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    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 197






    Demeton-S-methyl






        The issue of this document does not constitute formal publication.
    It should not be reviewed, abstracted, or quoted without the written
    permission of the Manager, International Programme on Chemical Safety,
    WHO, Geneva, Switzerland.

    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.


    Environmental Health Criteria  197


    First draft prepared by Dr. A. Moretto, Institute of Occupational
    Medicine, University of Padua, Italy


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.

    World Health Organization
    Geneva, 1997

         The International Programme on Chemical Safety (IPCS) is a joint
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    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Demeton-S-Methyl.

    (Environmental health criteria ; 197)

    1.Insecticides, Organophosphate - toxicity
    2.Insecticides, Organophosphate - adverse effects
    3.Environmental exposure                      4.Occupational exposure
    I.International Programme on Chemical Safety  II.Series

    ISBN 92 4 157197 7                 (NLM Classification: WA 240)
    ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL

    PREAMBLE

    ABBREVIATIONS

    1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

         1.1. Summary and evaluation
               1.1.1. Identity, physical and chemical properties, and
                       analytical methods
               1.1.2. Sources of human and environmental exposure
               1.1.3. Environmental transport, distribution and
                       transformation
               1.1.4. Environmental levels and human exposure
               1.1.5. Kinetics and metabolism
               1.1.6. Effects on laboratory animals and  in vitro
                       test systems
                       1.1.6.1   Single exposure
                       1.1.6.2   Short-term exposure
                       1.1.6.3   Long-term exposure
                       1.1.6.4   Skin and eye irritation and
                                 sensitization
                       1.1.6.5   Reproduction, embryotoxicity and
                                 teratogenicity
                       1.1.6.6   Mutagenicity and related end-points
                       1.1.6.7   Delayed neurotoxicity
                       1.1.6.8   Toxicity of metabolites
               1.1.7. Mechanism of toxicity - mode of action
               1.1.8. Effects on humans
               1.1.9. Effects on other organisms in the laboratory
                       and field
         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
         2.5. Formation of derivatives during storage

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrences
         3.2. Man-made sources
               3.2.1. Production
               3.2.2. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
         4.2. Abiotic and biotic transformation
               4.2.1. Hydrolytic degradation
               4.2.2. Photodegradation
               4.2.3. Degradation in soil
               4.2.4. Biodegradation in plants

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. General population exposure
         5.2. Occupational exposure during manufacture, formulation or
               use

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

         6.1. Absorption, distribution and excretion
         6.2. Metabolic transformation

    7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

         7.1. Single exposure
               7.1.1. Oral
               7.1.2. Inhalation
               7.1.3. Dermal
         7.2. Short-term exposure
               7.2.1. Rat
               7.2.2. Dog
         7.3. Long-term exposure
               7.3.1. Mouse
               7.3.2. Rat
         7.4. Skin and eye irritation and sensitization
               7.4.1. Skin and eye irritation
               7.4.2. Skin sensitization
         7.5. Reproduction, embryotoxicity and teratogenicity
               7.5.1. Reproduction
               7.5.2. Embryotoxicity and teratogenicity
                       7.5.2.1   Rat
                       7.5.2.2   Rabbit
         7.6. Mutagenicity and related end-points
               7.6.1. DNA damage and repair
               7.6.2. Mutation
               7.6.3. Chromosomal effects
         7.7. Delayed neurotoxicity
         7.8. Toxicity of metabolites
         7.9. Mechanism of toxicity - mode of action
         7.10. Potentiation

    8. EFFECTS ON HUMANS

         8.1. General population exposure
         8.2. Occupational exposure
               8.2.1. Acute poisoning
               8.2.2. Effects of short- and long-term exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         9.1. Aquatic organisms
               9.1.1. Algae
               9.1.2. Invertebrates
               9.1.3. Fish
         9.2. Terrestrial organisms
               9.2.1. Soil microorganisms
               9.2.2. Invertebrates
               9.2.3. Birds
               9.2.4. Effects in field

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

         10.1. Evaluation of human health risks
         10.2. Evaluation of effects on the environment
               10.2.1. Aquatic organisms
                       10.2.1.1  Acute risk
                       10.2.1.2  Chronic risk
               10.2.2. Terrestrial organisms
                       10.2.2.1  Birds
                       10.2.2.2  Mammals
                       10.2.2.3  Bees
                       10.2.2.4  Earthworms

    11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RÉSUMÉ ET ÉVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    RÉSUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

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    Environmental Health Criteria

    PREAMBLE

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    FIGURE 1

    150 EHC contact points throughout the world who are asked to comment
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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL

     Members

    Dr P.J. Abbott, Australia and New Zealand Food Authority
         (ANZFA), Canberra, Australia

    Dr K. Barabas, Department of Public Health, Albert Szent-Gyorgyi,
         University Medical School, Szeged, Hungary

    Dr A.L. Black, Woden, ACT, Australia

    Professor J.F. Borzelleca, Pharmacology and Toxicology,
         Richmond, Virginia, USA

    Dr P.J. Campbell, Pesticides Safety Directorate, Ministry of
         Agriculture, Fisheries and Food, Kings Pool, York,
         United Kingdom

    Professor L.G. Costa, Department of Environmental Health,
         University of Washington, Seattle, USA

    Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
         Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom

    Dr I. Dewhurst, Mammalian Toxicology Branch, Pesticides Safety
         Directorate, Ministry of Agriculture, Fisheries and Food,
         Kings Pool, York, United Kingdom

    Dr V. Drevenkar, Institute for Medical Research and Occupational
         Health, Zagreb, Croatia

    Dr W. Erickson, Environmental Fate and Effects Division,
         US Environmental Protection Agency, Washington, D.C., USA

    Dr A. Finizio, Group of Ecotoxicology, Institute of Agricultural
         Entomology, University of Milan, Milan, Italy

    Mr K. Garvey, Office of Pesticide Programs (7501C),
         US Environmental Protection Agency, Washington, D.C., USA

    Dr A.B. Kocialski, Health Effects Division, Office of Pesticide
         Programs, US Environmental Protection Agency,
         Washington, D.C., USA

    Dr A. Moretto, Institute of Occupational Medicine, University
         of Padua, Padua, Italy

    Professor O. Pelkonen, Department of Pharmacology and
         Toxicology, University of Oulu, Oulu, Finland

    Dr D. Ray, Medical Research Council Toxicology Unit, University
         of Leicester, Leicester, United Kingdom

    Dr J.H.M. Temmink, Department of Toxicology, Wageningen
         Agricultural University, Wageningen, The Netherlands

     Observers

    Dr J.W. Adcock, AgrEvo UK Limited, Chesterford Park, Saffron,
         Waldon, Essex, United Kingdom

    Mr D. Arnold, Environmental Sciences, AgrEvo UK Ltd.,
         Chesterford Park, Saffron Waldon, Essex, United Kingdom

    Dr E. Bellet, CCII, Overland Park, Kansas, USA

    Mr Jan Chart, AMVAC Chemical Corporation, Newport Beach,
         California, USA

