at 10
    mg/kg, and mean body weight gain was no different from that in
    controls. At 20 mg/kg of diet, one animal of each sex died. The
    maximum tolerated dose was calculated by extrapolation to be 15 mg/kg
    diet (NCI, 1978, 1979).

    8.2.1.3  Rabbit

         Four of five female rabbits given an oral dose of endrin at 1
    mg/kg body weight on five days per week died following the
    administration of 2, 30, 35, and 50 doses, respectively. The fifth
    rabbit survived 50 doses over a period of 10 weeks. Diffuse

    degenerative changes were observed in the liver and kidneys but not in
    the brain (Treon et al., 1955).

    8.2.1.4  Dog

         Dogs (mainly two per group) fed endrin at 5-50 mg/kg of diet died
    within 50 days. They regurgitated their food, became lethargic,
    salivated, and later refused to eat; they became emaciated and
    developed respiratory distress and signs of stimulation of the central
    nervous system. Diffuse degenerative lesions in the brain, heart,
    liver, and kidneys, together with pulmonary hyperaemia and oedema were
    observed. Three dogs fed diets containing 4 mg/kg of diet for 6 months
    survived, but they showed reduced body weight gain and a slight
    increase in liver:body weight ratio; no histopathological change was
    observed. At 3 mg/kg of diet or less, growth was normal (Treon et al.,
    1955).

         Beagles (one male and one female/group; control group, only one
    dog) were fed diets containing endrin at 0, 1, or 3 mg/kg for 80
    weeks. No sign of intoxication was observed, and the weight gain of
    treated animals was comparable to that of controls. The ratios of
    kidney and heart to body weight were increased at 3 mg but not at 1 mg
    (about 0.045 mg/kg body weight). No histopathological change was found
    in the viscera (Treon et al., 1955).

         Groups of three male and three female pure-bred beagle dogs
    (4-6 months old) were fed endrin in the diet at 0, 0.1, 0.5, 1, 2, or
    4 mg/kg for two years. Additional groups of four male and four female
    dogs were fed endrin at 0, 1, or 4 mg/kg of diet. Two males and two
    females of each group were killed after 6 and 12 months of feeding; no
    other death occurred during the study. Convulsions were observed in
    three dogs at 4 mg and in one female at 2 mg; no other sign of
    intoxication or illness was apparent during the study. No adverse
    effect was noted on growth, food consumption, haematology, or
    urinalysis, and no compound-related change was found in serum alkaline
    phosphatase, prothrombin time, or any of the other clinical chemical
    parameters measured at regular intervals. All organ weights, relative
    as well as absolute, were normal, except for occasional, slight
    increases in liver weight in some of the females at 2 and 4 mg in the
    diet. The only histopathological change found was a slight to moderate
    vacuolation of liver cells in dogs fed 2 and 4 mg in the diet. No
    renal change was observed in any of the dogs (Jolley et al., 1969).

    8.2.1.5  Domestic animals

         Sheep and cattle fed diets containing endrin at 2.5 or 5 mg/kg
    for 112 days showed no indication of harmful effects (details not
    given) (Radeleff, 1956). The convulsions and muscular tremors that
    were induced in six 10-18-month-old male buffalo calves administered
    a 20% emulsion of endrin led to a significant rise in lactic acid
    concentration in the blood of the animals, possibly due to excessive

    production of the acid inside the fasciculating muscles (Verma et al.,
    1970).

    8.2.2  Inhalation

         Three mice, three rats, two guinea-pigs, two hamsters, four
    rabbits, and one cat were exposed to sublimed endrin vapour at an
    actual concentration of 5.44 mg/m3 for 7 h/day on 5 days/week for up
    to 26 weeks. Two rabbits died after 26 and 90 exposures, respectively,
    and one mouse died after 22 exposures. No convulsions were observed,
    and all other animals survived. Surviving rabbits showed a
    granulomatous type of pneumonitis; no histological change was found in
    the other surviving animals (Treon et al., 1955).

    8.2.3  Dermal administration

         Three female rabbits with intact skin died after 19, 19, and 25
    applications, respectively, of endrin as a dry powder at 150 m/kg body
    weight for 2 h/day on 5 days/week. Applications of 75 mg/kg resulted
    in the death of one of three rabbits after 8 weeks; the other two
    survived for 13-14 weeks--the end of exposure. Convulsions, tremors,
    and twitching of the facial muscles were the main signs of
    intoxication. Two of five rabbits (dose not specified) showed severe
    fatty degeneration of the liver (Treon et al., 1955).

    8.3  Skin irritation

         Dry powdered endrin was applied repeatedly at a dose of 75 or 150
    mg/kg body weight for 2 h/day, 5 days/week for up to 14 weeks on
    intact or abraded skin of female rabbits (see section 8.2.3). No skin
    irritation was observed. Single applications of endrin as dry powder
    at doses up to 250 mg/kg body weight for 24 h on rabbit skin caused no
    gross or microscopic damage to the skin of the animals (Treon et al.,
    1955).

    8.4  Reproduction, embryotoxicity, and teratogenicity

    8.4.1  Reproduction

    8.4.1.1  Mouse

         CFW mice (20 males and 20 females) were fed diets containing
    endrin (96%) at 0 and 5 mg/kg for 120 days, beginning 30 days before
    mating. Significant parental mortality (32%) and reduced litter size
    were observed, but fertility, fecundity, and the number of litters
    produced per pair were not affected (Good & Ware, 1969).

    8.4.1.2  Rat

         Forty male and 80 female Long-Evans rats were fed endrin in the
    diet at 0, 0.1, 1, or 3 mg/kg over three generations, each generation

    breeding once. No difference in appearance, behaviour, body weight, or
    number or size of litters was seen. The weights of the liver, kidneys,
    and brain were normal, and no histopathological abnormality was seen
    in third-generation weanlings. The only significant effect was
    increased mortality of pups in the second and third generations of
    rats fed 3 mg/kg (Hine, 1965).

         Ten male and 20 female Long-Evans rats were treated similarly,
    but each generation bred twice. Weanling rats were mated after 79 days
    on the diets (when they were 100 days old). All pups from the first
    litters were discarded at weaning, and the parent rats were mated
    again. Randomly selected pups from the second litters were maintained
    on the diets and mated when 100 days old; this was done for three
    generations. The number of pups in each litter was counted on the day
    of birth and on the fifth day; on the twenty-first day, the weanlings
    were counted and weighed and either sacrificed or saved for
    continuation. Parent rats were weighed, sacrificed, and examined
    grossly when no longer needed. Ten male and 10 female F3b weanlings
    each from the controls and the highest dose-level group and five males
    and five females from the 0.1 and 1.0 mg groups were autopsied. Body,
    liver, kidney, and brain weights were recorded, and sections of these
    organs and from heart, lung, spleen, and testis were studied
    histologically. Appearance, behaviour, body weight, number and size of
    litters, organ weights, and histopathological appearance of F3b
    weanlings were comparable with those in control animals. No effect on
    reproduction was observed in rats fed diets containing endrin at 2
    mg/kg over three generations (Hine, 1968).

    8.4.2  Embryotoxicity and teratogenicity

    8.4.2.1  Mouse

         Groups of 10 CD-1 mice were given a single oral dose of endrin
    (99%) at 2.5 mg/kg body weight (stated to be half the LD50) in corn
    oil by gavage on day 9 of gestation; an untreated and a vehicle
    control group were also used. Fetuses were examined on day 18. No
    significant effect was observed on intrauterine death or fetal weight,
    but the incidence of total anomalies was increased over that in
    controls: 2/117 fetuses had cleft palates, three had open eye, and two
    had other anomalies. No data on maternal toxicity were reported
    (Ottolenghi et al., 1974).

         These results could not be repeated by Kavlock et al. Female CD-1
    mice were given endrin (99%) at 0 (vehicle), 0.5, or 1.0 (groups of 40
    mice), or 1.5 or 2.0 mg/kg body weight (groups of 20 mice) in corn oil
    by gavage on days 7-17 of gestation. The animals were killed on day
    18. Maternal deaths occurred in the 1.5 and 2 mg/kg groups, reduced
    maternal weight gain was observed at and above 1 mg/kg, and maternal
    liver weight was increased at 0.5 mg/kg and higher. Fetal weight and
    skeletal, and visceral maturity were adversely affected at doses of 1
    mg/kg and above. No teratogenic effect or embryonic lethality was

    observed, even at doses that caused maternal death (Kavlock et al.,
    1981, 1987).

         In a study of the effects of acute alterations in maternal health
    status upon fetal development in the mouse, groups of 21 or 40
    pregnant CD-1 mice were given a single oral dose of technical-grade
    endrin at 0 (vehicle), 7 or 9 mg/kg body weight in corn oil on day 8
    of gestation. The animals were killed on day 18 of gestation. Three of
    21 animals given 7 mg/kg (14%) and 19/40 mice gievn 9 mg/kg (47%)
    died. Maternal weight gain was decreased in both test groups; the
    total number of implantation sites and number of viable litters were
    not affected, but fetal weight was reduced. Delays in ossification of
    the skeleton and an increased incidence of supernumary lumbar ribs
    were observed. Although three fetuses from one litter in the 9 mg/kg
    group had fused ribs, no significant increase in the incidence of
    malformations was found. A statistically significant, linear, inverse
    relationship between maternal weight gain and the presence of
    supernumary ribs in their offspring was found (Kavlock et al., 1985).

    8.4.2.2  Rat

         Five groups of 25 female CD rats were administered endrin (97%)
    in methocel in oral doses of 0, 0.1, 0.5, or 2 mg/kg body weight per
    day on days 6-15 of gestation, or vitamin A, used as a positive
    control. The animals were killed on day 20. The largest dose of endrin
    caused maternal toxicity, as evidenced by weight loss and mortality
    (two animals). The fetuses showed some slight growth retardation (not
    significant) but no increase in intrauterine death rate. No effect
    attributable to endrin was seen on the mean number of viable fetuses,
    post-implantation losses, implantations, corpora lutea, fetal sex
    ratio, or fetal external, soft-tissue, or skeletal abnormalities. Bent
    ribs were observed in 6/522 fetuses treated with endrin, but not in
    relation to dose. An increase in delayed ossification in sternebrae
    and skull of fetuses was seen in the treated groups in comparison with
    the untreated control group. Animals given vitamin A had a
    significantly increased number of post-implantation losses and
    malformed fetuses (Goldentahl, 1978a).

         Groups of 32, 15, 28, 30, and 15 female CD rats were given oral
    doses of endrin (99%) in corn oil at 0, 0.075, 0.15, 0.30, or 0.45
    mg/kg body weight on days 7-20 of gestation. Rats were killed on day
    21. Maternal weight gain was reduced at dose levels above 0.15 mg/kg,
    but no increase in maternal liver weight was found. Fetal mortality,
    weight, degree of skeletal and visceral maturation, and incidences of
    skeletal and visceral anomalies showed no dose-related effect
    (Kavlock et al., 1981).

    8.4.2.3  Hamster

         Three groups of golden Syrian hamsters (7, 24, and 8
    animals/group) received a single oral dose of endrin (99%) in corn

    oil at 5 mg/kg body weight (stated to be half the LD50) on day 7,
    8, and 9 of gestation, respectively. Two control groups were used,
    consisting of 57 untreated and 41 vehicle controls. The animals were
    killed on day 14. The number of resorptions and of dead fetuses was
    increased after treatment on days 7 or 8 and to a lesser extent in the
    vehicle controls. The live fetuses in all three treated groups showed
    significant growth retardation when compared with controls. The
    incidence of anomalies was high only after treatment on day 8:
    congenital abnormalities were seen in 28% of fetuses, with open eye in
    22%, webbed foot in 16%, cleft palate in 5%, and fused ribs in 8%. The
    anomalies that appeared to be increased significantly but to almost
    the same extent at all three stages were fused ribs and cleft palate
    (Ottolenghi et al., 1974).

         These results could not be repeated by other workers. Groups of 
    27-29 golden Syrian hamsters were administered oral doses of endrin
    (97%) in methocel at 0 (two control groups), 0.1, 0.75, or 2.5 mg/kg
    body weight on days 4-13 of gestation. The animals were killed on
    day 14. Body weight gains of the animals given 2.5 mg/kg were
    slightly reduced. Maternal appearance, behaviour, and survival, mean
    number of viable fetuses, post-implantation losses, implantations,
    corpora lutea, fetal body weight, and crown-rump length showed no
    change attributable to treatment. The number of malformations in
    fetuses was not increased, but ossification of the sternebrae and
    certain ribs was delayed (Goldentahl, 1978b).

         Groups of 18-87 golden Syrian hamsters (LVG strain) were given
    endrin (98%) as a solution in corn oil by gavage either as a single
    dose of 0.5, 1.5, 5, 7.5, or 10 mg/kg body weight on day 8 of
    pregnancy or as multiple daily doses of 0.75, 1.5, 2.5, or 3.5 mg/kg
    body weight on days 5-14 of pregnancy. All animals were killed on day
    15. With single doses, no effect was found on maternal survival,
    pregnancy rate, weight change or liver:body weight ratio. The only
    sign of maternal toxicity was the occurrence of transient convulsions
    2 h after dosing in one hamster given 10 mg. No compound-related
    difference was noted in the number of implantation sites, fetal death
    rate, or fetal weight; indicators of skeletal maturity were not
    affected. A dose-related increase in the incidence of fused ribs was
    found in the groups given 7.5 and 10 mg/kg; increased incidences of
    meningo-encephaloceles were observed at 5 mg/kg and above, with no
    dose-response relationship. No other compound-related skeletal or
    visceral anomaly was noted. In the study of multiple doses, maternal
    toxicity (reduced weight gain and increased mortality) and fetal
    toxicity (increased mortality, reduced weight, reduced skeletal
    ossification, and an increased percentage of irregular
    supra-occipitalis) were observed at doses of 1.5 mg/kg and higher. No
    treatment-related maternal or fetal effect occurred at 0.75 mg/kg per
    day (Chernoff et al., 1979).

    8.4.2.4  Perinatal behavioural development

         Rats exposed perinatally to endrin at 0, 0.075, 0.15, or 0.3
    mg/kg body weight from gestation day 7 through day 15 of lactation
    showed no mortality and no influence on survival or growth. Pups of
    mothers exposed to 0.15 or 0.3 mg were more active than those of
    mothers exposed to 0.075 mg or those in the control group. No clear
    difference in ambulation was noted, and at 90 days of age there was no
    difference (Gray et al., 1981; Kavlock et al., 1987).

         Golden Syrian hamsters (LVG strain) given endrin (98%) at 0 or
    1.5 mg/kg body weight per day by gastric intubation on days 5-14 of
    gestation had a persistent increase in locomotor activity. Offspring
    of treated hamsters ambulated more than the controls in the open field
    at 15 days, and long-term observation of activity in the figure-8 maze
    indicated that a significant increase in this behaviour was still
    present at 125 days of age. Other behaviour patterns, including
    sexual, rearing and running, and wheel behaviour, were unaffected.
    Dams repeatedly exposed to endrin at 0.75 and 1.5 mg/kg body weight
    were markedly hypoactive under the same testing conditions in which
    the pups were hyperactive. The dose of 1.5 mg/kg body weight killed
    more than half of the dams (Gray et al., 1981; Kavlock et al., 1987).

    8.4.3  Appraisal of reproductive effects

         Endrin had no reproductive effects in three generations of rats
    at a level of 2 mg/kg of diet, equivalent to 0.1 mg/kg body weight. It
    had no teratogenic effect in mice, rats, or hamsters after oral
    exposure during the period of organogenesis. The significance of the
    anomalies observed in mice and hamsters by Ottolenghi et al. (1974) is
    uncertain. Studies in the same strain of the same species using more
    rigorous protocols and larger numbers of animals could not confirm
    their findings.