    Dr H. Egli, Novartis Crop Protection AG, Basel, Switzerland

    Dr P. Harvey, AgrEvo UK Ltd., Chesterford Park, Saffron Walden,
         Essex, United Kingdom

    Dr G. Krinke, Novartis Crop Protection AG, Basel, Switzerland

    Dr A. McReath, DowElanco Limited, Letcombe Regis, Wantage,
         Oxford, United Kingdom

    Dr H. Scheffler, Novartis Crop Protection AG, Basel, Switzerland

    Dr A.E. Smith, Novartis Crop Protection AG, Basel, Switzerland

     Secretariat

    Dr L. Harrison, Health and Safety Executive, Bootle, Merseyside,
         United Kingdom

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

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

    Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

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

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

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

    IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR DEMETON-S-METHYL

         The Core Assessment Group (CAG) of the Joint Meeting on
    Pesticides (JMP) met at the Institute for Environment and Health,
    Leicester, United Kingdom, from 3 to 8 March 1997. Dr L.L. Smith
    welcomed the participants on behalf of the Institute, and
    Dr R. Plestina on behalf of the three IPCS cooperating organizations
    (UNEP/ILO/WHO). The CAG reviewed and revised the draft monograph and
    made an evaluation of the risks for human health and the environment
    from exposure to demeton-S-methyl.

         The first draft of the monograph was prepared by Dr A. Moretto,
    Institute of Occupational Medicine, University of Padua, Italy.
    Extensive scientific comments were received following circulation of
    the first draft to the IPCS contact points for Environmental Health
    Criteria monographs and these comments were incorporated into the
    second draft by the Secretariat.

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

    ABBREVIATIONS

    ACGIH     American Conference of Governmental Industrial Hygienists
    AChE      acetylcholinesterase
    ADI       acceptable daily intake
    a.i.      active ingredient
    BuChE     butyrylcholinesterase
    b.w.      body weight
    ChE       cholinesterase
    EC50      median effective concentration
    GLC       gas-liquid chromatography
    HID       highest ineffective dose
    I50       concentration inhibiting 50% of the enzyme activity
    i.p.      intraperitoneal administration
    i.v.      intravenous administration
    JMPR      Joint Meeting on Pesticide Residues
    Kd        sorption coefficient
    LC50      median lethal concentration
    LD50      median lethal dose
    LED       lowest effective dose
    LOEC      lowest-observed-effect concentration
    MRL       maximum residue level
    NT        not tested
    NTE       neuropathy target esterase
    NOAEL     no-observed-adverse-effect level
    NOEC      no-observed-effect concentration
    PEC       predicted environmental concentration
    RBC       red blood cell
    s.c.      subcutaneous
    SCE       sister chromatid exchange
    STS       standard type of soil
    TER       toxicity-exposure ratio
    TLC       thin layer chromatography
    TLV       threshold limit value
    TWA       time-weighted average

    1.  SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS

    1.1  Summary and evaluation

    1.1.1  Identity, physical and chemical properties, and analytical
           methods

         Demeton-S-methyl, a pale yellow oily liquid with a penetrating
    odour, is a systemic and contact organophosphate insecticide and
    acaricide used to control  Acarina, Thysanoptera, Hymenoptera and
     Homoptera in fruits, cereals, ornamentals and vegetables. It has a
    vapour pressure of 63.8 mPa at 20°C, is readily soluble in most
    organic solvents, has a high water solubility of 3.3 g/litre at room
    temperature and an octanol-water partition coefficient (log Pow) of
    1.32. Demeton-S-methyl is stable in non-aqueous solvents.

         Residual and environmental analyses are performed by extraction
    with an organic solvent, followed by oxidation to the corresponding
    sulfone. Measurement is then performed by gas chromatography, using a
    phosphorus-specific detector.

    1.1.2  Sources of human and environmental exposure

         Prior to 1957, methyl-demeton was marketed as a mixture of
    demeton-S-methyl and demeton-O-methyl isomers.

         Demeton-S-methyl has been in use since 1957. It is formulated as
    an emulsifiable concentrate and used as a spray on cereals, fruits,
    ornamentals and vegetables. It is being replaced by oxydemeton-methyl,
    which is a plant, soil and mammalian metabolite of demeton-S-methyl.

    1.1.3  Environmental transport, distribution and transformation

         Hydrolytic degradation of demeton-S-methyl depends on the pH of
    the solution; at 22°C the half-life is 63 days at pH 4, 56 days at pH
    7 and 8 days at pH 9. In soil, biodegradation is the primary route of
    degradation. The half-life of demeton-S-methyl in soil is about 4 h.
    However, after 24 h, oxydemeton-methyl still represents 20-30% of the
    applied dose of demeton-S-methyl. The sorption coefficient (Kd) of
    demeton-S-methyl in soil is 0.68 to 2.66, depending on the soil
    composition.

         Photolysis is not one of the major mechanisms of degradation of
    demeton-S-methyl in the environment.

         Metabolism in spring wheat is rapid and similar to that in soil
    and mammals.

    1.1.4  Environmental levels and human exposure

         Primary exposure for the general human population is from
    residues of demeton-S-methyl on food crops. The Joint FAO/WHO Meeting
    on Pesticide Residues (JMPR) recommended acceptable daily intake (ADI)
    is 0.0003 mg/kg body weight. This is a group ADI for demeton-S-methyl,
    oxydemeton-methyl and demeton-S-methyl-sulfone, since the routine
    analytical methods do not discriminate between these three compounds.

         Excessive dermal exposure and absorption of demeton-S-methyl has
    caused cholinergic toxicity in workers inadequately protected during
    packaging of the concentrate formulation.

         When volunteers engaged in a simulated spray activity with a
    mixture of demeton-S-methyl and demeton-O-methyl (30 and 70%,
    respectively) were exposed to 8.8-27 mg/m3 of the two active
    ingredients combined, they experienced no adverse effects on plasma or
    erythrocyte cholinesterase activities.

    1.1.5  Kinetics and metabolism

         Demeton-S-methyl is rapidly and almost completely absorbed from
    the intestinal tract of rats and is uniformly (except for high
    concentration in erythrocytes) distributed to body tissues. It is
    rapidly metabolized and excreted via the urine. Blood concentration
    decreases with an initial half-life of about 2 h. About 1% of the oral
    dose is present in the body 24 h after treatment. The main metabolic
    pathway of demeton-S-methyl in rats is the oxidation of the side
    chain leading to the formation of the corresponding sulfoxide
    (oxydemeton-methyl) and, to a lesser extent, after further oxidation,
    to the sulfone. Another important metabolic route is O-demethylation.

    1.1.6  Effects on laboratory animals and in vitro test systems

    1.1.6.1  Single exposure

         Demeton-S-methyl causes cholinergic toxicity. The LD50 values
    for mammals range from 7 to 100 mg/kg body weight, depending on the
    route of administration and species.

    1.1.6.2  Short-term exposure

         An early dietary study showed that rats fed demeton-S-methyl at
    50 mg/kg diet had substantially reduced brain and erythrocyte
    cholinesterase activity after 26 weeks of exposure. Cholinergic signs
    were observed in rats fed 200 mg/kg diet during the first 5 weeks of
    exposure.

         In a one-year dietary study on dogs, a no-observed-adverse-effect
    level (NOAEL) of 1 mg/kg diet (equal to 0.036 mg/kg body weight per
    day) was established, based on effects on brain cholinesterase.

    1.1.6.3  Long-term exposure

         Mice were fed diets containing 0, 1, 15 or 75 mg/kg demeton-S-
    methyl for 21 months. The NOAEL was found to be 1 mg/kg diet (equal to
    0.24 mg/kg body weight per day) based on inhibition of brain
    cholinesterase.

         In rats fed diets containing 0, 1, 7 or 50 mg/kg demeton-S-
    methyl, the NOAEL, based on inhibition of brain cholinesterase, was
    1 mg/kg diet (equal to 0.05 mg/kg body weight per day).

         No increased tumour incidence was found in either species.

    1.1.6.4  Skin and eye irritation and sensitization

         Demeton-S-methyl is a mild skin and eye irritant. Positive
    results were obtained with the Magnusson and Klingman maximization
    test in guinea-pigs. However, the Buehler epidermal patch test gave no
    indication of skin sensitization, suggesting that sensitization should
    not be a problem in the practical use of demeton-S-methyl.

    1.1.6.5  Reproduction, embryotoxicity and teratogenicity

         In a two-generation dietary rat study, demeton-S-methyl caused
    reduced viability and body weight of pups (F1b generation only)
    at a dose level of 5 mg/kg diet. The NOAEL was 1 mg/kg diet, equal to
    0.07 mg/kg body weight per day.

         Demeton-S-methyl was neither embryotoxic nor teratogenic in rats
    and rabbits.

    1.1.6.6  Mutagenicity and related end-points

         Demeton-S-methyl induces point mutations  in vitro. Chromosomal
    effects have been demonstrated  in vivo with commercial formulations
    only. The available information is insufficient to permit an adequate
    assessment of the genotoxic potential of demeton-S-methyl.

    1.1.6.7  Delayed neurotoxicity

         Demeton-S-methyl caused neither delayed polyneuropathy nor
    inhibition of neuropathy target esterase (NTE) when tested in hens at
    a level equal to the oral LD50.

    1.1.6.8  Toxicity of metabolites

         Two plant and mammalian metabolites of demeton-S-methyl
    (i.e. oxydemeton-methyl and demeton-S-methylsulfone) are also
    commercial pesticides and have been extensively studied. It has been

    reported that the toxicological profile of these two compounds does
    not significantly differ, either quantitatively or qualitatively, from
    that of demeton-S-methyl.

    1.1.7  Mechanism of toxicity - mode of action

         Demeton-S-methyl is a direct cholinesterase inhibitor, and the
    toxicity it causes is related to inhibition of acetylcholinesterase
    (AChE) at nerve terminals. AChE inhibited by demeton-S-methyl
    reactivates spontaneously with an  in vitro half-life of about 1.3 h,
    as expected for dimethyl phosphorylated AChE.

    1.1.8  Effects on humans

         A few cases of acute intoxication with cholinergic syndrome,
    following suicide attempts, have been reported. Surviving patients,
    including a pregnant woman, did not show delayed effects.

         Following careless occupational exposure during packaging of
    the commercial formulation, some workers developed cholinergic
    toxicity which required pharmacological treatment. Absorption of
    demeton-S-methyl was probably through the skin. Similarly, improper
    working conditions may have caused excessive dermal absorption during
    application of demeton-S-methyl in cotton fields.

    1.1.9  Effects on other organisms in the laboratory and field

         The 96-h EC50s for green algae range from 8 to 37 mg/litre. The
    LC50s for a range of aquatic invertebrates range from 0.004 to
    1.3 mg/litre. The toxicity for fish varies, with 96-h LC50 ranging
    from 0.59 mg/litre for the rainbow trout to about 40 mg/litre for the
    golden orfe, the goldfish and the carp.

         The acute oral LD50 for the Japanese quail and the canary is
    10-50 mg/kg body weight. In starlings, a single oral dose of 2 mg/kg
    body weight caused 20% inhibition of brain AChE 3 h after treatment.

         The LC50 of demeton-S-methyl in soil for earthworms is 66 mg/kg
    for 14 days. The acute oral and contact LD50 for demeton-S-methyl are
    0.21 and 0.6 µg/bee respectively. When used on winter wheat at the
    suggested rate, demeton-S-methyl significantly reduced the number of
    crop foliage invertebrates (mainly  Empididae flies) but not the
    number of soil surface entomophagous invertebrates.

    1.2  Conclusions

         Demeton-S-methyl is a highly toxic (class Ib of the WHO
    classification) (WHO, 1996) organophosphorus ester insecticide. The
    mechanism of toxicity is that of AChE inhibition at nerve terminals.
    Exposure of the general population results mainly from residues
    present in crop commodities.

         With good work practices, hygienic measures and safety
    precautions, the use of demeton-S-methyl during manufacture or
    application should not cause adverse effects. Effects due to chronic
    exposure are unlikely to occur.

         Demeton-S-methyl does not persist in the environment and is not
    accumulated by organisms. It has high acute toxicity to aquatic
    invertebrates and is toxic to fish and birds, leading to high or
    moderate risk factors for these organisms. However, significant field
    kills of organisms have not been reported for the compound.
    Precautions should be taken to minimize exposure of non-target
    organisms (e.g., do not spray over water bodies, minimize exposure by
    spray drift).

    1.3  Recommendations

         For the health and welfare of workers and the general population,
    the handling and application of demeton-S-methyl should only be
    entrusted to supervised and well-trained operators who follow the
    required safety measures and good application practices.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    Chemical formula:             C6H15O3PS2

    Chemical structure:

                                                O
                                                "
                                  CH3CH2SCH2CH2SP(OCH3)2

    Relative molecular mass:      230.3

    Common name:                  demeton-S-methyl

    CAS chemical name:            S-[2-(ethylthio)ethyl] O,O-dimethyl
                                  phosphorothioate

    IUPAC name:                   S-2-ethylthioethyl O,O-dimethyl
                                  phosphorothioate

    CAS registry number:          919-86-8

    RTECS number:                 TG1750000

    Common synonyms and           AI3-24963; BAY 18436; Bayer 18 436;
    trade names:                  Bayer 25/154; Demetox; DEP 836 349;
                                  Duratox; ethanethiol,
                                  2-(ethylthio)-S-ester with O,O-dimethyl
                                  phosphorothioate; HSDB 6410;
                                  Isometasystox; Isomethylsystox;
                                  Metaisoseptox; Metaisosystox; Metasystox
                                  (I); metasystox forte; Metasystox I;
                                  Metasystox J; Metasystox 55; methyl
                                  demeton thioester; methyl isosystox;
                                  methyl-mercaptofos teolery;
                                  methyl-mercaptofos teolovy (USSR);
                                  methylmercaptofostiol (USSR); Mifatox;
                                  O,O-dimethyl S-(2-(ethylthio)
                                  ethylphosphorothioate; O,O-dimethyl
                                  S-ethylmercaptoethyl thiophosphate;
                                  O,O-dimethyl 2-ethylmercaptoethyl
                                  thiophosphate, thiolo isomer;
                                  phosphorothioic acid, O,O-dimethyl
                                  S-(2-(ethylthio)ethyl) ester;
                                  phosphorothioic acid,