         The lowest-observed-adverse-effect level for maternal toxicity
    was 1.0 mg/kg body weight in mice, 0.3 mg/kg body weight in rats, and
    1.5 mg/kg body weight in hamsters. Embryotoxicity was observed at
    doses of 1 mg/kg body weight in mice and 1.5 mg/kg body weight in
    hamsters. The overall no-observed-adverse-effect levels in mice, rats,
    and hamsters were 0.5, 0.15, and 0.75 mg/kg body weight, respectively
    (Table 27).

    8.5  Mutagenicity and related end-points

    8.5.1  Effects on microorganisms

         Endrin was not mutagenic in numerous studies using  Salmonella
     typhimurium (TA98, TA100, TA1535, TA1537, TA1538, TA1950, TA1978,
    SL4525, SL4700),  Escherichia coli (WP2  uvrA, WP2  uvr-, Gal
    Rs, WP2,  hcr, p3478, W3100), K-12 (Pol A1+/Pol1-), WP67,
    CM611, and CM571  Bacillus subtilis (M45),  Saccharomyces cerevisiae

    (D3, D7), and  Serratia marcescens (a21, a742), with or without
    metabolic activation by rat or mouse liver S9 (Fahrig, 1974; Van Dijck
    & van de Voorde, 1976; Ercegovich & Rashid, 1977; Simmon et al., 1977;
    Nishimura et al., 1982; Waters et al., 1982; Glatt et al., 1983;
    Moriya et al., 1983; Rashid & Mumma, 1986).

         No mutagenic effect was observed in  S. typhimurium strains
    TA98, TA100, TA1535, or TA1537, with and without metabolic activation
    with S9 from livers of Aroclor 1254-induced rats and hamsters in the
    presence of five concentrations of endrin (0-10 000 µg/plate) (Zeiger,
    1987; Zeiger et al., 1987). No mutagenic effect was observed in
     S. typhimurium strains TA97, TA98, TA100, or TA102 with and without
    metabolic activation with Aroclor 1254-induced rat liver microsome
    fraction in the presence of seven concentrations of endrin (99.0%),
    from 1 ng/plate up to 1 mg/plate (Mersch-Sundermann et al., 1988).

    8.5.2  Point mutations in mammalian cells

         Endrin was weakly mutagenic in 6-thioguanine-resistant mouse
    FM3A cells (Morita & Umeda, 1984; abstract only).

    8.5.3  Dominant lethal mutations

         Endrin did not show detectable dominant lethality when given as
    a single intraperitoneal dose (0.76 or 3.8 mg/kg body weight) or daily
    oral doses (0.1 or 0.25 mg/kg body weight) for 5 days to seven or nine
    male ICR/Ha Swiss mice, respectively. This study involved a sequential
    mating procedure, in which one male was housed with three females for
    one week, repeated for 8 weeks (Epstein et al., 1972).

    8.5.4  Chromosomal and cytogenetic effects

         Endrin at 10-5 and 10-4 M, but not at 10-6, produced a
    dose-related increase in the percentage of M1 metaphases and a
    dose-related decrease in that of M3 metaphases at 48 h in treated
    LAZ-007 human lympoid cells. This effect is closely related to the
    reduced rate of cell proliferation induced by endrin (Sobti et al.,
    1983).

         Intratesticular injection of 0.25 mg endrin in saline to three
    albino rats doubled the percentage of chromosomal changes in
    comparison with that in the single control when the testes were
    studied histologically 10 days after the injection. Changes were
    scored in 70-75 cells/animal (Dikshith & Datta, 1973). The use of a
    single dose does not aid interpretation, and the increase in
    chromosomal abnormalities may be related to cytotoxicity rather than
    to a genetic effect. The relevance of this type of study in
    mutagenicity testing is unknown.

        Table 27.  Teratogenicity and effects on reproduction of oral administration of endrin
                                                                                                                              
    Animal             Exposure                    NOAEL             LOAEL                             Reference
    (strain)           period
                                                                                                                              
    Rat (Long Evans)   3 generations, 1 litter     1 mg/kg diet      3 mg/kg diet (0.15 mg/kg bw):     Hine (1965)
                                                   (0.05 mg/kg bw)   increased mortality of pups in
                                                                     F2 and F3 generations

    Rat (Long Evans)   3 generations, 2 litters    2 mg/kg diet                                        Hine (1968)
                                                   (0.1 mg/kg bw)

    Mice (CD-1)        Days 7-17 of gestation      0.5 mg/kg bw      1 mg/kg bw: maternal and fetal    Kavlock et al. (1981,
                                                                     weight, skeletal and visceral     1987)
                                                                     maturity

    Rat (CD)           Days 7-20 of gestation      0.15 mg/kg bw     0.30 mg/kg bw: reduced            Kavlock et al. (1981)
                                                                     maternal weight gain

    Rat (CD)           Days 6-15 of gestation      0.5 mg/kg bw      2 mg/kg bw: maternal toxicity     Goldentahll  (1978a)

    Hamster            Days 5-14 of gestation      0.75 mg/kg bw     1.5 mg/kg bw: maternal and        Chernoff et al. (1979)
                                                                     fetal toxicity
                                                                                                                              
    
         Chromosomal studies were carried out on lymphocytes from eight
    male workers exposed to endrin and from six unexposed workers from the
    same work area. No increase in the frequency of chromosomal
    abnormalities was found, whether taken individually or collectively
    (Dean, 1977).

         Chromosomal aberrations were found in meiotic cells of barley and
    somatic cells of barley and  Vicia faba grown from endrin-treated
    seeds (Wuu & Grant, 1966, 1967a,b). After treatment of root tips with
    0.1% endrin (EC20 solution) for 1.5-2 h at 10 °C, the function of the
    spindle was destroyed and did not interfere with the spreading of the
    chromosomes during squash preparation. The centromeric region became
    distinct and visible in prophase-metaphase chromosomes. At higher
    concentrations contraction, stickiness, and fragmentation of
    chromosomes were seen (Bhowmik, 1978).

    8.5.5  Host-mediated effects

         In two studies, male CF1 mice were given single oral doses of
    endrin in dimethyl sulfoxide at 3.75 or 7.5 mg/kg body weight. Control
    mice were dosed with the solvent, and positive control groups were
    given a single oral dose of ethylmethanesulfonate at 400 mg/kg body
    weight.  Saccharomyces cerevisiae JD1 suspensions were then injected
    intraperitoneally into each mouse, and the suspensions of
     S. cerevisiae were harvested and analysed after 5 h. No increase in
    mitotic gene conversion was detected (Brooks, 1976).

    8.5.6  Sister chromatid exchange

         Endrin at concentrations of 10-6-10-4 mol/litre in dimethyl
    sulfoxide (the latter dose was a cytotoxic concentration) failed to
    increase the frequency of sister chromatid exchange significantly over
    the control value in rat liver microsomal S9-activated and unactivated
    incubation experiments using human lymphoid cells of the LAZ-007 cell
    line (Sobti et al., 1983).

    8.5.7  Effects in Drosophila melanogaster

         Endrin was not mutagenic to  Drosophila melanogaster after
    injection at 0.2 µlitre of a 0.001% aqueous solution, in the Muller-5
    test for recessive lethal mutations on the X-chromosome (Benes & Sram,
    1969).

    8.5.8  Effects on DNA

         Endrin at 10-3 or 3 x 10-3 mol/litre did not induce mutation
    in the adult rat liver epithelial culture/hypoxanthineguanine
    phosphoribosyl transferase assay (Williams, 1979).

         DNA repair was not elicited in primary cultures of hepatocytes
    from CD-1 mice, Fischer 344 rats, or Syrian hamsters exposed to endrin
    for 18 h together with tritium-labelled thymine deoxyribonucleotide
    for incorporation during repair synthesis. DNA repair was measured
    autoradiographically. In rat and hamster liver cell cultures, a
    concentration of 10-3 mol/litre and in mouse liver cell cultures,
    10-4 mol/litre endrin was tested (Maslansky & Williams, 1981).

         Endrin did not induce unscheduled DNA synthesis in human lung
    fibroblast cells with or without metabolic activation by rat liver
    microsomes (five concentrations were tested, but they were not given
    in the paper) (Waters et al., 1982).

         Endrin at eight concentrations ranging from 0.5 up to 1000
    nmol/ml did not induce unscheduled DNA synthesis in primary rat
    hepatocytes or in a modified Ames test utilizing concentration
    gradient plates and 10 bacterial tester strains (eight  S. typhimurium
    and two  E. coli) (Probst et al., 1981)

    8.5.9  Appraisal of mutagenicity and related end-points

         Garrett et al. (1986) evaluated the activity of endrin in a
    series of tests: for reverse mutation (point/gene mutations in
    prokaryotes), forward mutation (point/gene mutations in eukaryotes),
    differential toxicity (primary DNA damage in prokaryotes), enhanced
    mitotic recombination, gene conversion and crossing-over, unscheduled
    DNA synthesis (primary DNA damage in eukaryotes), sister chromatid
    exchange, chromosomal breakage, and dominant lethality (chromosomal
    effects). Endrin gave negative results in all these tests.

         The vast majority of the data indicate that endrin is not
    genotoxic; however, many of the studies would not reach current
    standards, or they give insufficient data to allow an independent
    assessment.

    8.6  Long-term exposure

         Groups of 20 male and 20 female Carworth rats (28 days old) were
    given diets containing endrin at 0, 1, 5, 25, 50, or 100 mg/kg. With
    100 mg, two males and one female survived for 2 years; with 50 mg,
    four males but no female survived; and with 25 mg, 11 males and 5
    females survived. Survival at the lower concentrations was comparable
    to that of the control group. Males appeared to be less susceptible
    than females to the toxic action of endrin. Signs of intoxication,
    hypersensitivity to external stimuli, and occasional convulsions were
    observed only at the two highest levels. The weight gain of females
    fed 1, 5, or 25 mg/kg of diet was equal to or greater than that of the
    controls after 40 weeks of feeding. In males fed 5 mg, growth
    retardation occurred during the first 20 weeks only, while males that
    received 25 mg showed significant reduction in body weight gain. The
    body weight gain of males fed 1 mg was comparable to that of controls.

    The liver:body weight ratios were increased in males fed 5 mg or more
    and in females fed diets with 25 mg or more. Histopathological
    examination of animals that died during exposure to the three higher
    dietary levels revealed diffuse degeneration of the liver, kidneys,
    brain, and adrenal glands. The few survivors at 50 and 100 mg showed
    degenerative changes in the liver only. No histopathological change
    was found in surviving rats fed 1, 5, or 25 mg/kg diet. There was no
    increase in the incidence of neoplasia in the treated groups compared
    to the control group (Treon et al., 1955).

         This study indicates a no-effect level for endrin of 1 mg/kg of
    diet (about 0.05 mg/kg body weight) but is inadequate in several
    respects, e.g., survival rate, details of pathology, and
    haematological and clinical chemical data are not reported.

    8.7  Carcinogenicity

    8.7.1  Oral administration

    8.7.1.1  Mouse

         Groups of 100 male and female C57B1/6J mice, an inbred strain
    with a low incidence of tumours, and C3D2F1/J mice, a hybrid strain
    with a high incidence of hepatomas in males and a high incidence of
    mammary tumours in females, were fed endrin (99%) at dietary
    concentrations of 0.3 or 3 mg/kg from the age of five weeks throughout
    life. A control group consisted of 200 mice of each sex of each
    strain. Except for all groups of female animals of the C3D2F1/J
    strain, this part of the experiment was terminated at the 78th week
    because of the early occurrence of high numbers of mammary
    fibroadenomas in 70-90% of control and treated mice. Survival, growth,
    food intake, and haematology were not impaired. Mice of both strains
    fed 3 mg/kg diet occasionally developed convulsions in the early
    stages of feeding but recovered and survived without signs of illness.
    They generally showed the typical histological changes in the liver
    characteristic of high doses of chlorinated hydrocarbon insecticides.
    No effect was observed on mice fed 0.3 mg/kg diet. The tumour
    incidence and type of tumours were not influenced by the feeding of
    endrin, and it had no influence on the incidence of fibroadenomas in
    female C3D2F1/J mice (Witherup et al., 1970).

         Groups of 50 B6C3F1 mice of each sex were given endrin in the
    diet for 80 weeks and were then observed for a further 10 or 11 weeks.
    The initial doses of endrin (97%) (2.5 and 5 mg/kg of diet) were
    poorly tolerated by males and were therefore reduced after 25 weeks to
    1.2 and 2.5 mg/kg diet for males; but females received 2.5 and 5 mg/kg
    diet during the whole experiment. The time-weighted average doses were
    1.6 and 3.2 mg/kg diet for males and 2.5 and 5.0 mg/kg diet for
    females. Matched controls consisted of groups of 10 mice of each sex;
    pooled controls, used for statistical evaluation, consisted of the
    matched control groups combined with 50 untreated male and 50

    untreated female mice from similar bioassays of other chemicals. All
    surviving mice were killed at 90 or 91 weeks. Mean body weight was not
    affected, but the survival of males at the high dose was lower than
    that of the controls. The survival of the low-dose males could not be
    evaluated due to accidental administration of excessive quantities of
    endrin to this group during week 66. The tumour (neoplastic lesions in
    the liver) incidences in the high-dose males were higher than those of
    the pooled or matched controls, but not significantly so, and the
    increase was not considered to be related to the administration of
    endrin (Fredrickson, 1978;NCI, 1978).

    8.7.1.2  Rat

         A study of groups of 20 male and 20 female Carworth rats
    administered endrin at 0, 1, 5, 25, 50, and 100 mg/kg of diet was
    reviewed in Section 8.6.1.1. Bearing in mind the limitations of this
    study, such as small group sizes and low survival at the high doses,
    no evidence of an increase in the incidence of neoplasia was found in
    any of the groups (Treon et al., 1955).

         Groups of 50 weanling Osborne-Mendel rats of each sex were fed
    diets containing endrin (98%) at 2, 6, or 12 mg/kg for 29 months. The
    control groups consisted of 100 males and 100 females. During the
    first 10 weeks of the study, only half the nominal dietary
    concentrations of endrin were fed. Signs of toxicity occurred in a few
    animals in all treatment groups, mainly in females, and included
    episodes of tremor and clonic convulsions with 'outcries', the
    incidence of these signs being dose-related. Weight gain was
    unaffected, and the survival rates in control and treated rats were
    similar. The liver:body weight ratios were unaffected. A moderate (not
    dose-related) increase in the incidence of centrilobular cloudy
    swelling in the liver and of cloudy swelling of the renal tubular
    epithelium was observed. The lungs of the animals fed endrin exhibited
    a moderate increase in the incidence of congestion and focal
    haemorrhages. The tumour incidence in the treatment groups was
    comparable with that in control rats, and no difference in the type of
    tumours was found (Deichmann et al., 1970a,b; Deichmann & MacDonald,
    1971).

         In a life-time study, groups of 24 male and 24 female
    Osborne-Mendel rats (22 days old) were fed diets containing endrin at
    0, 0.1, 1, 5, 10, or 25 mg/kg. Because 50% of the rats at 25 mg/kg
    died within the first week, this group was restarted with 32-day-old
    rats. Survival did not appear to be affected by treatment. The highest
    incidence of malignant tumours in male and female rats occurred at 0.1
    mg/kg, but the malignancies were not dose-related. Treated male rats
    had a higher incidence of renal disease than controls, but this also
    was not dose-related (details not available) (Reuber, 1978).