                                  S-(2-(ethylthio)ethyl) O,O-dimethyl
                                  ester; S-(2-(ethylthio)ethyl);
                                  dimethyl phosphorothiolate;
                                  S-(2-(Ethylthio)ethyl) O,O-dimethyl
                                  phosphorothioate (8CI)(9CI);
                                  S-(2-(ethylthio)ethyl) O,O-dimethyl
                                  phosphorothioate; S-(2-ethylthio)ethyl)
                                  O,O-dimethyl phosphorothioate;
                                  S-(2-ethylthioetyl)0,0-dimethyl
                                  phosphorothioate; S-2-Ethylthioethyl-
                                  dimethyl phosphorothioate; USP 2 571
                                  989; 2-Ethylthioethyl dimethyl
                                  phosphorothioate.

    Formulations:                 EC (250 or 500 g a.i./litre), DSM
                                  (Campbell), Metasystox55 (Bayer),
                                  Mepatox (FCC),
                                  EC (580 g/litre).

    Purity:                       >90%

    Impurities:                   O,O,S-trimethylthiophosphate (maximum of
                                  1.5%)

                                  O-methyl-S-2-(ethylmercapto)-ethylthioph
                                  osphate (maximum of 3.0%)

                                  2-ethylthioethylmercaptan max 0.8%
                                  bis(2-ethylthioethyl)-disulfide (maximum
                                  of 0.8%)

                                  Various ionic components (sulfonium
                                  compounds, organic salts) (total maximum
                                  of 2.5%)

                                  Oligomeric alkyl(thio) phosphates
                                  (maximum of 1.0%)

                                  Water (maximum of 0.1%)

    2.2  Physical and chemical properties

         Some relevant physical and chemical properties are summarized in
    Table 1.

    Table 1.  Some chemical and physical properties of demeton-S-methyl
                                                                        

    Physical state:               oily liquid

    Colour:                       pale yellow

    Odour:                        penetrating, reminiscent of leeks

    Boiling point                 74°C at 6.65 Pa (0.05 mmHg)
                                  92°C at 26.6 Pa (0.20 mmHg)
                                  102°C at 53.2 Pa (0.40 mmHg)
                                  118°C at 133 Pa (1.00 mmHg)

    Vapour pressure:              21.3 mPa (1.6 × 10-4 mmHg) at 10°C
                                  63.8 mPa (4.8 × 10-4 mmHg) at 20°C
                                  193 mPa (1.45 × 10-3 mmHg) at 30°C
                                  400 mPa (3.8 × 10-3 mmHg) at 40°C

    Relative density at 20°C:     1.21

     n-Octanol/water partition
    coefficient:                  log Pow = 1.32

    Solubility in water:          3.3 g/litre (at room temperature)

    Solubility in organic         readily soluble in most organic
    solvents:                     solvents; limited solubility in
                                  petroleum ether

    Stability:                    hydrolysed by alkali and oxidized to the
                                  sulfoxide (oxydemeton-methyl) and
                                  sulfone (demeton-S-methylsulfone)

                                  Half-life in water:  11 days at 37°C
                                  Half-lives at 22°C:  63 days at pH 4
                                                       56 days at pH 7
                                                       8 days at pH 9
                                                                        

    2.3  Conversion factors

         1 ppm = 9.42 mg/m3 (at 25°C)
         1 mg/m3 = 0.106 ppm

    2.4  Analytical methods

         Analytical methods for the determination of residues of the
    demeton-S-methyl group (i.e. demeton-S-methyl, its sulfoxide and its
    sulfone) are either identical or very similar.

         Originally, colorimetric methods (i.e. determination of total
    phosphorus) were used (FAO/WHO, 1993). Current methods are based on
    GLC. In principle, these methods involve an oxidation step, using
    potassium permanganate, to produce demeton-S-methylsulfone, which is
    then determined with a thermoionic emission detector.

         A GLC method (Wagner & Thornton, 1977) is suitable for
    determining residues in plants, soil and water. The method is based on
    the principle of oxidation described above, with variations depending
    on the sample to be analysed. Before the oxidation step, maceration
    with acetone is used for samples with a high fat or oil content. The
    macerate and water samples are then extracted with chloroform or
    dichloromethane. Since the analytical method involves the oxidation to
    the sulfone, the determination is of demeton-S-methylsulfone, from
    which the demeton-S-methyl residue can be calculated. The method was
    used to determine residues in a wide range of crops with a minimum
    recovery above 80%. The limit of determination depends upon the sample
    and generally lies between 0.01 and 0.2 mg/kg. Another method, based
    on similar principles, has been described for oxydemeton-methyl
    residues in plant and animal tissues and in soil (Thornton et al.,
    1977).

         An alternative GLC method for sulfides (including demeton-S-
    methyl), sulfoxides and sulfones has been proposed by Hill et al.
    (1984), who reported that the use of acetone as a co-solvent during
    potassium permanganate oxidation causes unpredictable (from negligible
    to complete) loss of demeton-S-methyl. These authors used ethyl
    acetate for extraction of organophosphorus compounds from fruit and
    vegetable samples (Anonymous, 1977). The extracts were cleaned-up by
    chromatography on a column of activated charcoal, magnesium oxide and
    Celite. The compounds were eluted from the column using a mixture of
    ethyl acetate, acetone and toluene. A mean recovery of >68% (mainly
    >80%) was found for a number of organophosphorus sulfides, sulfoxides
    and sulfones, that of demeton-S-methyl being 82.4±6.6% (mean ± SD,
    n=10) when determined in lettuce.

         Wilkins et al. (1985) reported the characterization of nearly
    90 organophosphorus sulfides, sulfoxides and sulfones by gas
    chromatography and mass spectrometry. Using similar experimental
    conditions with three different mass spectrometers, the spectra
    produced from a given compound were almost identical.

         A TLC method for 10 different organophosphorus insecticides
    (including demeton-S-methyl and demeton-S-methylsulfone) was reported
    by Funk et al. (1989). This method has a limit of detection of
    4-10 ng/spot.

    2.5  Formation of derivatives during storage

         Storage of "pure" demeton-S-methyl in the dark at room
    temperature leads to the formation of sulfonium derivatives. This was
    found to be associated with increased intravenous toxicity but not
    oral toxicity (Heath & Vandekar, 1957). Hecht (1960) reported that the
    oral toxicity in rat did not change if 4- or 24-hour-old aqueous
    solutions of demeton-S-methyl were used.