         Groups of 50 Osborne-Mendel rats of each sex were fed endrin
    (97%) in their diet for 80 weeks and then observed for 31 or 34 weeks.

    Males received doses of 2.5 or 5 mg/kg diet; in females, the initial
    doses of 5 and 10 mg/kg of diet were poorly tolerated and were reduced
    after 9 weeks to 2.5 and 5 mg/kg. The time-weighted average doses were
    2.5 and 5.0 mg/kg for males and 3 and 6 mg/kg for females. Matched
    controls consisted of groups of 10 rats of each sex; pooled controls
    used for statistical evaluation consisted of the matched control
    groups combined with 40 untreated male and 40 untreated female rats
    from similar bioassays of other chemicals. All surviving rats were
    killed at 100-114 weeks. Body weights and survival were not affected
    by administration of endrin. A slight increase in the incidences of
    pituitary and thyroid tumours was observed, but no consistent
    statistical significance or dose-response relationship was found
    (Fredrickson, 1978; NCI, 1978).

    8.7.1.3  Tumour promotion

         No significant increase in the development of preneoplastic
    changes (hyperplastic nodules) was observed in rat liver after partial
    hepatectomy and initiation with  N-nitrosodimethylamine or
     N-2-fluorenylacetamide in combination with the administration of
    endrin (Ito et al., 1980).

          In vitro, endrin at levels of above 2.5 µg/ml appeared to
    inhibit metabolic cooperation in the hypoxanthineguanine
    phosphoribosyl transferase system using wild-type
    6-thioguanine-sensitive V79 cells and variant 6-thioguanine-resistant
    cells. Such inhibition is reported to be an index of potential tumour
    promoting activity, although the test has not been validated (Kurata
    et al., 1982).

         Endrin stimulated protein kinase C activity  in vitro only
    slightly, whereas a representative endogenous ligand of protein kinase
    C,  syn-1,2-didecanoylglycerol, stimulated protein kinase C to a
    maximal velocity (Moser & Smart, 1989).

    8.7.2  Appraisal of carcinogenicity

         One of several studies in mice suggests an increased incidence of
    nonmalignant tumours in animals of one sex, but this study was
    considered inadequate for assessing carcinogenicity because an
    increased number of tumours was seen in controls. A second study using
    a different mouse strain did not corroborate the increase in tumour
    incidence. Several long-term feeding studies in rats provide no
    evidence of a carcinogenic effect of endrin. Its tumour promoting
    activity was tested  in vitro using protein kinase C stimulation and
    ATPase inhibition; the results do not suggest any overwhelming effect
    in these systems. After a careful review of this evidence, and taking
    into consideration the fact that most of the data indicate that endrin
    is not genotoxic, the Task Group concluded that the data are
    insufficient to indicate that endrin is a carcinogenic hazard to
    humans.

    8.8  Special studies

    8.8.1  Nervous system

    8.8.1.1   Electrophysiological studies

         The effects of endrin on bioelectrogenesis was studied in
    anaesthetized pigeons and squirrel monkeys with chronically implanted
    electrodes. Endrin was administered intravenously to pigeons at doses
    of 0.5-4 mg/kg body weight. Doses of 2-4 mg/kg and higher caused
    seizure activity throughout the telencephalon; the lower dose levels
    caused activity only in the ectostriatum, a telecephalic visual
    projection area. At doses of 0.5-2 mg/kg body weight, endrin caused a
    specific increase in the evocation of potentials in the ectostriatum
    by stimulation of the nucleus rotundus, a diencephalic visual
    projection area. Reticular formation functions were not or little
    affected. Administration of endrin to squirrel monkeys at doses of
    0.2-3 mg/kg body weight on 5 days/week intramuscularly in corn oil and
    saline emulsion induced characteristic changes in the
    electro-encephalogram (EEG), culminating in electrographic seizures;
    these were transient and disappeared when endrin administration was
    stopped. Seizures reappeared under stress conditions, however, several
    months after endrin treatment (Revzin, 1966, 1980).

         Groups of 20-60 Sprague-Dawley rats with previously implanted
    electrodes were given endrin in peanut oil orally at 0.8, 1.7, or 3.5
    mg/kg body weight per day on 5 days/week for 28 weeks. Dose-dependent
    mortality occurred during the first week and again at the end of the
    study. Most changes in the EEG were seen after one week of exposure:
    these included severe bursts of multiple spikes accompanied by clonic
    convulsions; other animals had runs of spikes without full-fledged
    convulsions. The convulsions were usually preceded by a period of
    hyperventilation. After a further week of exposure, the rats showed
    normal EEG traces. Some irregular slow-wave activity was seen in
    animals that were moribund in the last month of feeding (Speck &
    Maaske, 1958).

          The convulsive properties of endrin at 1-2 mg/kg body weight
    were studied by intravenous injection in locally anaesthetized,
    paralyzed male cats, in which electrodes were placed in the
    subcortical structures of the brain. Endrin was dissolved in ethanol
    (which itself stimulates or inhibits the central nervous system,
    depending on dose). Changes in the EEG and evoked responses were
    studied. Hypersynchrony, rhythmic bursts of spikes and waves, and
    isolated spikes characterized the preictal state. Seizures were always
    bilateral and symmetrical and of a general tonic-clonic type.
    Responses in sensory and motor cortexes to sensory nerve stimulation
    were enhanced three to five fold. The authors concluded that endrin is
    directly toxic to the mammalian nervous system, is a potent rapidly
    acting convulsant, and does not require metabolic activation to an
    active metabolite (Joy, 1976).

    8.8.1.2  Histopathological studies

         Male CD1 Swiss mice were administered endrin or sesame oil daily
    by intraperitoneal injection in gradually increasing doses of 1.5-4.0
    mg/kg for 4-20 days. Electron microscopic examination of sciatic nerve
    tissue revealed no morphological change in myelinated nerve fibres,
    myelin, or associated Schwann cells, but morphological alterations
    were observed in unmyelinated nerve fibres and associated Schwann
    cells: axons were swollen, microtubules and neurofilaments showed
    dissolution, axoplasm was replaced by large clear vesicles,
    vacuolization was present, and Schwann cells and adaxonal spaces also
    contained vesicles (Walker & Phillips, 1987; abstract only).

    8.8.1.3  Neurotransmitter systems

          gamma-Aminobutyric acid systems: The role of the inhibitory
    neuro-transmitter of the central nervous system, gamma-aminobutyric
    acid (GABA),in the production of convulsions is well established.
    Polychloro-cycloalkane insecticides such as endrin have a potent
    excitatory action on the nervous system, and the interaction between
    GABA function and endrin has been studied.

          Endrin strongly inhibited GABA-dependent 36Cl uptake by mouse
    brain vesicles, with an IC50 (the concentration required to cause
    50% inhibition) of 2.8 µmol/litre. Inhibition was confined to that
    portion of 36Cl uptake that is GABA-dependent. The result
    demonstrates disruption of GABA ionophore function in mammalian brain,
    possibly providing the principal mechanism of toxicity (Bloomquist &
    Soderlund, 1985). In a comparison of the inhibitory potential of
    several polychlorocycloalkane insecticides on GABA-dependent 36Cl
    uptake, the most potent inhibitor was 12-ketoendrin, followed by
    isobenzan, endrin, and then dieldrin, heptachlor epoxide, aldrin,
    heptachlor and lindane. This order closely parallels their acute
    toxicities (Bloomquist et al., 1986).

         The effect of these chemicals was also studied in the  tert
    butylcyclo-phosphorothioate (TBPS) system, which has been shown to
    bind convulsants with varying affinities. The IC50 for endrin on
    35S-TBPS binding was 0.22 µmol/litre and that for 12-ketoendrin,
    0.036 µmol/litre. These were the most potent inhibitors of TBPS
    binding, and there was a significant linear correlation between 36Cl
    flux and TBPS binding (Bloomquist et al., 1986).

          In vitro, endrin inhibited 35S-TBPS binding in tissue from
    male Swiss-Webster mice with an IC50 of 18 nmol/litre (range, 4-90).
     In vivo, doses representing 25, 50, and 100% of the LD50 (8 mg/kg
    intraperitoneally) inhibited 35S-TBPS binding with IC50s of 77 ±
    7 nmol/litre (LD50) and 39 ± 6 nmol/litre (LD50/2); no inhibition
    was observed at LD50/4, indicating a possible no-observed-adverse-
    effect level. Brain P2 membranes of treated mice contained endrin and
    12-ketoendrin. The finding that the brains of treated mice contained

    sufficient endrin or its biotransformed products to achieve TBPS
    binding and that this was correlated with the severity of the
    poisoning indicates that the acute toxicity of endrin to mammals is
    regulated by GABA (Cole & Casida, 1986).

          GABA-induced 36Cl flux into membrane microsacs was inhibited
    by endrin at 3.9 ± 0.2 nmol/mg protein, which also suggests that
    endrin inhibits the function of this receptor (Abalis et al., 1985,
    1986). The IC50 for 36Cl influx was 0.19 ± 0.06 µM and that for
    35S-TBPS binding was 0.003 µM (Gant et al., 1987).

         Endrin inhibited both insect and rat GABA receptors in a
    dose-related, non-competitive manner. It acts in a similar manner on
    the GABA receptors in the central nervous system of the two species.
    The blocking action may involve non-competitive binding to an
    allosteric site associated with the receptor's chloride channel
    (Wafford et al., 1989a).

          Endrin potentially inhibits 35S-TBPS binding to rat brain
    membranes and also potentiates the protective effect of NaCl (200 mM)
    against heat inactivation of 3H-flunitrazepam binding sites on the
    same membranes. The time courses of heat inactivation of these binding
    sites in the presence of NaCl and saturating concentrations of endrin
    revealed monophasic components constituting about 88% of the binding
    sites (Squires & Saederup, 1989).

         Endrin has also been shown to inhibit GABA-ergic function in
     Torpedo fish (Matsumoto et al., 1988), chicken embryos (Seifert,
    1988, 1989), the mosquito fish  (Gambusia affinis) (Bonner &
    Yarbrough, 1989), and the cockroach  (Periplaneta americana) (Wafford
    et al., 1989b).

          Other amine systems: Studies on the effects of orally
    administered endrin on the content of biogenic amines in the brain of
    rats did not contribute to an understanding of the convulsive action
    of endrin (Miller & Fink, 1973; Hrdina et al., 1974).

          Cyclic AMP metabolism: Endrin did not affect adenylate cyclase
    activity or inhibit the activity levels of synaptosomal
    phosphodiesterase, enzymes involved in cyclic AMP metabolism, in rat
    brain. The authors interpreted their results to support their
    postulation that organochlorine insecticides exert their neurotoxic
    action by selective inhibition of ATPases in synaptosomes (Kodavanti
    et al., 1988).

          ATPase systems: Inhibition of rat brain Na+-K+ATPase by
    chlorinated insecticides varied considerably: endrin and dieldrin were
    the least active in inhibiting both this enzyme and K+-stimulated
     para-nitrophenyl phosphatase at a concentration of 2 x 10-5
    mol/litre. Results of experiments on ATP-32Pi exchange suggest
    that DDT is a powerful inhibitor of oxidative phosphorylation, which

    may lead to depletion of ATP. This effect was much less evident with
    endrin (Folmar, 1978).

          Endrin caused about 15% inhibition of the activity of
    Na+-K+ATPase in rat brain synaptosomes at the highest
    concentration tested, 120 µM, and oligomycin-sensitive Mg2+-ATPase
    in rat brain synaptosomes was significantly inhibited in a
    concentration-dependent manner, to a maximal inhibition of 33% at the
    highest dose. Endrin did not inhibit oligomycin-insensitive
    Mg2+-ATPase, and it did not affect K+-stimulated
     para-nitrophenyl phosphatase from rat brain synaptosomes; this
    enzyme represents the dephosphorylation step of the overall reaction
    to the Na+-K+ATPase. Oligomycin-sensitive Mg2+-ATPase in beef
    heart mitochondria was significantly inhibited. The results of this
    study suggest that the ATPase system in rat heart and central nervous
    system is not selectively inhibited by endrin (Mehrotra et al., 1989).

          Sodium channel: It has been demonstrated using voltage clamp
    techniques in single cells that application of DDT prolongs the sodium
    current, which in turn decreases the depolarizing after-potential to
    initiate repetitive after-discharges in the cell. The repetitive
    after-discharges facilitate synaptic transmission and result in
    nervous system hyperexcitability, which at the functional level is
    registered as tremors and eventually convulsions and death (Narahasi,
    1987). Even if less than 1% of the sodium channels respond in this
    manner to insecticides, it is sufficient to cause toxicity in the
    animal. Narahasi (1987) reported these effects with pyrethroids and a
    series of DDT analogues; such studies have not been carried out with
    endrin. Lund & Narahasi (1983) suggested that because of the
    similarity in the symptomatology of intoxication by the family of
    organochlorine insecticides, the target site of endrin may also be the
    sodium channels.

    8.8.1.4  Appraisal of effects on the nervous system

         The effect of endrin on the nervous system has received attention
    because it has the well established ability to cause convulsions
    following acute exposures. Endrin causes considerable changes in EEG
    activity, which are associated with convulsions, at intramuscular
    doses in experimental animals as low as 0.2 mg/kg body weight.

         The probable underlying mechanisms are associated with a
    dose-related, non-competitive inhibition of the GABA-ergic
    neurotransmitter system. This is an inhibitory system, and removal of
    its action leads to increased excitation in the nervous system. While
    inhibition of GABA-ergic function is common to a number of
    polychlorocycloalkane insecticides, endrin, and particularly its
    metabolite 12-ketoendrin, have been shown to be extremely potent
    inhibitors of this function. It appears therefore that the acute
    toxicity of endrin is due to disruption of GABA-related mechanisms.

    8.8.2  Cardiovascular system

         Studies have been conducted on the physiological effects of
    endrin on the peripheral vascular system, renal function, renal
    haemodynamics, and the cardiovascular system of the dog (Emerson et
    al., 1963, 1964; Reins et al., 1964; Emerson, 1965; Emerson & Hinshaw,
    1965; Reins et al., 1966; Hinshaw et al., 1966; Reddy et al., 1967).
    After a lethal dose of endrin was administered intravenously, most of
    the effects appeared to be the direct or indirect result of the
    stimulating action of endrin on the central nervous system.
    Bradycardia, hypertension, salivation, hyperexcitability, tonic-clonic
    convulsions, increased body temperature, leukocytosis,
    haemoconcentration, and decreased blood pH were seen. Elevation of
    cerebral venous pressure and cerebrospinal fluid pressure were also
    prominent features. Increased levels of adrenaline and noradrenaline
    in blood plasma cause increased venous return and cardiac output and
    increased arterial blood pressure in the absence of a rise in total
    peripheral resistance. There was a large increase in total limb
    vascular resistance and also a decrease in renal blood flow due to
    arteriolar vasoconstriction. In studies on intact dogs and isolated
    heart-lung preparations, high doses of endrin appeared to have a toxic
    action on the left ventricle of the heart, causing sudden left heart
    failure.

          Aldrin, dieldrin, and endrin inhibited rat brain synaptosomal
    and heart sarcoplasmic reticulum  in vitro in a
    concentration-dependent manner. Calmodulin-depleted Ca2+ pump
    activity was insensitive to the action of these compounds. Oral
    administration of endrin at 0.5-10 mg/kg to rats similarly decreased
    Ca2+ pump activity, in addition to decreasing the levels of
    calmodulin in both brain and heart, indicating disruption of membrane
    Ca2+ transport mechanisms. Exogenous addition of calmodulin
    (1-20 µg) effectively reversed the endrin-induced inhibition. Ca2+
    pump activity in brain is more sensitive to endrin than that in heart.
    The results indicate that endrin may produce neurotoxic effects by
    altering calmodulin-regulated calcium-dependent events in neurons
    (Mehrotra et al., 1989).

    8.8.3  Effects on liver enzymes

         It is well known that chlorinated hydrocarbon insecticides such
    as DDT and dieldrin stimulate hepatic microsomal drug metabolism,
    stimulating the activity of enzymes for the metabolism of drugs and
    endogenous compounds such as hormones (Kinoshita & Kempf, 1970).

    8.8.3.1  Mouse

         A single oral, convulsive dose of endrin (20 mg/kg body weight)
    dissolved in corn oil was administered to 9-week-old male
    Swiss-Webster mice. Control groups consisted of a group of untreated
    mice and a group receiving corn oil. When convulsions began, blood

    serum was examined for serum glutamic oxaloacetic transaminase, serum
    glutamic pyruvic transaminase, and serum lactic dehydrogenase. The
    activities of the three enzymes were significantly increased above
    those seen in the two control groups (Luckens & Phelps, 1969).

          After intraperitoneal injection of a single dose of endrin at
    6.25 mg/kg body weight to mice, hexobarbital sleeping time was
    decreased, starting 3 h after the injection and lasting for 3 days
    (Hart & Fouts, 1963). Stimulating effects on the hepatic
    mixed-function oxidase system were reported in ICR mice after single
    oral doses of 4 and 10 mg/kg body weight (Hartgrove et al., 1977).

    8.8.3.2  Rat

         Feeding Sprague-Dawley rats on diets containing endrin at 1, 5,
    25, 50, or 100 mg/kg for 16 weeks caused high mortality in all groups,
    especially among male rats. The serum alkaline phosphatase
    concentration was reported to be dose-relatedly increased in all
    groups as compared to control animals. The effect was clearest in the
    groups fed 25 mg/kg of diet or more (Nelson et al., 1956).

          In strain FW 49 rats, a single oral dose of endrin at 5 mg/kg
    body weight had no effect on pentobarbital sleeping time; 10 mg/kg
    caused a significant reduction, which, however, disappeared after 10
    days (Schwabe & Wendling, 1967).

          Endrin caused a significant shortening of the duration of the
    paralysis induced by zoxazolamine in male Sprague-Dawley rats aged
    5-6 weeks. Endrin was injected intraperitoneally at 2 mg/kg body
    weight daily for 3 days, and zoxazolamine was injected
    intraperitoneally on the fourth day (Truhaut et al., 1974).

         Male rats given single oral doses of 2.5, 3.75, or 5.0 mg/kg body
    weight showed no effect on the various parameters (details not given)
    of mixed-function oxidase activity after 12 h, but the level of
    microsomal protein and electron transport components per gram of liver
    were significantly increased after 108 h, in a dose-dependent fashion.
    Thiopentone and pentobarbital sleeping times were reduced by a 24-h
    prior intraperitoneal injection of endrin at 5 mg/kg body weight
    (Kachole & Pawar, 1977).

          A single oral dose of endrin at 10 mg/kg body weight to male
    albino rats increased serum glutamic oxaloacetic transaminase and
    glutamic pyruvic transaminase activities, and decreased ATPase, acid-
    and alkaline phosphatase, succinic dehydrogenase, and
    glucose-6-phosphatase activities significantly 2-48 h after treatment
    (Meena et al., 1978). After three successive daily oral doses of
    endrin at 15 mg/kg body weight to Sprague-Dawley rats, significant
    increases in total lipids and triglycerides in liver and in serum
    glutamic pyruvic transaminase activity were seen (Borady et al.,
    1983).

         When two groups of six adult female rats were fed 0 or 28.7 µg/kg
    body weight, endrin accumulated in the liver (5.47 mg/kg),and its
    concentration in blood increased progressively up to 28 days. Growth
    was depressed. The activities of the enzymes aspartate amino
    transferase and alanine amino transferase were slightly increased
    (Illahi et al., 1986). Similar results were obtained in a study in
    which rats were fed 20 µg/kg body weight for 28 days (Illahi et al.,
    1987).

    8.8.3.3  Guinea-pig

         Groups of six female guinea-pigs were administered three
    successive intraperitoneal injections of endrin in sunflower oil at 3
    mg/kg body weight, and liver and kidneys were studied 24 h after the
    last injection. Treatment caused a significant increase in liver
    weight and a decrease in hepatic microsomal protein content; renal
    weight and renal microsomal protein content were not affected. Hepatic
    cytochrome b5 and cytochrome-c reductase activities were increased,
    while cytochrome P450 and total haem levels were significantly
    decreased. Related to the decrease in cytochrome P450 was a decrease
    in TPNH-linked aminopyrine-N-demethylation, but an increase in
    DPNH-linked demethylation was related to the increase in cytochrome b5
    and cytochrome-c reductase. Lipid peroxidation was increased in both
    liver and kidneys (Pawar & Kachole, 1978).

    8.8.3.4   In-vitro studies

         To test the possibility that phenobarbital induces cytochrome
    P450p indirectly by increasing the availability of endogenous
    glucocorticoids in the liver, phenobarbital and phenobarbital-like
    inducers, including endrin, were added to primary monolayer cultures
    of adult Sprague-Dawley rat hepatocytes incubated in serum-free medium
    without glucocorticoids. De-novo synthesis of cytochrome P450p,
    measured as increased incorporation of 3H-leucine into
    immunoprecipitable P450p protein, was increased. Endrin at a
    concentration of 1x10-5 M was half as potent as phenobarbital at 2
    x 10-3 M (Schuetz et al., 1986).

    8.8.4  Miscellaneous studies

         Endrin inhibited rabbit muscle lactate dehydrogenase  in vitro
    (Hendrickson & Bowden, 1976). Exposure of isolated rat enterocytes to
    endrin reduced the efficiency of the neuropeptide vasoactive
    intestinal peptide after stimulation of cyclic AMP accumulation, as
    was observed with lindane (Carrero et al., 1989).

          Endrin at single oral doses of 25 mg/kg body weight or daily
    doses of 1 mg/kg body weight daily for 8 days induced various shifts
    in the mobilization of the ions of biologically important metals such
    as magnesium, iron, zinc, and copper from liver, kidneys, brain,
    heart, spleen, and blood (Coleman et al., 1968; Lawrence et al.,

    1968). Rats receiving intraperitoneal injections of 1 mg/kg body
    weight in peanut oil over periods up to 19 days showed no alteration
    in the concentrations of serum proteins or serum lipoproteins,
    separated by paper electrophoresis, or of albumin, alpha 1, alpha 2,
    beta, or gamma globulins. Protein-bound sialic acid and methylpentose
    were increased only temporarily; the level of bound hexose increased
    with time and that of bound hexosamine decreased (Coleman, 1968).

         Rats receiving a single oral dose of 50 mg/kg body weight, daily
    intraperitoneal doses of 2 mg/kg body weight, or daily intramuscular
    injections of 0.5 or 2.0 mg/kg body weight for 45 days showed
    increased activity of a number of the enzymes that are involved in
    gluconeogenesis in liver cells and cells of the renal cortex. A
    significant decrease was noted in hepatic glycogen, an increase in
    blood glucose and urea, as well as a significant rise in hepatic and
    renal pyruvate carboxylase, phosphoenol pyruvate carboxykinase,
    fructose-1,6-diphosphatase, and glucose-6-phosphatase. Furthermore,
    endogenous levels of cyclic AMP were increased (Kacew et al., 1973;
    Singhal & Kacew, 1976).

    8.8.5  Factors that influence toxicity

    8.8.5.1  Nutrition

         The nutritional state of Wistar rats was found to alter their
    susceptibility to the acute toxic action of endrin. Three groups of
    approximately 100 rats were fed a normal diet, a diet containing
    casein as the only source of protein, or a low protein diet for 28
    days, and the acute toxicity of endrin was determined after a single
    intragastric administration. The following LD50 values were
    calculated: 27 mg, 17 mg, and 7 mg/kg body weight, respectively (Boyd
    & Stefec, 1969).

    8.8.5.2  Potentiation

         The acute oral LD50s of equitoxic doses of combinations of 10
    pesticides, including endrin, were studied in Swiss mice. No evidence
    of potentiation was seen with combinations with dieldrin, diazinon,
    malathion, toxaphene, parathion, DDT, or dioxathion, but more than
    additive effects, i.e., possible potentiation, were found with
    chlordane and possibly with aldrin (Keplinger & Deichmann, 1967).

         Five groups of 20 male and 20 female Sprague-Dawley rats were fed
    for 91 days on a diet containing a combination of 15 'persistent'
    chemicals added at concentrations of 0, 1, 10, 100, and 1000 times the
    water quality objective applied in Canada. For endrin, these
    corresponded to 0.002, 0.02, 0.2, and 2.0 µg/kg of diet. No effect on
    food intake, growth, clinical chemistry, bone marrow, or
    histopathology were observed. It was concluded that the presence of
    these chemicals at 1000 times the water quality objective had no
    toxicological effect (Cote et al., 1985).

          Six male and six female Sprague-Dawley rats were fed a control
    diet or diets containing endrin at 5 or 10 mg/kg, endrin aldehyde at
    10 mg/kg, or endrin ketone at 5 mg/kg for 15 days, at which time three
    to six rats from each treatment group were given a single
    intraperitoneal dose of carbon tetrachloride at 100 µlitre/kg body
    weight in corn oil (1 mg/kg). Levels of serum enzymes, bile flow, and
    biliary excretion of an anionic model compound, phenolphthalein
    glucuronide, were measured on day 16. Dietary treatment with endrin at
    either dose level did not elevate serum enzyme levels. Treatment with
    5 mg/kg significantly reduced bile flow and a corresponding reduction
    in phenolphthalein glucuronide excretion, whereas the 10 mg/kg dose
    reduced only phenolphthalein glucuronide excretion in male rats.
    Female rats treated with either dose showed a dose-dependent
    choleretic effect with a commensurate increase in phenolphthalein
    glucuronide excretion. Treatment of rats with endrin and carbon
    tetrachloride did not result in potentiation of hepatobiliary
    functions. The levels of some serum enzymes were elevated (two-fold)
    in rats given endrin plus carbon tetrachloride over those in rats
    given endrin or carbon tetrachloride alone, indicating an additive
    interaction. Dietary treatment with endrin aldehyde slightly increased
    the levels of serum glutamic oxaloacetic transaminase and glutamic
    pyruvic transaminase; and endrin ketone induced a small elevation in
    glutamic pyruvic transaminase levels. Neither compound altered bile
    flow or biliary phenolphthalein glucuronide excretion. Combination
    with carbon tetrachloride increased the levels of some serum enzymes
    (two-fold) over those seen with the aldehyde or the ketone or carbon
    tetrachloride alone (Young & Mehendale, 1986).

    9.  EFFECTS ON HUMAN BEINGS

    9.1  Exposure of the general population

    9.1.1  Acute toxicity

         In mild cases of poisoning, dizziness, weakness of the legs,
    abdominal discomfort, nausea, and vomiting have been reported. Some
    patients have complained of temporary deafness or were slightly
    disorientated or aggressive. The onset of poisoning is variable and
    may occur 0.5-10 h after consumption of contaminated food or
    contamination of the skin; the interval is usually 1-4 h, depending on
    the quantity ingested. Severe poisoning is manifested by sudden
    epileptiform fits, with frothing at the mouth, facial congestion, and
    violent convulsive movements of the limbs, sometimes leading to
    dislocation of a shoulder or other injury. The fits may last for
    several minutes and may be followed by a period of semiconsciousness
    for 15-30 min or until the next fit. In general, these convulsions
    occur suddenly, with no prodromal sign or symptom. An uncommon but
    very serious symptom observed in two children was hyperthermia (41 °C
    or higher); the high fever was followed by decerebrate rigidity. In
    fatal cases, death occurs within 2-12 h. In survivors, recovery is
    rapid, within 24 h, and uneventful, although some patients have
    complained of headache, dizziness, weakness, and anorexia for several
    weeks (Davis & Lewis, 1956; Jacobziner & Raybin, 1959; Hoogendam et
    al., 1962; Hayes, 1963; Weeks, 1967; Hayes, 1982). After clinical
    recovery, EEG changes consisting of bilateral synchronous theta-wave
    activity and occasional bilateral synchronous spike and wave
    complexes, believed to be associated with brain stem irritation, may
    still be found and may persist for up to several weeks (Hoogendam et
    al., 1962, 1965; Weeks, 1967).

    9.1.2  Poisoning incidents

         Hayes (1982) reviewed poisoning cases caused by endrin. Outbreaks
    of acute intoxication due to endrin have occurred by contamination of
    flour during transport in railway cars. A first episode, which was
    well studied, occurred in 1956 in Wales, United Kingdom (Davis &
    Lewis, 1956): At least 59 people were ill enough to require medical
    treatment, and at least 100 more had some symptoms, which were not
    severe enough to require medical advice. No one died. On the basis of
    the concentration of endrin in bread prepared from the flour (150
    mg/kg), Hayes (1963) estimated that 0.20-0.25 mg/kg body weight may
    cause a single convulsion and that the dose necessary to produce
    repeated convulsions is about 1 mg/kg body weight. Karplus (1971)
    estimated the lethal dose in man to be approximately 10 mg/kg body
    weight.

         A few conflicting data are available on the concentration of
    endrin in the tissues of victims of fatal intoxication. Hayes (1982)
    quoted levels of 7-10 mg/kg in the liver and 0.7-4.4 mg/kg in the

    brain; however, 10-fold lower levels were reported in the tissues of
    autopsied victims of an outbreak of poisoning caused by ingestion of
    bread prepared from contaminated flour in the Middle East (Curley et
    al., 1970). In another incident, two sacks of contaminated flour
    contained endrin at 184.5 and 234.5 mg/kg, and the bread and rolls
    prepared from the contaminated flour contained 125.67-176.11 mg/kg.
    The levels of endrin in serum, collected 30 min, 20 h, and 30 h after
    convulsions in one person were 0.053, 0.038, and 0.021 mg/litre,
    respectively; three other cases had 0.003-0.004 mg/litre of blood
    serum 9-19 h after convulsions. One of these three people had no
    symptoms (Coble et al., 1967). The reported serum or blood levels of
    endrin associated with convulsions must be interpreted in the context
    of the rapid removal of endrin from blood and the often significant
    time lag in taking blood samples after convulsions. When the time
    between convulsion and blood sampling is long, the endrin levels
    reported are likely to be much lower than those at the time of the
    convulsion.

         Four outbreaks of endrin intoxication occurred in Doha (Qatar)
    and Hofuf (Saudi Arabia) in 1967, during which 874 people were
    hospitalized of whom 26 died; another 500-750 people showed symptoms
    of intoxication but required no hospitalization. These outbreaks were
    due to contamination of flour by endrin leaking from drums during
    shipment. The endrin concentrations found in bread were 48-1807 mg/kg,
    and those in the blood of patients were 0.007-0.032 mg/litre (Weeks,
    1967; Curley et al., 1970).

         Between July and September 1984, an epidemic of endrin poisoning
    occurred in Pakistan, resulting in acute convulsions. In 18 of 21
    affected villages surveyed, 70% (106/152) of the cases for which age
    was known were in children aged 1-9 years; 9.8% (19/194) of the
    affected people died. A composite sugar sample taken from the houses
    of three cases contained endrin at 0.04 mg/kg. Endrin was detected in
    the blood of 12/18 patients, at levels of 0.3-254.0 µg/litre of serum.
    It was also determined in brain, kidneys, adipose tissue, and liver of
    one person and found at levels of 1680, 1760, 4010, 1430 µg/kg
    respectively (Anon., 1984; Hill et al., 1986; Rowley et al., 1987).