         The concentration in a water suspension of 1 g a.i./litre
    decreased by about 50 and 75% after 7 and 28 days of storage
    (apparently at 37°C), respectively (Hecht, 1960) (see also section
    7.1).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrences

         Demeton-S-methyl does not occur as a natural product.

    3.2  Man-made sources

    3.2.1  Production

         In 1954, a reaction mixture containing demeton-S-methyl and
    demeton-O-methyl (O-2-ethylthioethyl O,O-dimethyl phosphorothioate)
    was introduced by Farbenfabrik Bayer AG (now Bayer AG) with the common
    name of demeton-methyl. An improved manufacturing process led to the
    introduction, in 1957, of demeton-S-methyl by Bayer AG. Information on
    the global production is not available. It is formulated as an
    emulsifiable concentrate.

    3.2.2  Uses

         Demeton-S-methyl is a systemic and contact insecticide and
    acaricide used to control  Acarina, Thysanoptera, Hymenoptera and
     Homoptera on cereals, fruits, ornamentals and vegetables. It is
    applied as an emulsifiable concentrate formulation mainly as a spray
    and usually at a concentration of 0.025% a.i. (FAO/WHO, 1974). It has
    been reported that most national registrations for demeton-S-methyl
    should be transferred during the next few years to oxydemeton-methyl,
    which has similar use and is applied at similar rates (FAO/WHO, 1993).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         The sorption behaviour of demeton-S-methyl and three other
    organophosphorus pesticides in natural pond sediments was tested by
    Froebe et al. (1989). Two different sediments were used, containing
    9.3 and 6.2% organic matter, at pH 5.9 and 6.5, and a specific surface
    area of 23.7 and 16.7 m2/g, respectively. The semi-quantitative
    mineralogical composition was similar. For the four pesticides, their
    sorption coefficients (Kd) followed the same sequence as their
    lipophilicity (expressed as  n-octanol/water coefficient). The
    sorption efficiency for demeton-S-methyl was higher in the sediment
    with a lower content of organic matter (Kd of 0.689 and 2.66,
    respectively).

    4.2  Abiotic and biotic transformation

    4.2.1  Hydrolytic degradation

         In water at 22°C demeton-S-methyl has a half-life of 63 days at
    pH 4, 56 days at pH 7, and 8 days at pH 9. The main reactions are
    demethylation in acid medium and hydrolysis of the phosphorus-ester
    bond in basic medium (Krohn, 1984) (see also section 2.2).

    4.2.2  Photodegradation

         Demeton-S-methyl in aqueous solution does not absorb any light at
    247 nm or longer wavelengths. Therefore, no direct photo-degradation
    of demeton-S-methyl in the environment is to be expected
    (Hellpointner, 1990). When solutions of demeton-S-methyl in water
    (3.6-3.7 mg/litre) were irradiated for 8 h with a high-pressure
    mercury vapour lamp, no photodegradation was detected. However, when
    solutions were fortified with humic acid (10 mg/litre), the half-life
    of photodegradation was
    8 h (the degradation products were not identified). This suggests that
    degradation by sensitized or indirect photolysis may also occur in the
    environment (Wilmes, 1984).

    4.2.3  Degradation in soil

         The metabolism of demeton-S-methyl in soil is shown in Fig. 1.

         The ability of microbial organisms to biodegrade demeton-S-methyl
    sulfoxide was evaluated in a laboratory test and under aerobic
    conditions using various species  (Nocardia, Arthrobacter, 
     Corynebacter, Brevibacterium, Bacillus and Pseudomanas) and strains
    (Ziegler et al., 1980). Almost all the organisms were able to degrade
    the insecticide. The amount of insecticide degraded ranged between 65%
     (Arthrobacter roseoparaffineus) and 99%  (Pseudomonas putida) after
    14 days of incubation. The biodegradation process led to the

    FIGURE 1

    production of several metabolites. In particular,  P. putida and
     Nocardia sp. during growth were able to metabolize almost completely
    2 mmol/litre of demeton-S-methyl sulfoxide (99% and 98% respectively)
    within 13 days. Three major metabolites, i.e., O-demethyl-demeton-S-
    methyl, demeton-S-methyl sulfoxide and bis[2-ethylsulfinyl)ether]
    disulfide, were found to be produced by Pseudomonas, whereas Nocardia
    showed different pathways leading to the formation of different
    metabolites, i.e., 2-(ethylsulfonyl)ethane sulfonic acid,
    demeton-S-methyl sulfone and bis[2-(ethylthio)ethyl] disulfide. In
    sterile controls about 48% of the parent compound remained after 20
    days of incubation.

         In a laboratory study, biodegradation of demeton-S-methyl was
    investigated in two different standardized soils (S1, and S2) with
    different characteristics particularly in terms of organic matter
    content and cation exchange capability (Wagner et al., 1985). The
    study was conducted under aerobic and anaerobic conditions with
    sterile controls and using 14C-labelled demeton-S-methyl. One day
    after the start of the test no parent compound could be detected.
    After 63 days under aerobic conditions 54% (S1) and 34% (S2) of the
    14C activity applied was eliminated as 14CO2, indicating a higher
    activity in the soil with higher organic matter content and cation
    exchange capability. Various metabolites were isolated and identified
    (Fig. 1). Under anaerobic conditions 0.5% (S1) and 1.1% (S2) of the
    14C activity applied was eliminated as 14CO2, and there was a
    predominance of the metabolites O-demethyl-demeton-S-methyl and
    demeton-S-methyl sulfoxide. The half-lives of demeton-S-methyl were
    approximately 5 h in the non-sterile soil and 70 h in the sterile test
    control.

    4.2.4  Biodegradation in plants

         The metabolic behaviour of ethylene-1-14C demeton-S-methyl in
    spring wheat (Schirokko variety) was investigated in a greenhouse test
    (Wagner & Oehlmann, 1987). The distribution of the 14C radioactivity
    in the wheat matrix was determined at 3, 14, 42 and 60 days after
    application of demeton-S-methyl during crop stage 0 (flowering), and
    the isolated biotransformation products were analysed by spectroscopy.
    The composition of the applied spray was 241.5 µCi ethylene-1-14C
    demeton-S-methyl (corresponding to about 0.5 kg a.i./hectare as
    opposed to a use rate of 0.15 kg a.i./hectare) in 2 ml benzene plus
    1 drop emulsifier Np10 plus 20 ml water. The majority of the applied
    radioactivity was found in the wheat straw (about 85% of total
    radioactivity corresponding to 10.3 mg a.i. equivalents/kg, 60 days
    after application), while the amount in the kernels at harvest was
    substantially smaller (0.7 mg a.i. equivalents/kg). About 0.5 mg a.i.
    equivalents/kg could not be extracted with water and organic solvents,
    and 24% of the 14C activity could not be extracted from the straw
    using solvents of different polarity. Only a minor portion of the a.i.
    was detected 3 days after application. Identified metabolites were