         In mid-March 1988, three members of a family in Orange County,
    California, USA, became ill within 1 h of eating taquitos (baked corn
    shell filled with spicy meat and salad). Two of the three had multiple
     grand mal seizures. Subsequently, two other people were reported to
    have had seizures less than 12 h after eating taquitos. All five
    patients had obtained the taquitos from the same shop within 5 days.
    The food was analysed, and the presence of endrin was confirmed but
    not quantified. The origin of the endrin could not be identified
    (Anon., 1989).

         An episode of acute endrin poisoning was reported in 33 Mexican
    children, who had sudden seizures without sensory alterations (Singh
    & West, 1985).

         Several other cases have been published of single accidental or
    intentional intoxications, in children and in adults (Jacobziner &
    Raybin, 1959; Karplus, 1971). Reddy et al. (1966) described 60 cases
    of fatal endrin poisoning out of 95 encountered in India after the
    introduction of endrin in agricultural work as an insecticide in 1959.
    The majority of the cases were suicidal. Froth, petechial
    haemorrhages, a kerosene-like smell and massive pulmonary oedema were
    the characteristic autopsy findings. Respiratory failure was the most
    common cause of death. The authors concluded that the toxic dose of
    endrin is 5-50 mg/kg body weight or about 1 g; the lethal dose is
    about 6 g. In a poisoning case in a 19-year-old male who ingested an
    unknown amount of endrin, convulsions and gross pulmonary oedema were
    found (Jedeikin et al., 1979). No histological changes were found in
    the liver. At least some of the pulmonary changes seen in such cases
    may be due to aspiration of the petroleum hydrocarbon solvent in
    formulations of endrin.

         A case of polyneuropathy of the Guillain-Barré type was
    attributed to exposure to a mixture of DDT and endrin. Since
    convulsions were not recorded, the causal relationship remains
    doubtful (Jenkins & Toole, 1964).

          In a fatal case of endrin poisoning, ingestion of 12 g of endrin
    by a 49-year-old man caused convulsions (persisting for 4 days),
    hypersalivation, hyperthermia, renal insufficiency, thrombocytopenia,
    and recurrent hypotension. Death followed after 11 days due to
    pulmonary complications (infection and haemorrhage) and hypoxaemia
    causing bradycardia and cardiac arrest. The endrin concentrations in
    blood 4 h and 6 and 11 days after ingestion were 450, 86 and 71
    µg/litre. Endrin levels in adipose tissue, heart, brain, kidneys, and
    liver, 11 days after ingestion were 89.5, 0.87, 0.89, 0.55, and 1.32
    mg/kg, respectively (Runhaar et al., 1985).

         The medical treatment of endrin poisoning is described in Annex
    II.

    9.2  Occupational exposure

    9.2.1  Factory workers

         No fatal case has been reported due to occupational exposure in
    manufacturing and formulating plants (Van Raalte, 1965; Jager, 1970),
    which may be due in part to underreporting but is also certainly due
    to the fact that occupational exposure involving the absorption of
    lethal doses occurs rarely under practical circumstances. Furthermore,
    the rapid metabolism of endrin minimizes build-up of toxic levels in
    tissues during normal working days.

         Several cases of acute, non-fatal poisoning occurred in a
    manufacturing plant in The Netherlands due to accidental over-exposure
    to endrin (Jager, 1970). Endrin had been manufactured in this plant

    since 1957. During the first 9 years of production of aldrin,
    dieldrin, and endrin in the plant, 17 cases of poisoning with
    convulsions occurred, five of which involved more than one convulsion.
    Three of the cases were due to acute over-exposure to endrin among
    workers who were handling these materials at high concentrations every
    day. There was no fatality during 1300 man-years of exposure. No
    evidence was found of skin sensitization, and there was no case of
    permanent, partial, or complete incapacity. No difference was seen in
    absenteeism due to illness among these workers in comparison with
    those in other plants, and the results of liver function tests and
    complete blood cell counts were within normal limits. In the cases of
    poisoning, recovery from clinical and neurological signs, including
    EEG tracings, was rapid and complete (Hoogendam et al., 1962, 1965;
    Jager, 1970; Versteeg & Jager, 1973).

         A series of studies has been published on the results of
    continuing medical supervision of workers in this plant. A
    complementary follow-up of 189 workers and of 52 workers who had left
    employment at the plant for various reasons was published in 1973
    (Versteeg & Jager, 1973). These workers had been exposed to endrin for
    up to 14.5 years in 1973. In agreement with data published from a
    study of 71 workers in an endrin manufacturing plant in the USA (Hayes
    & Curley, 1968), endrin was not found in the blood of these workers,
    except in cases of accidental, acute over-exposure. Medical
    supervision of workers employed in the manufacture and formulation of
    endrin and other pesticides for 1-19 years (average, 12 years), data
    on absenteeism, the results of tests for liver function and blood
    chemistry, blood morphology, urine analysis, the occurrence of
    sensitization, the pattern and course of EEG changes in cases of
    poisoning, other medical studies (including electrocardiography, chest
    x rays, blood pressure, body weight), and the incidence and pattern of
    diseases, including the occurrence of malignant growths, showed no
    difference between workers exposed to endrin and other chemical plant
    operators. Residues of endrin were not found in plasma (< 3 µg/litre)
    or in adipose tissue (< 0.03 mg/kg).

         A significant difference was found between workers exposed to
    aldrin and dieldrin only, workers not exposed to insecticides, and
    workers exposed to endrin only: endrin workers had lower blood levels
    of the DDT metabolite  para,para'-DDE than the other workers, and the
    levels were lower than those in the general population of the
    surrounding area, although DDT and related compounds had never been
    manufactured in the plant. A second parameter that was compared was
    excretion of 6-beta-hydrocortisol in the urine. (Increased activity of
    the drug-metabolizing enzyme system increases the activity of the
    oxidative pathway by which 6-beta-hydroxylase converts endogenous
    cortisol to 6-beta-hydrocortisol and thus, relatively, diminishes the
    contribution of the reductive pathway, leading to excretion of
    17-hydroxycorticosteroids.) The ratio of the urinary excretion of
    6-beta-hydroxycortisol to that of 17-hydroxysteroids was significantly

    higher in the endrin workers than in workers not exposed to endrin
    (Jager, 1970).

         A third parameter of this enzyme system that was studied was
    urinary excretion of D-glucaric acid (an end-product of the glucuronic
    acid pathway in the liver), which has been shown to increase after
    exposure to microsomal enzyme-stimulating compounds, like endrin
    (Hunter et al., 1971; Notten & Henderson, 1975). In the endrin
    workers, urinary excretion of D-glucaric acid after a week of exposure
    increased significantly over pre-exposure levels and those in a
    control group of workers. Excretion diminished again after 3 days
    without exposure (Hunter et al., 1972; Ottevanger &Van Sittert, 1979;
    Vrij-Standhardt et al., 1979; Van Sittert, 1985).

         Since  anti-12-hydroxyendrin is the only metabolite found in the
    urine of endrin-exposed workers, a study was initiated to find whether
    there is a correlation between the quantity of this metabolite and
    that of D-glucaric acid excreted in the urine. A positive relationship
    was found between excretion of the endrin metabolite and of D-glucaric
    acid after 7 days. After exposure was discontinued, excretion of
     anti-12-hydroxyendrin decreased faster than that of D-glucaric acid.
    The fact that endrin-exposed workers had D-glucaric acid levels within
    the normal range after 6 weeks indicates that enzyme induction in
    endrin workers is reversible. The authors concluded that a urinary
    level of  anti-12-hydroxyendrin of  0.130 µg/g of creatinine is the
    threshold exposure level, below which enzyme induction is not produced
    (Ottevanger & Van Sittert, 1979; Van Sittert, 1985). Endrin did not
    increase total urinary porphyrin excretion over that in a control
    group of employees (Strik, 1979; Nagelsmit et al., 1979;
    Vrij-Standhardt et al., 1979).

         In a follow-up mortality study of the same group of workers,
    vital status and cause of death were assessed for 232 of a group of
    more than 1000 workers. This group was selected because they had
    experienced high exposures in the initial years of manufacture and
    formulation and because of the long periods of exposure (mean, 11
    years; range, 4-27) and observation (mean, 24 years; range, 4-29).
    Total observed mortality was 25, whereas 38 deaths were expected on
    the basis of mortality statistics for the male Dutch population. Of
    the nine cancer deaths, three were due to lung cancer; the remaining
    six were due to cancers of stomach, pancreas, bladder, and kidney,
    multiple myeloma, and cerebral glioma. It was concluded that the
    pesticides manufactured had no specific carcinogenic activity
    (Ribbens, 1985).

    9.2.2  Dose-response relationships

         It has not been possible to establish a dose-response
    relationship between single or repeated oral exposures and endrin
    concentrations in blood, adipose tissue, or organs and severity of
    intoxication, because the actual oral intake in the accidental cases

    was not known, and the onset of symptoms of intoxication and the time
    of measuring concentrations of endrin in blood, organs, or tissues
    were not comparable (Davis & Lewis, 1956; Hayes, 1963; Coble et al.,
    1967; Weeks, 1967; Curley et al., 1970; Karplus, 1971; Hayes, 1982;
    Anon., 1984).

         Blood samples have been analysed in three cases of acute
    over-exposure (Table 28): A formulator and an operator were
    accidentally splashed with a 20% endrin emulsifiable concentrate,
    which was washed off within 10 min. Neither developed signs or
    symptoms of intoxication. The third case was in a formulator who
    handled technical-grade endrin powder without wearing a dust-mask. He
    had convulsions 4 h after starting work, but after treatment recovered
    fully the next day. Blood samples from four colleagues working next to
    him, but wearing dust-masks, were also examined. The author estimated
    that the threshold level of endrin in the blood below which no sign or
    symptom of intoxication occurs is 50-100 µg/litre and that the
    half-life of endrin in blood is in the order of 24 h (Jager, 1970).

    9.2.3  Exposures to mixtures

         A retrospective mortality study was carried out on workers
    employed in the manufacture of heptachlor and endrin in a plant in
    Tennessee, USA, between 1952 and 1976. The study comprised 835 men who
    had worked for more than 3 months up to 20 years at the plant. No
    overall excess of deaths from cancer was found; however, there was an
    excess of deaths from cerebrovascular disease (7 observed, 2.3
    expected) (Wang & MacMahon, 1979).

         A further retrospective cohort study was conducted to examine the
    mortality of workers employed in the manufacture of chlordane,
    heptachlor, DDT, aldrin/dieldrin, and endrin in a plant in Colorado,
    USA, where endrin was manufactured from 1953 until 1965. Approximately
    2100 workers who had been employed for at least 6 months in the plants
    were involved. No excess of cerebrovascular disease was observed
    (Ditraglia et al., 1981).

         Neither study proves conclusively that exposure to these
    organochlorine insecticides is associated with increased prevalence of
    malignancy or other cause of death, but they are limited in design and
    in the desciption of exposure.

         A field study was carried out in 1983 in the Ivory Coast to
    assess the health hazards associated with the handling and application
    by hand-held sprayers of an ultra-low volume formulation consisting of
    endrin at 85 g/litre, DDT at 333 g/litre, and methylparathion at 85
    g/litre in petroleum solvent. Groups of five or six farmers sprayed 3
    litre/ha of the formulation 4-6 weeks after sowing cotton and again 15
    or 30 days after the first application. The spray apparatus was filled
    and cleaned by the same men. The recommended protective clothing was
    worn only rarely, and the handling and application techniques were

    careless, resulting in many cases in appreciable skin contamination.
    No adverse health effect was observed. Absorption of endrin was
    monitored by measuring the concentration of  anti-12-hydroxyendrin in
    spot samples of urine collected about 20 h after spraying. The mean
    concentrations after the first, second, and third applications were
    0.34 (range, 0.04-0.59), 0.52 (range, 0.09-1.4), and 0.45 mg/g of
    creatinine (range, 0.0-0.92). One person who had handled and sprayed
    the formulation carefully still had  anti-12-hydroxyendrin in the
    urine after the third application, but at a very low level (0.03 mg/g
    of creatinine). Measurements of  para-nitrophenol, a metabolite of
    methyl-parathion, in urine indicated that the rate of metabolism of
    methylparathion was increased as a result of enzyme induction by
    endrin in the liver (Kummer & Van Sittert, 1984, 1986). It was
    concluded that endrin accumulated in most of the farmers after three
    applications within a short period. An increase to toxic levels might
    result if spraying were more frequent and at shorter intervals and if
    the recommended clothing was not worn.

    9.2.4  Appraisal of effects of occupational exposures

         Endrin is a very toxic compound. Several episodes of fatal and
    non-fatal poisoning have occurred, mostly from accidental
    contamination of food and also from intentional (suicidal) ingestion.
    The lethal oral dose is estimated to be 10 mg/kg body weight. In
    non-fatal cases, recovery is rapid and complete within a few days. The
    oral dose that causes a single convulsion is estimated to be 0.25
    mg/kg body weight, and that which induces repeated convulsions, 1.0
    mg/kg body weight.

         Exposure of workers to endrin for long periods did not induce
    adverse effects that were attributed to this compound, although
    occasional cases of acute, non-fatal intoxication due to accidental
    over-exposure have occurred. Endrin was not detected in the blood of
    workers exposed to endrin at < 3.0 µg/litre. The threshold level of
    endrin in blood that results in intoxication is estimated to be 50-100
    µg/litre. Absorption of a toxic dose is therefore unlikely during
    occupational exposure if recommended controls and precautions are
    used. In fatal cases, endrin concentrations in blood as high as 450
    µg/litre have been reported; however, it is not possible to establish
    a dose-response relationship. Since endrin is not normally found in
    air, water, or food, except under conditions of contamination,
    exposure of the general population is not significant.

        Table 28.  Concentrations of endrin in blood from acutely over-exposed workers
                                                                                    
    Case                Time of first     Endrin concentration (µg/litre)
                        sampling                                                   
                                          First    12 h     24 h     36 h    5 days
                                          sample   later    later    later   later
                                                                                    
    Formulator          1 h after         90                                 ND
                        accident

    Operator            40 min after      27       25                ND
                        accident

    Formulator          Directly after    80                20               ND
    without dust-mask   convulsion

    Four colleagues     Same time         ND-10
    with dust-masks     time as above
                                                                                    
    ND, not detectable (< 5 µg/litre)
    
    10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Endrin was evaluated by the Joint FAO/WHO Expert Committee on
    Pesticide Residues in 1963, 1965, and 1970 (FAO/WHO, 1964, 1965,
    1971). In 1970, the Committee established an acceptable daily intake
    (ADI) for humans of 0-0.0002 mg/kg body weight, which was based on the
    level that causes no toxicological effect in rats and dogs, 1 mg/kg of
    diet (equivalent to 0.05 mg/kg body weight per day in rats and 0.025
    mg/kg body weight per day in dogs).

         The Joint FAO/WHO Codex Alimentarius Commission has published
    maximum residue limits for endrin (Table 29; (FAO/WHO, 1986b).