    O,O-dimethyl-S-[2-(ethylsulfonyl)-ethyl]-thiophosphate (11.7% of
    recovered radioactivity at 60 days), O,O-dimethyl-S-[2-
    (ethylsulfonyl)-ethyl]-thiophosphate (9.8% of recovered radioactivity
    at 60 days), 2-ethylsulfonyl-ethanesulfonic acid (8.2% of recovered
    radioactivity at 60 days), S-(2-(ethylsulfonyl)-ethyl)-thiophosphate
    (5.2% of recovered radioactivity at 60 days), 1-(ethylsulfinyl)-2-
    (methylsulfinyl)-ethane (8.9% of recovered radioactivity at 60 days),
    and 2-ethylsulfinylethanol (5.1% of recovered radioactivity at 60
    days). Additional biotransformation products occurred to a minor
    extent (<0.2%) in the kernels only.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  General population exposure

         Data on residues in crops resulting from the use of demeton-S-
    methyl have been summarized by FAO/WHO (1974). Maximum residue limits,
    varying from 0.01 to 1 mg/kg, have been recommended for a range of
    commodities. These residue limits were previously expressed as
    demeton-S-methyl but now as oxydemeton-methyl, and are common for
    demeton-S-methyl, oxydemeton-methyl and demeton-S-methylsulfone
    (see section 2.4). More updated values referring to the use of
    oxydemeton-methyl have been reported by FAO/WHO (1993). Data on
    residue levels in meat and milk from cows, and in chickens, eggs and
    fish have been reported for oxydemeton-methyl in the same document
    but not for demeton-S-methyl. Some data are also available for
    demeton-S-methylsulfone (FAO/WHO, 1993). The JMPR recommended a group
    ADI of 0-0.003 mg/kg body weight for demeton-S-methyl,
    oxydemeton-methyl and demeton-S-methyl sulfone (FAO/WHO, 1990).

    5.2  Occupational exposure during manufacture, formulation or use

         When Metasystox (30% demeton-S-methyl, 70% demeton-O-methyl) was
    sprayed with a hand-held nebulizer, the concentration of the two
    active ingredients combined was 8.8-27 mg/m3 of ambient air (Klimmer
    & Pfaff, 1955; see also section 8.2.2).

         The ACGIH proposed a very conservative TLV/TWA for methyl-demeton
    of 0.5 mg/m3 with the "skin" notation (ACGIH, 1993). The "skin"
    notation indicates that dermal absorption is likely to occur and
    therefore adequate protective equipment should be used.

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption, distribution and excretion

         Absorption, distribution and excretion of (ethylene-1-14C)-
    demeton-S-methyl (93% radiochemical purity) were studied in SD SPF
    rats. Male rats (n=5 per group) were given a single oral dose of 0.1,
    0.5, 5 or 10 mg/kg body weight or a single intravenous dose of 0.5 or
    1 mg/kg body weight of radio-labelled compound. Female rats (n=5)
    received a single oral dose of 0.5 mg/kg body weight. Total
    radioactivity recovery was 90-100% in each animal. The authors
    reported that kinetic parameters did not change with dose or sex;
    therefore, only data on male rats given 5 mg/kg orally have been
    reported. Absorption after oral administration was rapid (peak blood
    concentration was reached within one hour) and almost complete (98-99%
    of the administered radioactivity was, in fact, eliminated through the
    urine). The blood concentration decreased with a half-life of about
    2 h during the first 6 h and then with a half-life of about 6 h for
    the next 48 h. The half-life thereafter was even longer. The
    radioactivity associated with erythrocytes accounted for almost all of
    the blood radioactivity found 24 h or more after dosing. The half-life
    of urinary elimination was 2-3 h during the first 24 h and 1.5 days
    thereafter. Elimination through faeces and exhaled air accounted for
    0.5-2% and about 0.2% of the applied dose, respectively. Except for
    erythrocytes, radioactivity was distributed rather uniformly in
    various body tissues and organs. At 2, 24 and 48 h after dosing, the
    radioactivity remaining in the body was about 60%, 1% and 0.5% of the
    administered dose, respectively. At 10 days, radioactivity was almost
    undetectable in most organs except in the erythrocytes. In a separate
    experiment, whole-body autoradiography indicated some localized
    accumulation of radioactivity in the pineal gland, thyroid and some
    glands of the genital tract (Cowper's gland, seminal vesicle,
    accessory genital gland). When the labelled compound (0.5 mg/kg body
    weight) was administered into the duodenum of rats with cannulated
    bile ducts, it was shown that about 3% of the radioactivity was
    excreted into the bile in the first 24 h (Weber et al., 1978).

    6.2  Metabolic transformation

         The proposed metabolic pathway of demeton-S-methyl in rats
    is shown in Fig. 2. This was derived from the analysis of urine
    samples of SD rats given a single oral dose of 5 or 10 mg/kg of
    (ethylene-1-14C)-demeton-S-methyl. Urine samples were collected
    for 8 or 24 h after dosing and there was a 92% or 96% recovery,
    respectively, of the applied dose. The main metabolic route was
    oxidation of the side chain leading to the formation of the
    corresponding sulfoxide oxydemeton-methyl, and to a lesser extent, 
    after further oxidation, the sulfone; O-demethylation was also an
    important route. Neither glucuronide nor sulfate conjugates were found
    (Ecker, 1978; Ecker & Cölln, 1983).

    FIGURE 2

    7.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    7.1  Single exposure

         Demeton-S-methyl causes cholinergic toxicity. The acute toxicity
    data are reported in Table 2.

         Heath & Vandekar (1957) and Vandekar (1958) showed a significant
    increase in intravenous but not oral toxicity after storage of
    demeton-S-methyl ("pure") at room temperature in the dark. This was
    associated with the formation of sulfonium derivatives, which have a
    lower oral toxicity, possibly because of poor absorption.

         Dilution with water also increased the intravenous toxicity, and
    this was again associated with the formation of sulfonium derivatives.
    The maximum toxicity of a 1 mg/ml suspension kept at 35°C for one day
    was about 30 times the initial toxicity (the LD50 decreased from
    about 60 to about 2 mg/kg in rats) (Heath & Vandekar, 1957). Similar
    results were obtained with commercial Metasystox (70% demeton-O-
    methyl, 30% demeton-S-methyl) (see also section 2.2.)

    7.1.1  Oral

         Following oral dosing with demeton-S-methyl performed on a very
    small number of animals (one per dose level), one rabbit given
    50 mg/kg died within 2 h, while the dose of 20 mg/kg caused symptoms
    but the animal recovered. A cat given 10 mg/kg died after 2 days,
    while the dose of 5 mg/kg caused signs that were reversible and
    animals recovered (few details given) (Hecht, 1955).

         Single oral doses (180 mg/kg) of metasystox, containing 25%
    demeton-S-methyl, were administered to seven male buffalo calves
    (10-12 months of age). Signs of poisoning appeared 15 to 35 min later.
    Two calves were treated repeatedly with atropine (1.5 mg/kg body
    weight, i.v.), D-tubocurarine (0.1 mg/kg body weight, i.v.) and
    glucose (3-4 mg/kg body weight, i.v.). Another two calves were treated
    repeatedly with atropine (1.5 mg/kg body weight, i.v.), gallamine
    (1 mg/kg body weight, i.v.) and glucose (3-4 mg/kg body weight, i.v.)