    Table 29.  Codex maximum limits for the sum of residues of
               endrin and delta-ketoendrin
                                                        
    Commodity                      Maximum residue limit
                                   (mg/kg product)
                                                        
    Apples                         0.02a
    Barley                         0.02a
    Cottonseed                     0.1
    Cottonseed oil (crude)         0.1
    Cottonseed oil (edible)        0.02a
    Eggs (without shells)          0.2
    Meat (carcass fat)             0.1b
    Milk                           0.0008b
    Poultry (carcass fat)          1
    Rice (husked or polished)      0.02a
    Sorghum                        0.02a
    Sweet maize                    0.02a
    Wheat                          0.02a
                                                        
    aAt or near the limit of detection
    bExtraneous residue limit

         The International Agency for Research on Cancer (IARC) concluded
    in 1974 and 1987 that there was inadequate evidence for the
    carcinogenicity of endrin in experimental animals and that the
    evidence from studies in humans was inadequate. Endrin was therefore
    classified in Group 3: not classifiable as to its carcinogenicity to
    humans (IARC, 1974, 1987).

         In 1988, the Pesticide Development and Safe Use Unit, Division of
    Vector Biology and Control, WHO, classified technical-grade endrin as
    highly hazardous in normal use (WHO, 1992). A data sheet on endrin was
    issued in 1978 (WHO/FAO, 1975).

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    ANNEX I  CHEMICAL NAMES OF ENDRIN AND ITS METABOLITES

         Two main systems are currently used for the nomenclature of
    cyclodiene insecticides: 'polyhydroaromatic' names, used by Chemical
    Abstracts (American Chemical Society) and the International Union for
    Pure and Applied Chemistry (IUPAC), and the von Baeyer/IUPAC system
    for polycyclic aliphatic compounds. Benson (1969) and Bedford (1974)
    proposed that the latter system be used for the cyclodiene
    insecticides.

         The 'polyaromatic' system has, unfortunately, been subject to
    historical variation, and there are differences between the IUPAC,
    British and American conventions for defining the three-dimensional
    stereochemistry in this system. As a consequence of differences in the
    numbering of carbon atoms in the two systems and the modification of
    the Chemical Abstracts 'polyaromatic' name for dieldrin since 1971,
    considerable confusion can arise in the nomenclature of metabolites.
    The possible misunderstandings that may occur, particularly among
    people who are not familiar with the various conventions of chemical
    nomenclature, are illustrated by the different names that are given to
    the major metabolite of endrin; this one compound may be designated
    as:

               anti-9-hydroxyendrin (former Chemical Abstracts system)
               anti-8-hydroxyendrin (current Chemical Abstracts system)
               anti-12-hydroxyendrin (von Baeyer/IUPAC system).

         A useful discussion of nomenclature was given by Brooks (1974).

         The chemical names for endrin and its metabolites are summarized
    in Table 30.

        Table 30.  Chemical nomenclature of endrin and its metobolites
                                                                                                                                    
    Trivial namesa               Polycyclic aliphatic name (von Baeyer/ IUPAC)        Alternative or former names
                                                                                                                                    
    Endrin (I)                   1,8,9,10,11,11-Hexachloro-4,5- exo-epoxy-2,3-7, 6-   1,2,3,4,10,10-Hexachloro-6,7-epoxy-1,4,
                                  endo-2,1-7,8- endo-tetracyclo[6.2.1.13,6.02,7]-     4a,5,6,7,8,8a-octahydro-1,4- endo,endo-
                                 dodec-9-ene                                          5,8-demethanonaphthalene (former CAS
                                                                                      name)

                                                                                      1aa,2b,2ab,3a,6a,6b,7b,7a)-3,4,5,6,9,9-
                                                                                      Hexachloro-1a,2,2a,3,6,6a,7,7a,-octahydro-
                                                                                      2,7:3,6-dimethanonaphth[2,3- b]oxirene
                                                                                      (current CAS name)

                                                                                      (IR,4S,4aS,5S,7R,8R,8aR)-1,2,3,4,10,10-
                                                                                      Hexachloro-1,4,4a,5,6,7,8,8a-octahydro-6,7-
                                                                                      epoxy-1,5:5,8-dimethanonaphthalene
                                                                                      (current IUPAC name)

     syn-12-Hydroxyendrin (II)    1,8,9,11,11-Hexachloro-4,5- exo-epoxy-12-
    (9- syn-hydroxyendrin)        ( syn-epoxy)hydroxy-2,3-7,6- endo-2,1-7,8- endo-
                                 tetracyclo[6.2.1.13,6.02,7] dodec-9-ene

     anti-12-Hydroxyendrin (III)  1,8,9,10,11,11-Hexachloro-4,5- exo-epoxy-12-
    (9- anti-hydroxyendrin)       ( anti-epoxy)hydroxy-2,3-7,6- endo-2,1-7,8-
                                  endo-tetracyclo[6.2.1.13,6.02,7]dodec-9-ene

    3-Hydroxyendrin (IV)         1,8,9,10,11,11-Hexachloro-4,5- exo-epoxy-3-
    (5-hydroxyendrin)            hydroxy-2,3-7,6- endo-2,1-7,8- endo-tetracyclo-
                                 [6.2.1.13,6.02,7] dodec-9-ene

    12-Ketoendrin (V)            1,8,9,10,11,11-Hexachloro-4,5 - exo-epoxy-2,3-7,6-
    (9-ketoendrin)                endo-2,1-7,8- endo-tetracyclo[6.2.1.13,6.02,7]-
                                 dodec-12-one

    Endrin  trans-diol (IV)       1,8,9,10,11,11-Hexachloro-4,5-( exo)trans-dihydroxy-
                                 2,3-7,6- endo-2,1-7,8- endo-tetracyclo[6.2.1.13,6.02,7]
                                 dodec-9-ene
                                                                                                                                    
    aRoman numerals in parentheses refer to the structures in Figure 2.
    
    ANNEX II

    MEDICAL TREATMENT OF ENDRIN POISONING

    1.  Symptoms of poisoning

         Endrin is readily absorbed and is toxic when taken by mouth, by
    skin contact (especially liquid formulations), and by inhalation. It
    stimulates the central nervous system, and an oral dose of 0.25 mg/kg
    body weight can cause convulsions in humans. Following accidental
    ingestion or gross over-exposure, symptoms appear between 20 min and
    12 h and may include headache, dizziness, nausea, vomiting, weakness
    in the legs, and convulsions, sometimes leading to death.

         Organochlorine compounds can cause respiratory depression, and
    they may sensitize the heart to endogenous catecholamines, leading to
    ventricular fibrillation and cardiac arrest in severe cases.
    Respiratory depression may lead to metabolic acidosis, and if
    necessary blood gases should be checked. Use of an
    electrocardiographic monitor is recommended if symptoms are severe.

         Endrin is eliminated very quickly from the blood and can be
    detected for only 1 or 2 days even after massive over-exposures. Signs
    and symptoms of poisoning occur only at levels in whole blood of above
    0.05 µg/ml.

    2.  Medical treatment

         Medical treatment is largely symptomatic and supportive and is
    directed against convulsions and hypoxia. If endrin is swallowed, the
    stomach should be emptied as soon as possible by careful gastric
    lavage (with a cuffed endotracheal tube already in place), avoiding
    aspiration into the lungs. In a rural situation where this is not
    feasible, vomiting should be induced immediately. This should be
    followed by (intragastric) administration of 50 g of activated
    charcoal and 30 g of magnesium or sodium sulfate in a 30% aqueous
    solution. Oily purgatives are contraindicated, and no fats, oils, or
    milk should be given.

         If convulsions occur, anticonvulsants should be given immediately
    but slowly, and repeated as necessary. Diazepam can be given at 10 mg
    (children, 1-5 mg) intravenously; thiopental sodium or hexobarbital
    sodium can be given intravenously at a dose of 10 mg/kg, with a
    maximum total dose of up to 750 mg for an adult; or paraldehyde can be
    given at 5 ml by intramuscular injection. These short-acting
    anticonvulsants should always be followed by phenobarbital given
    orally at 3 mg/kg (up to 200 mg for an adult), or phenobarbital sodium
    given intramuscularly at 3 mg/kg (up to 200 mg for an adult).

         Morphine and its derivatives, adrenaline and noradrenaline,
    should never be given.

         The airway must be kept unobstructed. Respiratory inadequacy,
    which may be accentuated by barbiturate anticonvulsants, should be
    corrected, and oxygen and/or artificial ventilation may be needed.

         A guideline for the management of major status epilepticus is
    added as Annex III.

    ANNEX III

    MANAGEMENT OF MAJOR STATUS EPILEPTICUS IN ADULTSa

    1.  Initial management

         1.   Assess the patient, verify the diagnosis, remove false
              teeth, place the patient in a lateral semi-prone position,
              and establish an airway.

         2.   Give diazepam intravenously (see Note 1, below), usually at
              10 mg in 2 ml (0.15-0.25 mg/kg), followed immediately by a
              further 10 mg (2 ml) over 1-2 min. This may be repeated
              according to response.

         3.   Take blood to measure levels of anticonvulsant drug,
              ethanol, and blood sugar (5 ml of blood in a sugar tube); a
              sample to measure calcium (5 ml in a plain tube); and a drop
              of blood to determine blood glucose.

         4.   If the latter measurement shows low blood glucose level, 25
              ml of 50% glucose should be given intravenously, preferably
              by catheter and not into a small distal vein. If ethanol is
              likely to be present, give thiamine intravenously at 100 mg.

         5.   Give phenytoin intravenously at 250 mg in 5 ml (10-15 mg/kg)
              no faster than 50 mg (1 ml)/min by infusion pump or slow
              intravenous injection (see Note 2, below).

    2.  If fits continue, transfer patient to the intensive care unit and
        consult an anaesthetist

         6.   Give chlormethiazole intravenously at 8 mg/ml: a loading
              dose of up to 800 mg (100 ml) over 10 min at 10 ml/min,
              maintained with 0.5-1 ml/min (4-8 mg).

         7.   Give thiopentone intravenously at 5 mg/kg as a loading dose,
              then 1-3 mg/kg per h to a maximum blood level of 100
              mg/litre.

         8.   If this fails, consult a neurologist.

    3.  Notes

         1.   Diazepam: A bolus injection of 10 mg may cause respiratory
              depression and hypotension, which may be pronounced if there
              is concurrent use of other central nervous system depressant
              drugs, especially phenobarbital.

                 
    aAdapted from guidelines issued at Guy's Hospital, London

              Diazepam must  not be given intramuscularly:

              --added to an intravenous infusion
              --with phenobarbital, unless artificial ventilation is
                available.

              Rectal administration of diazepam (using a rectal
              administration set), at 5 or 10 mg in 2.5 ml, may be used
              for the immediate treatment of epilepsy instead of
              intravenous diazepam.

         2.   Phenytoin must  not be given:

              --intramuscularly
              --by central line
              --into a dextrose infusion
              --with any other drug.

              Intravenously administered phenytoin should be monitored by
              continuous electrocardiographic recording. If this is not
              available, it may be safer to use a diluted solution of 250
              mg (5 ml) in 250 ml of normal saline, no faster than 50
              mg/min. The diluted solution should be used immediately
              provided there is no evidence of precipitation (this use of
              phenytoin is not licensed).

    4.  Options

              The following drugs may also be used:

         1.   Paraldehyde: 2 x 5 ml by separate deep intramuscular
              injection or 10 ml diluted in 100 ml of normal saline given
              intravenously over  10-15 min. Note: Paraldehyde should be
              administered only with glass syringes.

         2.   Phenobarbital: 200 mg/ml, should not be given intravenously
              except when artificial ventilation is available, and not at
              all if the patient normally takes phenobarbital. The maximal
              rate of infusion is 100 mg/min to a maximum dose of 15
              mg/kg.

         3.   Lignocaine: 100 mg by slow intravenous injection, followed
              by 50-100 mg in 250 ml of 5% dextrose at 1-2 mg/min. Note:
              This treatment must be monitored by electrocardigram.

         4.   Diazepam: 10 mg in 2 ml intravenously, or 40 mg in 500 ml of
              5% dextrose at a maximal infusion rate of 100 mg/h.

         5.   Sodium valproate: 400 mg in 4 ml, or 400-800 mg
              intravenously over 3-5 min (up to 10 mg/kg), followed by
              intravenous. infusion to a maximum of 2.5 g/day
              (unlicensed).

    5.  Paediatric doses

         For children, dosing should be adapted as follows:

              Diazepam:              0.2-0.3 mg/kg intravenously
              Phenytoin:             10-20 mg/kg intravenously
              Chlormethiazole:       5-10 mg/kg per h, equivalent to
                                     0.6-1.25 ml/kg per h

    RESUME ET EVALUATION; CONCLUSIONS; RECOMMANDATIONS

    Résumé et évaluation

    Exposition

         L'endrine est un insecticide organochloré utilisé depuis les
    années 1950 contre toute sorte de ravageurs, qui s'attaquent notamment
    au coton mais également au riz, à la canne à sucre, au maïs et à
    d'autres cultures. On l'utilise également comme rodenticide et
    avicide. Il est disponible dans le commerce sous forme de poudres, de
    granulés, de pâtes et de concentrés émulsionnables.

         L'endrine pénètre principalement dans l'atmosphère par
    volatilisation et dispersion. En général, la volatilisation se produit
    après épandage sur le sol et sur les récoltes et elle est tributaire
    de nombreux facteurs comme la teneur en matières organiques et en eau
    du sol, l'humidité, les courants aériens et l'aire foliaire des
    végétaux.

         C'est principalement par lessivage à partir du sol que se produit
    la contamination des eaux superficielles. Les précipitations, qu'il
    s'agisse de neige ou de pluie, n'ont qu'une part négligeable dans
    cette contamination.

         Localement, une contamination peut également se produire par
    suite du déversement d'effluents industriels ou de négligences dans
    les techniques d'épandage.

         C'est principalement par suite d'un épandage direct sur les
    terrains et les récoltes que l'endrine pénètre dans le sol. Elle peut
    y être retenue, transportée ou dégradée, en fonction d'un certain
    nombre de facteurs. C'est dans les sols riches en matières organiques
    que la rétention est la plus importante. La persistance de l'endrine
    dépend dans une large mesure des conditions locales; sa demi-vie dans
    le sol peut aller jusqu'à 12 ans. La disparition de l'endrine présente
    en surface s'effectue principalement par volatilisation et
    photodécomposition. Sous l'influence de la lumière solaire
    (rayonnement ultra-violet), l'endrine est isomérisée en delta-
    cétoendrine. En présence de lumière solaire intense, on a observé une
    isomérisation de 50% de l'endrine en l'espace de sept jours.
    L'isomérisation peut également s'effectuer par action microbienne
    (champignons et bactéries), notamment en anaérobiose.

         Les invertébrés aquatiques et les poissons absorbent rapidement
    l'endrine présente dans l'eau mais, transvasés dans une eau non
    contaminée, les poissons exposés éliminent sans délai le pesticide. En
    cas d'exposition continue, le facteur de bioconcentration peut
    atteindre 14-18 000.

         Il est possible que les invertébrés terricoles absorbent
    facilement l'endrine. La présence occasionnelle de faibles quantités
    d'endrine dans l'air ainsi que dans les eaux de surface, notamment
    destinées à la consommation, en zone agricole, n'a guère d'importance
    au point de vue de la santé publique. La seule vole d'exposition
    importante est la voie alimentaire. En général, toutefois, les
    quantités ingérées se situent très largement en-dessous de la dose
    journalière admissible qui a été fixée à 0,0002 mg/kg de poids
    corporel en 1970 (FAO/OMS, 1971).

    1.2  Absorption, métabolisme et excrétion

         Contrairement à la dieldrine, son stéréoisomère, l'endrine est
    rapidement métabolisée par l'organisme animal et, comparativement à
    d'autres composés de structure chimique semblable, elle s'accumule
    très peu dans les tissus adipeux.