         Three calves were not treated. All calves displayed typical
    cholinergic signs. Treatments delayed but did not prevent death, which
    occurred in about 2 h in calves not treated with antidotes and in
    about 23 h in calves treated with antidotes (Mitra et al., 1978).

    7.1.2  Inhalation

         The LC50 (4 h of exposure) for Wistar rats was found to be 310
    and 210 mg/m3 for males and females, respectively (Flucke & Pauluhn,
    1983).

        Table 2.  LD50 of demeton-S-methyl for various species and different routes of administration
                                                                                                                                           

    Species        Sex       Observation       Route     Purity             LD50              Vehicle             References
    (strain)                 period                                         (mg/kg
                             (days)                                         body weight)
                                                                                                                                           

    Mouse          M         3                 oral      ?                  17                ?                   Klimmer & Pfaff (1955)

    Mouse          ?         7                 i.v.      ?                  7                 water               Hecht (1960)

    Rat            F         1                 oral      "pure"             63                ?                   Heath & Vandekar (1957)
                                                                                                                  Vandekar (1958)

    Rat            M         3 days minimum    oral      ?                  40                ?                   Klimmer & Pfaff (1955)

    Rat            ?         ?                 oral      ?                  35                ?                   Hecht (1955)

    Rat            M         14                oral      25% formulation    33                water               Klimmer (1964)
    (Wistar)

    Rat            M         ?                 oral      86-89%             57-64             Lutrol 9            Klimmer (1964)
    (Sprague-
    Dawley)

    Rat            M & F     14                oral      50% formulation    64-65             water               Flucke & Pauluhn (1983)
    (Wistar)

    Rat            M         7                 oral      50% formulation    129               water               Edson (1960)
    (Wistar)

    Rat            M         14                oral      90% formulation    44                cremophor EL        Flucke & Kimmerle (1977)
    (Wistar)
                                                                                                                                           

    Table 2.  (con't)
                                                                                                                                           

    Species        Sex       Observation       Route     Purity             LD50              Vehicle             References
    (strain)                 period                                         (mg/kg
                             (days)                                         body weight)
                                                                                                                                           

    Rat            F         10                oral      ?                  80                ethanol (20%)       DuBois & Doull (1955)
    (Sprague-                                                                                 and                 DuBois & Plzak (1962)
    Dawley)                                                                                   propylene
                                                                                              glycol (80%)

    Rat            M & F     14                i.p.      ?                  7.5               ethanol (20%)       DuBois & Doull (1955)
    (Sprague-                                                                                 and propylene       DuBois & Plzak (1962)
    Dawley)                                                                                   glycol (80%)

    Rat            ?         ?                 i.p.      formulation        10                water               Hecht (1960)

    Rat            ?         ?                 dermal    ?                  85                ?                   Edson (1960)

    Rat            M         14                dermal    50% formulation    71                none                Flucke & Pauluhn (1983)
    (Wistar)

    Rat            F         14                dermal    50% formulation    45                none                Flucke & Pauluhn (1983)
    (Wistar)

    Rat            ?         7                 dermal    technical          100-200           none                Hecht (1960)

    Rat            ?         7                 dermal    25% formulation    about 10          none                Hecht (1960)

    Rat            F         1                 i.v.      "pure"             65                ?                   Heath & Vandekar (1957)
                                                                                                                  Vandekar (1958)
                                                                                                                                           

    Table 2.  (con't)
                                                                                                                                           

    Species        Sex       Observation       Route     Purity             LD50              Vehicle             References
    (strain)                 period                                         (mg/kg
                             (days)                                         body weight)
                                                                                                                                           

    Guinea-        M         10                oral      ?                  110               ethanol (20%)       Du Bois & Doull (1955)
    pig                                                                                       and propylene
                                                                                              glycol (80%)

    Guinea-        M         14                i.p.      ?                  12.5              ethanol (20%)       Du Bois & Plzak (1962)
    pig                                                                                       and propylene
                                                                                              glycol (80%)
                                                                                                                                           
             When rats (n=2) and mice (n=4) were exposed for 1 h to 1, 2.5 or
    5 g/m3 of demeton-S-methyl (alcohol solution), all mice died whereas
    rats displayed signs but recovered (few experimental details given)
    (Hecht, 1955).

         Rats (n=20) were exposed for 8 h to nebulized demeton-S-methyl
    (0.5 g/m3 of air), which was obtained from a 25% emulsifiable
    commercial formulation diluted 1:250 (0.1% final concentration of
    active ingredient). None of the animals died or showed overt
    cholinergic signs. Erythrocyte cholinesterase activity, determined in
    three animals immediately after the end of exposure, was reduced by
    70%. When purified active ingredient was used, lower erythrocyte
    cholinesterase inhibition (60%) was found under the same experimental
    conditions. This was paralleled by an increased rat LD50 (from 10 to
    27.5 mg/kg i.p.) (Hecht, 1960).

    7.1.3  Dermal

         Doses of 20 or 100 mg/kg demeton-S-methyl applied to the shaved
    skin of two cats caused death. A dose of 10 mg/kg caused mild signs;
    very few details were given (Hecht, 1955).

    7.2  Short-term exposure

    7.2.1  Rat

         Groups of six male rats (strain not specified) were fed
    demeton-S-methyl at levels of 0, 50, 100 or 200 mg/kg diet in
    the diet (equivalent to 0, 5, 10 and 20 mg/kg body weight per day,
    respectively) for 6 months. Cholinergic signs (slight tremors and
    fasciculations) were observed at the highest dose-level during the
    first 5 weeks of the study. Brain and erythrocyte cholinesterase
    activities were reduced at 50 mg/kg diet (by about 80 and 88%,
    respectively), 100 mg/kg diet (by about 85 and 92%) and 200 mg/kg diet
    (by about 90 and 94%) groups. Body weight gain was depressed at 100
    and 200 mg/kg diet. Gross microscopic examination of tissues (liver,
    kidney and adrenals) showed no treatment-related changes (Vandekar,
    1958).

         Groups of 30-day-old female Holtzman rats were fed dietary
    levels of 0, 1, 5 or 25 mg/kg diet of demeton-S-methyl (purity not
    reported) for 1 week. At termination, serum, liver and brain
    acetylcholinesterase (n=3) and liver and serum aliesterase (n=3) with
    diethylsuccinate and tributyrin as substrates activities were
    measured. Interpolated dietary levels producing 50% inhibition were
    15-28 mg/kg diet for acetylcholinesterase, 4-6 mg/kg diet for liver
    aliesterase and about 25 mg/kg diet for serum aliesterase, equivalent
    to 1.5-2.8, 0.4-0.6 and 2.5 mg/kg body weight per day, respectively
    (Su et al., 1971).