         L'absorption et l'excrétion sont rapides après administration
    orale à des rats et la demi-vie biologique se situe entre 1 et 6 jours
    selon les quantités ingérées. Un régime stationnaire, c'est à dire un
    état d'équilibre entre la quantité excrétée et la dose ingérée,
    s'établit au bout de 6 jours. On constate une différence entre les
    deux sexes en ce sens que les mâles excrètent l'endrine et ses
    métabolites par la voie biliaire plus rapidement que les femelles,
    d'où une moindre accumulation de pesticides dans les tissus adipeux
    des mâles. Les rats excrètent ce composé principalement dans leurs
    matières fécales sous forme d'endrine, d' anti-12-hydroxyendrine
    ainsi que sous la forme d'un dérivé hydroxyle de l'endrine, en
    l'espace de 24 heures (70-75 %); un troisième métabolite, la 12-
    cétoendrine, s'accumule dans les tissus. Les lapins excrètent 50% des
    métabolites de l'endrine par la voie urinaire, l'excrétion urinaire
    n'étant que de 2% chez le rat; dans les matières fécales des lapins,
    on ne retrouve que de l'endrine non modifiée.

         Des vaches à qui l'on avait administré de l'endrine à raison de
    0, 1 mg/kg de nourriture pendant 21 jours en ont excrété jusqu'à 65%
    sous forme de métabolites urinaires, 20% sous forme de métabolites
    fécaux ou d'endrine non modifiée et 3% dans leur lait, cette fois,
    principalement sous forme d'endrine non modifiée. Chez ces vaches, les
    résidus atteignaient 0,003-0,006 mg/litre dans le lait, 0,001-0,002
    mg/kg dans la viande, et 0,02-0,1 mg/kg dans la graisse.

         Chez des poules pondeuses ayant reçu une alimentation additionnée
    d'endrine, on a observé des résidus (selon la dose ingérée) qui
    atteignaient 0.1 mg/kg dans la chair, 1 mg/kg dans la graisse, 0,2-0,3
    mg/kg dans les oeufs (jaune), 0,2 mg/kg dans les reins et 0,5 mg/kg
    dans le foie. Sauf dans le cas du foie et des reins, les résidus
    présents étaient essentiellement formés d'endrine non modifiée.
    Environ 50% de la quantité d'endrine administrée a été excrétée dans
    les matières fécales, principalement sous la forme de métabolites.

         Chez l'homme, le rat, le lapin, la vache et la poule, le
    principal métabolite de l'endrine est l' anti-12-hydroxyendrine,
    accompagnée de ses sulfo- et glucuro-conjugués. On trouve également 4
    autres métabolites, mais en quantités minimes. Dans les tissus et le
    lait on retrouve essentiellement de l'endrine non modifiée. Après
    épandage sur des végétaux, on a retrouvé de l'endrine sous forme non
    modifiée ainsi que deux produits de transformation hydrophiles.

    1.3  Effets sur les êtres vivants dans leur milieu naturel

         L'endrine n'exerce que des effets minimes sur les bactéries et
    les champignons terricoles. Aux doses de 10-1000 mg/kg de terre, le
    composé n'a aucun effet sur la décomposition des matières organiques,
    sur la dénitrification ou sur la production de méthane. L'endrine est
    très toxique pour les poissons, les invertébrés aquatiques et le
    phytoplancton; la CL 50 à 96 h, est dans la plupart des cas
    inférieure à 1,0 µg/litre. La dose nocive la plus faible observée au
    cours d'un test portant sur le cycle évolutif d'un crevette,
     Mysidopsis bahia, était de 30 ng/litre.

         Les épreuves de toxicité aiguë effectuées sur des organismes
    aquatiques ont été pratiquées dans des aquariums ne comportant pas de
    sédiments, on peut penser que la présence de sédiments atténue l'effet
    de l'endrine. D'ailleurs la présence de sédiments fortement contaminés
    n'a guère eu d'effet sur les espèces de pleine eau, ce qui incite à
    penser que l'endrine fixée aux sédiments présente une faible
    biodisponibilité. On n'a pas pratiqué d'épreuves sur des animaux
    aquatiques vivant dans les sédiments.

         Pour les mammifères terrestres et les oiseaux, la DL50 est de
    l'ordre de 1,0-10,0 mg/kg de poids corporel. Des canards de l'espèce
     Anas platyrhynchos qui avaient reçu pendant 12 semaines de l'endrine
    dans leur nourriture à des doses allant jusqu'à 3,0 mg/kg de poids
    corporel, n'ont présenté aucun effet délétère que ce soit sur la
    ponte, la fécondité ou l'éclosion des oeufs.

         Il semblerait que certaines espèces d'invertébrés aquatiques, de
    poissons et de petits mammifères résistent à l'action toxique de
    l'endrine; d'ailleurs l'exposition à divers pesticides organochlorés
    a pu entraîner la sélection de souches résistantes à l'endrine.

         Dans des zones où existent des décharges industrielles et où
    l'endrine peut être entraînée par ruissellement à partir des champs
    traités, on a observé une mortalité parmi les poissons; par ailleurs,
    le déclin des populations de pélicans bruns (en Louisiane) et de
    caugeks (aux Pays-Bas) a été attribuée à une exposition à l'endrine et
    à d'autres dérivés halogénés.

    1.4  Effets sur les animaux d'expérience et sur les systèmes in vitro

         L'endrine est un pesticide fortement toxique dont les signes
    d'intoxication sont de type neurologiques. Chez les animaux de
    laboratoire, la DL50 par voie orale de l'endrine de qualité
    technique se situe dans les imites de 3-43 mg/kg de poids corporel; la
    DL50 dermique va de 5-20 mg/kg de poids corporel pour le rat. Il n'y
    a pas de différence notable concernant la toxicité aiguë par voie
    orale et percutanée entre le produit technique et les diverses
    formulations (concentrés émulsionnables ou poudres mouillables).

         Des épreuves de courte durée portant sur la toxicité par voie
    orale de l'endrine ont été effectuées sur (les souris, des rats, des
    lapins, des chiens et autres animaux domestiques. Chez les souris et
    les rats, les doses maximales tolérées ont été respectivement de 5 et
    15 mg/kg de nourriture pendant 6 semaines (soit l'équivalent de 0,7
    mg/kg de poids corporel). Les rats ont survécus à une dose de 1 mg/kg
    de nourriture pendant 16 semaines (soit l'équivalent de 0,05 mg/kg de
    poids corporel); les lapins sont morts après avoir reçu à plusieurs
    reprises une dose de 1 mg/kg de poids corporel. chez le chien, une
    dose de 1 mg/kg de nourriture (soit approximativement 0,025 mg/kg de
    poids corporel) administrée sur une période de 2 ans, n'a produit
    aucun effet.

         Du point de vue neurologique, les signes d'intoxication observés
    sont dus à l'inhibition de la fonction de l'acide gamma-aminobutyrique
    (GABA) à faible dose. Comme les autres hydrocarbures chlorés
    insecticides, l'endrine agit également au niveau du foie et la
    stimulation des systèmes enzymatiques intervenant dans le métabolisme
    des autres substances chimiques se manifeste, notamment chez la
    souris, par une diminution de la durée du sommeil induit par
    l'hexobarbital.

         Des doses de 75-150 mg/kg appliquées sur l'épiderme des lapins
    sous forme de poudre sèche, tous les jours pendant deux heures ont
    entraîné des convulsions et la mort chez ces animaux sans toutefois
    provoquer d'irritation cutanée. Cette intoxication par voie générale
    sans irritation locale mérite d'être signalée.

         Des études de toxicité et de cancérogénicité à long terme ont été
    effectuées sur des souris et des rats. Aucun effet cancérogène n'a été
    observé mais ces études présentaient un certain nombre d'insuffisances
    notamment la faible survie des animaux. Lors d'une étude de deux ans
    sur des rats traités par de l'endrine administrée dans leur
    nourriture, on a estimé à 1 mg/kg de nourriture, soit l'équivalent
    d'environ 0,05 mg/kg de poids corporel, la dose sans effets toxiques
    observables. Après administration d'endrine avec des quantité
    infinitésimales de substances chimiques cancérogènes pour l'animal, il
    n'a pas été possible de mettre en évidence d'effet tumoro-promoteur.
    Le Groupe de travail en a conclu que les données sont insuffisantes
    pour permettre de considérer l'endrine comme cancérogène pour l'homme.

         Plusieurs études ont également révélé que l'endrine n'était pas
    génotoxique.

         Dans la plupart des études, l'endrine s'est révélée non
    tératogène pour la souris, le rat ou le hamster, même à des doses
    toxiques pour la mère ou le foetus. La dose sans effet nocif
    observable a été évaluée à 0,5 mg/kg de poids corporel chez la souris
    et le rat et à 0,75 mg/kg de poids corporel chez les hamsters.
    L'endrine n'a pas eu d'effets sur la reproduction des rats suivis
    pendant trois générations qui en recevaient dans leur nourriture à
    raison de 2 mg/kg (soit environ 0, 1 mg/kg de poids corporel).

         Un certain nombre de métabolites de l'endrine sont plus ou moins
    toxiques que le composé initial. Ainsi la delta-cétoendrine est moins
    toxique de l'endrine, en revanche la 12-cétoendrine est considérée
    comme le métabolite le plus toxique de l'endrine pour les mammifères,
    avec une DL50 par voie orale de 0,8-1,1 mg/kg de poids corporel chez
    le rat.

    1.5  Effets sur l'homme

         Plusieurs cas d'intoxication mortels ou non mortels consécutifs
    à un accident ou à une tentative de suicide ont été observés. Les cas
    d'intoxication aiguë non mortels résultant d'une, surexposition
    accidentelle ont été observés chez les ouvriers d'une usine de
    production d'endrine. On estime que par voie orale, la dose mortelle
    est (l'environ 10 mg/kg de poids corporel, une dose unique prise par
    voie orale de 0,25-1,0 mg/kg de poids corporel peut provoquer des
    convulsions.

         C'est au niveau du système nerveux central que l'endrine exerce
    principalement son action. Après exposition à dose toxique, des signes
    d'intoxication peuvent faire leur apparition et se manifestent sous la
    forme d'un hyperexcitabilité et de convulsions, la mort pouvant
    survenir dans les 2-12 heures suivant l'exposition si un traitement
    approprié n'est pas institué immédiatement. En revanche, après une
    intoxication non mortelle, la récupération est rapide et complète.

         L'endrine ne s'accumule pas dans le corps humain de manière
    importante. Chez 232 travailleurs exposés de par leur profession, on
    n'a pas constaté d'effets indésirables à long terme (durée
    d'exposition 4-27 ans) lors des examens médicaux pratiqués (durée de
    l'observation 2-29 ans). Le seul effet observé, indirectement
    d'ailleurs, consistait en une stimulation réversible des enzymes
    pharmacométabolisantes.

         Des analyses ont été pratiquées dans de nombreux pays sur un
    grand nombre d'échantillons de tissus adipeux, de sang et de lait
    maternel sans qu'il soit possible de mettre en évidence la présence
    d'endrine. Le Groupe de travail attribue l'absence d'endrine dans ces

    échantillons à la faible exposition de la population général à ce
    pesticide et à sa métabolisation rapide.

         En revanche la présence d'endrine a été décelée dans le sang (à
    des concentrations atteignant 450 µg/litre) et dans les tissus adipeux
    (à la dose de 89,5 mg/kg) chez les personnes décédées d'une
    intoxication accidentelle. Dans les conditions normales, on n'a pas
    retrouvé d'endrine chez les travailleurs exposés. Le seuil
    d'apparition des symptômes d'intoxication est estimé à 50-100 µg/litre
    de sang. On pense que la demi-vie de l'endrine dans le sang est de
    l'ordre de 24 heures.

    2.  Conclusions

         L'endrine est un 'Insecticide qui présente une très forte
    toxicité aiguë. Il peut entraîner des intoxications graves en cas
    d'exposition excessive due à une manipulation négligente lors de sa
    production, de son utilisation ou par suite de la consommation
    d'aliments contaminés. L'exposition de la population générale est
    principalement due à la présence de résidus dans les denrées
    alimentaires; toutefois on estime que la quantité d'endrine ingérée
    est en général très inférieure à la dose journalière admissible fixée
    par le Comité FAO/OMS d'experts des résidus de pesticides. Il n'y a
    pas de danger pour la population générale qui résulterait d'une
    exposition de ce genre à l'endrine. Moyennant de bonnes méthodes de
    travail et le respect des mesure d'hygiène et de sécurité, l'endrine
    ne devrait pas constituer un danger pour les ouvriers exposés.

         Il est évident que des rejets incontrôlés d'endrine lors de la
    production, de la formulation et de l'utilisation de ce pesticide
    peuvent créer des problèmes écologiques dus à sa forte toxicité. Il
    n'est pas possible d'être aussi catégorique en ce qui concerne les
    effets que peut avoir son utilisation en agriculture sur la faune et
    la flore, encore que l'entraînement par ruissellement du pesticide
    puisse constituer une menace pour les poissons et les oiseaux
    piscivores. Le déclin des populations de certaines espèces d'oiseaux
    a été attribué à la présence de résidus élevés de divers organochlorés
    dans les tissus des adultes et dans les oeufs. On a procédé au dosage
    de l'endrine chez certaines de ces espèces; toutefois il est difficile
    de faire la part des différents organochlorés qui sont en cause.

    3.  Recommandations

         1.   L'endrine ne doit être utilisée qu'en cas de nécessité et
              seulement lorsqu'il n'existe pas d'autre produit moins
              toxique.

         2.   Afin de préserver la santé et le bien-être des travailleurs
              et de la population générale, on ne doit confier la
              manipulation et l'épandage qu'à des personnes bien encadrées
              et bien formées qui appliqueront des mesures de sécurité

              convenables et épandront le produit conformément aux règles
              de bonne pratique en la matière.

         3.   Il convient de s'entourer de toute les précautions
              nécessaires lors de la production, de la formulation, de
              l'utilisation en agriculture et du rejet de l'endrine afin
              de contaminer le moins possible l'environnement et en
              particulier les eaux de surface.

         4.   Les personnes qui sont habituellement exposées à l'endrine
              doivent subir des examens médicaux périodiques.

         5.   Il faut poursuivre l'étude épidémiologique des travailleurs
              exposés.

         6.   Dans les pays où l'on utilise encore de l'endrine, on devra
              contrôler la présence de résidus d'endrine dans les denrées
              alimentaires.

         7.   Au cas où l'on continuerait à utiliser de l'endrine, il
              faudrait obtenir davantage de données sur la présence, la
              destinée ultime et la toxicité de la 12-cétoendrine et de la
              delta-cétoendrine.

    RESUMEN Y EVALUACION; CONCLUSIONES; RECOMENDACIONES

    1.  Resumen y evaluación

    1.1  Exposición

         La endrina es un insecticida organoclorado que se utiliza desde
    los años cincuenta para combatir muy diversas plagas agricolas, sobre
    todo en el algodón aunque también en el arroz, la caña de azúcar, el
    maíz y otros cultivos. Se utiliza asimismo como rodenticida. En el
    comercio se encuentra en forma de polvos, gránulos, pastas y
    concentrado emulsionable.

         La endrina se incorpora al aire principalmente por volatilización
    y arrastre aéreo. En general, la volatilización tiene lugar después de
    aplicarla a suelos y cultivos y depende de muchos factores, como el
    contenido de materia orgánica y agua del suelo, la humedad, el flujo
    de aire y la superficie cultivada.

         La vía más importante de contaminación de las aguas de superficie
    es la escorrentía desde el suelo. La contaminación por precipitación
    en forma de nieve o lluvia es insignificante. Puede producirse
    contaminación local del medio debida a efluentes industriales y
    prácticas de aplicación poco meticulosas.

         La principal fuente de endrina en el suelo es la aplicación
    directa a éste y a los cultivos. Puede quedar retenida, ser
    transportada o degradarse en el suelo, atendiendo a diversos factores.
    La retención más intensa se produce en suelos con contenido elevado de
    materia orgánica. La persistencia de la endrina depende en gran medida
    de las condiciones locales; su semivida en el suelo puede llegar a los
    12 años. La volatilización y la fotodescomposición son los principales
    factores de la desaparición de la endrina de las superficies del
    suelo. La luz del sol (luz ultravioleta) induce la formación del
    isómero delta-cetoendrina. En verano, bajo insolación intensa, se
    observó que alrededor del 50% de la endrina se isomerizaba a esta
    cetoendrina en un plazo de siete días. Se produce transformación
    microbiana (en hongos y bacterias), especialmente en condiciones
    anaerobias, originándose la misma sustancia.

         Los invertebrados acuáticos y los peces absorben rápidamente la
    endrina a partir del agua, si bien los peces expuestos transferidos a
    agua no contaminada pierden el plaguicida rápidamente. Se han
    registrado factores de bioconcentración de 14-18 000 tras una
    exposición continua. Los invertebrados del suelo también absorben
    fácilmente el compuesto.

         La presencia ocasional de niveles reducidos de endrina en el aire
    y en las aguas de superficie y de bebida en zonas agrícolas reviste
    escasa importancia desde el punto de vista de la salud pública. La
    única exposición que merece consideración es la ingesta en la dieta.

    En general, no obstante, los niveles comunicados de ingesta se
    encuentran muy por debajo de la ingesta diaria admisible de 0,0002
    mg/kg de peso corporal, establecida en 1970 (FAO/OMS, 1971).

    1.2  Absorción, metabolismo y excreción

         A diferencia de la dieldrina, su estereoisómero, la endrina se
    metaboliza rápidamente en los animales, y se acumula en muy pequeña
    cantidad en las grasas en comparación con compuestos de estructura
    química análoga.

         En la rata, tanto la absorción como la excreción tras la
    administración oral se producen rápidamente; su semivida biológica es
    de 1-6 días, según la dosis administrada. Al cabo de 6 días se alcanza
    un estado de equilibrio en el que la cantidad excretada es igual a la
    ingesta diaria. Se observan diferencias de un sexo a otro: los machos
    excretan endrina y metabolitos con la bilis mucho más deprisa que las
    hembras, lo que produce una acumulación menor en el tejido adiposo de
    aquéllos. Las ratas excretan este compuesto principalmente en las
    heces en forma de endrina, anti-12-hidroxiendrina, y un derivado
    hidroxilado durante las primeras horas (70-75%); un tercer metabolito,
    la 12-cetoendrina, se acumula enlos tejidos. El conejo excreta el 50%
    de los metabolitos del compuesto enla orina, mientras que en la rata
    sólo el 2% se excreta por esta vía; en lasheces del conejo sólo se
    detecta endrina sin alterar.

         Las vacas a las que se administró endrina a razón de 0,1 mg/kg de
    la dieta durante 21 días excretaron hasta el 65% en forma de
    metabolitos en la orina, el 20% en las heces, parcialmente en forma de
    endrina no alterada, y el 3% en la leche, también principalmente en
    forma de endrina. Estas vacas presentaron niveles residuales de
    0,003-0,006 mg/litro en la leche, 0,001-0,002 mg/kg en la carne, y
    0,02-0,1 mg/kg en la grasa.

         En gallinas ponedoras a las que se administró endrina por vía
    oral seobservaron niveles residuales (dependientes de la dosis
    administrada) de hasta 0,1 mg/kg en la carne, 1 mg/kg en la grasa,
    0,2-0,3 mg/kg en los huevos (yema), 0,2 mg/kg en el riñón y 0,5 mg/kg
    en el hígado. Salvo en el hígado y el riñón, los residuos encontrados
    estaban formados principalmente por endrina no alterada. Alrededor del
    50% de la endrina administrada se excretó en las heces, principalmente
    en forma de metabolitos.

         En el ser humano, la rata, el conejo, la vaca y la gallina, el
    principal metabolito biotransformado de la endrina es la
     anti-12-hidroxiendrina, junto con su sulfato y su glucur nido
    conjugados. Se encontraron cuatro metabolitos más, si bien en
    cantidades muy reducidas. En los tejidos corporales y en la leche se
    encuentra sobre todo endrina inalterada. Tras la aplicación de este
    plaguicida a plantas, seidentificaron endrina inalterada y dos
    productos de transformación hidrófilos.

    1.3  Efectos en los organismos del medio ambiente

         El efecto de la endrina en las bacterias y los hongos del suelo
    es mínimo. Con dosis de 10-1000 mg/kg de suelo no se observó efecto
    alguno en la descomposición de materia orgánica, la desnitrificación
    ni la generación de metano. La endrina es sumamente tóxica para los
    peces, los invertebrados acuáticos y el fitoplancton: los valores de
    la CL50 a las 96 horas se encuentran en su mayoría por debajo de 1,0
    µg/litro. El nivel sin observación de efectos más bajo en un ensayo de
    ciclo biológico del crustáceo Mysidopsis bahia se fijó en 30 ng/litro.

         Los ensayos comunicados sobre la toxicidad aguda de la endrina
    para los organismos acuáticos se llevaron a cabo en acuarios sin
    sedimentos; cabría esperar que la presencia de sedimentos atenuara el
    efecto del insecticida. Los sedimentos muy contaminados ejercieron
    escaso efecto en las especies de aguas libres, lo que indica que la
    endrina ligada a los sedimentos tiene una biodisponibilidad reducida.
    Aún no se han llevado a cabo ensayos en animales acuáticos que viven
    en los sedimentos.

         La DL50 para mamíferos terrestres y aves oscila entre 1,0 y
    10,0 mg/kg de peso corporal. Los patos silvestres a los que se
    administraron 3,0 mg/kg de peso corporal durante 12 semanas no
    mostraron efecto alguno en la producción de huevos, la fertilidad o la
    eclosión.

         Ciertas especies de invertebrados acuáticos, peces y mamíferos de
    pequeño tama o son resistentes a la toxicidad de la endrina; la
    exposición a diversos plaguicidas organoclorados llevó a la selección
    de estirpes resistentes a la endrina.

         Se observaron muertes masivas de peces en zonas de escorrentía
    agrícola y descargas industriales; el declive de las poblaciones de
    pelícanos pardos (en Luisiana, EE.UU.) y de golondrinas de mar
    (Thalasseus sandvicensis) en los Países Bajos se ha atribuido a la
    exposición a la endrina en combinación con otras sustancias químicas
    halogenadas.

    1.4  Efectos en animales de experimentación in vitro

         La endrina es un plaguicida sumamente tóxico; los signos de
    intoxicación son de carácter neurotóxico. La DL50 por vía oral de la
    endrina de calidad técnica en animales de laboratorio oscila entre 3
    y 43 mg/kg de peso corporal; la DL50 por vía cutánea en la rata es
    de 5-20 mg/kg peso corporal. No se ha encontrado ninguna diferencia en
    la toxicidad aguda por vía oral o cutánea entre los productos de
    calidad técnica y los formulados (concentrado emulsionable y polvos
    humectables).

         Se han llevado a cabo experimentos de breve duración para
    estudiar la toxicidad por vía oral en el ratón, la rata, el conejo, el
    perro y animales domésticos. En el ratón y la rata, las dosis máximas
    toleradas durante 6 semanas fueron 5 y 15 mg/kg de la dieta
    (equivalentes a 0,7 mg/kg de peso corporal), respectivamente. Las
    ratas sobrevivieron tras una exposición a 1 mg/kg de la dieta
    (equivalente a 0,05 mg/kg de peso corporal) durante 16 semanas; los
    conejos murieron tras recibir dosis repetidas de 1 mg/kg de peso
    corporal. En el perro, no se observó efecto alguno tras la
    administración de 1 mg/kg de la dieta (equivalente aproximadamente a
    0,025 mg/kg de peso corporal) durante más de 2 años.

         La base neuroógica de los signos de intoxicación observados es la
    inhibición de la función del ácido gamma-aminobutírico (GABA) con
    dosis reducidas. Al igual que otros insecticidas a base de
    hidrocarburos clorados, la endrina afecta también al hígado, y se
    observa claramente la estimulación de sistemas enzimáticos que
    participan en el metabolismo de otras sustancias químicas, como lo
    demuestra, por ejemplo, la menor duración del sueño por hexobarbital
    en el ratón.

         Con dosis de 75-150 mg/kg aplicadas por vía cutánea en forma de
    polvo seco durante 2 horas al día se produjeron convulsiones y la
    muerte en el conejo pero sin irritación cutánea. Esta toxicidad
    sistémica sin irritación en el lugar de contacto resulta muy notable.

         Se han llevado a cabo en ratones y ratas estudios prolongados de
    toxicidad y carcinogenicidad. No se observó efecto carcinogénico, pero
    estos estudios tenían ciertos defectos, entre ellos la reducida
    supervivencia de los animales. El nivel sin observación de efectos en
    cuanto a la toxicidad en un estudio de dos años de duración en la rata
    fue de 1 mg/kg de la dieta (equivalente a unos 0,05 mg/kg de peso
    corporal). No se demostró ningún efecto de favorecimiento de tumores
    cuando se ensayó la endrina en combinación con cantidades submínimas
    de sustancias químicas de conocido efecto carcinogénico en los
    animales. El Grupo de Trabajo concluyó que los datos de que se dispone
    no bastan para indicar que la endrina supone un riesgo carcinogénico
    para el ser humano.

         En varios estudios se observó que la endrina no es genotóxica.

         En la mayoría de los estudios no resultó teratogénica para el
    ratón, la rata o el hámster, ni siquiera con dosis suficientes para
    provocar toxicidad materna o fetal. El nivel sin observación de
    efectos adversos fue de  0,5 mg/kg de peso corporal en ratones y ratas
    y de 0,75 mg/kg de peso corporal en el hámster. La endrina no indujo
    efecto alguno en la reproducción de ratas estudiadas durante tres
    generaciones cuando se administró a razón de 2 mg/kg de la dieta (unos
    0,1 mg/kg de peso corporal).

         Algunos metabolitos de la endrina tienen toxicidades agudas
    iguales o más altas que el compuesto originario. El producto de
    transformación, la delta-cetoendrina, es menos tóxico que la endrina,
    pero la 12-cetoendrina se considera el metabolito más tóxico en los
    mamíferos, con una DL50 por vía oral en la rata de 0,8-1,1 mg/kg de
    peso corporal.

    1.5  Efectos en el ser humano

         Se han producido varios episodios de intoxicación mortal y no
    mortal, tanto accidentales como suicidas. Los casos de intoxicación
    aguda no mortal debida a exposición excesiva accidental se observaron
    en trabajadores de una planta de fabricación de endrina. Se ha
    calculado que la dosis que por vía oral provoca la muerte es de
    aproximadamente 10 mg/kg de peso corporal; la dosis única por vía oral
    que provoca convulsiones se fijó en 0,25-1,0 mg/kg de peso corporal.

         El lugar principal de acción de la endrina es el sistema nervioso
    central. La exposición del ser humano a una dosis tóxica puede
    producir al cabo de pocas horas signos y síntomas de intoxicación
    tales como excitabilidad y convulsiones; la muerte puede producirse en
    las 2-12 horas que siguen a la exposición si no se administra
    inmediatamente el tratamiento apropiado. La recuperación después de
    una intoxicación no mortal es rápida y completa.

         La endrina no se acumula en el cuerpo humano en grado
    significativo. No se comunicaron efectos adversos a largo plazo en 232
    trabajadores expuestos (duración de la exposición: 4-27 años) bajo
    supervisión médica (tiempo de observación: 4-29 años). El único efecto
    observado fueron pruebas indirectas de una estimulación reversible de
    las enzimas metabolizadoras de fármacos.

         No se detectó endrina en prácticamente ninguna muestra de tejido
    adiposo, sangre y leche humana analizadas en numerosos países. El
    Grupo de Trabajo atribuyó la ausencia de endrina en las muestras
    humanas a la baja exposición de la población general a este plaguicida
    y a su rápido metabolismo.

         La endrina se detectó en la sangre (con concentraciones de hasta
    450 µg/litro) y en el tejido adiposo (en concentraciones de 89,5
    mg/kg) en casos de envenenamiento accidental mortal. No se encontró
    endrina en los trabajadores en circunstancias normales. El nivel
    umbral de endrina en la sangre por debajo del cual no se produce
    ningún signo o síntoma de intoxicación se ha fijado en 50-100
    µg/litro. La semivida de la endrina en la sangre puede ser del orden
    de 24 horas.

    2.  Conclusiones

         La endrina es un insecticida con elevada toxicidad aguda. Puede
    provocar envenenamiento grave en casos de exposición excesiva
    provocada por un manejo poco meticuloso durante su fabricación y uso
    o por el consumo de alimentos contaminados. El público está expuesto
    a la endrina principalmente por sus residuos en los alimentos; no
    obstante, los niveles de ingesta de endrina que se han comunicado
    están por lo general muy por debajo de la ingesta diaria admisible
    establecida por la FAO/OMS. Esas exposiciones en principio no
    constituyen un riesgo para la salud de la población general. Cuando se
    aplican buenas prácticas de trabajo, medidas higiénicas y precauciones
    de seguridad, es poco probable que la endrina suponga un riesgo para
    los trabajadores expuestos.

         Está claro que las descargas no controladas de endrina durante su
    manufactura, formulación y uso pueden originar graves problemas
    ambientales asociados a su elevada toxicidad. Los efectos del uso
    agrícola del insecticida en la fauna y la flora están menos claros, si
    bien los peces y las aves ictívoras están expuestos por la escorrentía
    a partir de las superficies. El declive de las poblaciones de algunas
    especies de aves se ha atribuido a la presencia de niveles elevados de
    residuos de diversos compuestos organoclorados en los tejidos de
    adultos y en los huevos. Se ha medido la endrina presente en algunas
    de estas especies, pero es muy difícil separar los efectos de los
    distintos compuestos organoclorados presentes.

    3.  Recomendaciones

         1.   No debe utilizarse la endrina a menos que sea indispensable
              y sólo cuando no se disponga de una alternativa menos
              tóxica.

         2.   Para la salud y el bienestar de los trabajadores y de la
              población general, el manejo y el uso de la endrina se
              confiarán sólo a operarios bien supervisados y adiestrados
              que apliquen las medidas de seguridad adecuadas y utilicen
              la endrina de acuerdo con las prácticas agrícolas correctas.

         3.   La fabricación, la formulación, el uso agrícola y la
              evacuación de endrina se tratarán cuidadosamente para
              reducir al mínimo la contaminación del medio, en particular
              de las aguas de superficie.

         4.   Las personas expuestas regularmente a la endrina deben
              someterse a revisiones médicas periódicas.

         5.   Proseguirán los estudios epidemiológicos sobre las
              poblaciones de trabajadores expuestos.

         6.   En los países en los que aún se usa la endrina, deben
              vigilarse sus residuos en los alimentos.

         7.   Si sigue utilizándose la endrina, debe obtenerse más
              información sobre la presencia, el destino último y la
              toxicidad de la 12-cetoendrina y la delta-cetoendrina.


    See Also:
       Toxicological Abbreviations
       Endrin (HSG 60, 1991)
       Endrin (ICSC)
       Endrin (FAO Meeting Report PL/1965/10/1)
       Endrin (AGP:1970/M/12/1)
       Endrin (WHO Pesticide Residues Series 4)
       Endrin (WHO Pesticide Residues Series 5)
       Endrin (IARC Summary & Evaluation, Volume 5, 1974)