    7.2.2  Dog

         In a one-year study, pure-bred beagle dogs (n=6 animals of each
    sex per group) were fed 0, 1, 10 or 100 mg a.i./kg diet (day 1-36) or
    50 mg a.i./kg diet (day 37-termination) of demeton-S-methyl (52.2% in
    xylene). Haematological, blood biochemical and urinalysis parameters
    were determined during pretest period and at months 1, 2, 3, 4, 5, 6,
    8, 10, 12. Hearing tests and ophthalmoscopic examinations were
    performed once in the pretest period and at months 3, 6 and 12 of
    treatment. At termination animals were killed for pathology, and
    determination of organ weights, brain cholinesterase activity, hepatic
    cytochrome P-450 and triglyceride contents and  N-demethylase
    activity were carried out.

         All animals survived the study. Diarrhoea and vomiting were
    observed in all animals, most frequently in the high-dose group: these
    animals also showed reduced food consumption before the dose was
    reduced to 50 mg/kg diet. The mean daily compound intake was found to
    be 0.036, 0.36 and 4.6/1.5 mg/kg body weight at 1, 10 and 100/50 mg/kg
    diet, respectively. Body weight was similar in all groups. No
    alterations were observed in the hearing test and ophthalmoscopic
    examination. Haematological, blood chemistry (excluding cholinesterase
    activities) and urinalysis parameters and organ weights at termination
    were not significantly altered by any of the treatments. Hepatic
    biochemical parameters were not altered by any of the treatments. No
    treatment-related gross pathology alterations were found. However,
    multifocal slight/moderate atrophy and/or hypertrophy of proximal
    renal tubules was demonstrated in three males and three females of the
    high-dose group. Plasma cholinesterase activity was reduced as
    compared to controls by 20-30% and 5-20% in males and females,
    respectively, at 10 mg/kg diet, and by 45-65% (males) and 50-70%
    (females) at 50 mg/kg diet. Erythrocyte cholinesterase activity was
    reduced by 25-35% and 30-45% in males and females, respectively, at
    10 mg/kg diet. A higher inhibition was found at 50 mg/kg diet, where
    inhibition was 80-90% and 55-65% in males and females, respectively.
    Brain cholinesterase activity was reduced by 25% in males at 10 mg/kg
    diet and by 64% (males) and 15% (females) at 50 mg/kg diet. Based on
    effects on brain cholinesterase activity, the NOAEL was 1 mg/kg diet,
    equal to 0.036 mg/kg body weight per day (Bathe, 1983).

    7.3  Long-term exposure

    7.3.1  Mouse

         A long-term carcinogenicity study was conducted in NMRI mice
    (70 animals of each sex per group) that were given demeton-S-methyl
    (about 50% in xylene) mixed into the feed with approximately 10 mg/kg
    diet of groundnut oil at concentrations of 0, 1, 15 or 75 mg a.i./kg
    diet, or xylene (75 mg/kg diet). Groups were subdivided into two
    subgroups: one (n=20) was terminated at 12 months, the second one was
    terminated at 21 months.

         Animals in the high-dose group had a lower (significantly lower
    during the first 4 weeks only) food consumption and a reduced (about
    10% throughout the study in males only, and at the beginning in
    females) body weight. The mean daily intake of demeton-S-methyl was
    (males/females): 0.24/0.29, 3.47/4.18, 17.81/20.0 mg/kg body weight
    at 1, 15, 75 mg/kg diet, respectively. Clinical signs due to
    cholinesterase inhibition were not observed. Mortality at 21 months
    was (males/females) 16/30, 13/34, 17/35, 16/35 and 16/32% in the
    control, low-, mid-, high-dose and xylene groups, respectively.
    Haematological and clinical chemical parameters were not affected by
    the treatment except plasma urea (lower than control in the high-dose
    males) and plasma and erythrocyte cholinesterase activities. Plasma
    cholinesterase activity was significantly decreased in mid- (by
    63-74%) and high-dose (by 91-97%) groups. Erythrocyte cholinesterase
    activity was only slightly reduced in the mid- and high-dose groups.
    Brain cholinesterase activity (n=10 per group) was reduced in
    high-dose groups (in males by 70% and in females by 59%) and in the
    mid-dose group (in males by 44% and in females by 38%). Histological
    examination did not reveal an increased incidence of neoplastic and
    non-neoplastic lesions in treated groups. Based on inhibition of brain
    cholinesterase, the NOAEL was 1 mg/kg diet, equal to 0.24 mg/kg body
    weight per day (Schmidt & Bomhard, 1988).

    7.3.2  Rat

         Wistar rats (60 animals of each sex per group) were given
    demeton-S-methyl (about 50% in xylene mixed into the feed with
    approximately 10 mg/kg of groundnut oil) at concentrations of 0, 1, 7
    or 50 mg a.i./kg diet, or 50 mg/kg diet of xylene. Groups were
    subdivided into two subgroups; one (n=10) was terminated at 12 months,
    the second one was terminated at 24 months.

         Hair loss (up to 50% of females) and diarrhoea (up to 50% of
    males) were observed significantly more frequently in the animals of
    the high-dose group. Body weight was reduced in mid-dose males (by
    5-10%) and in both males (by 10-20%) and females (by 5%) in the
    high-dose group. Food consumption was similar in all groups. The mean
    daily intake of demeton-S-methyl was (males/females): 0.05/0.06,
    0.31/0.41, 2.59/3.09 mg/kg body weight at 1, 7 and 50 mg/kg diet,
    respectively. Mortality at 24 months was (males/females) 12/26, 10/20,
    10/20, 4/26 and 8/24% in the control, low-, mid-, high-dose and xylene
    groups, respectively. Haematological and clinical chemical parameters,
    except for cholinesterases, measured at months 6, 12, 18 and 24, were
    unaffected by the treatments. Plasma and erythrocyte cholinesterase
    activities, measured at months 3, 6, 12 and 24, were significantly
    decreased in groups given 7 mg/kg diet (plasma cholinesterase by
    30-56%, erythrocyte cholinesterase by 12-31%) or 50 mg/kg diet (plasma
    cholinesterase by 75-92%, erythrocyte cholinesterase by 20-44%). Brain
    cholinesterase activity (measured at 12 and 24 months) was reduced in
    the high-dose group (by 67-75%) and in the mid-dose group (by 15-47%).

    A statistically significant decrease in brain cholinesterase activity
    (33%) was observed in males given 1 mg/kg diet at 24 months but not at
    12 months. The toxicological significance of this finding is not
    clear; it should also be noted that brain cholinesterase activity at
    7 mg/kg diet was higher than at 1 mg/kg diet and that plasma
    cholinesterase and erythrocyte cholinesterase activities were not
    inhibited at either of these dose levels. Histological examination did
    not reveal an increased incidence of neoplastic lesions in treated
    groups. Increased incidence of retinal atrophy (78% of males, 92% of
    females as compared to 36-63% and 61-70% in the other groups) and
    keratitis (44% of males, 22% of females as compared to 4-12% and 0-2%,
    respectively, in the other groups) was observed at 50 mg/kg diet. The
    retinal atrophy mainly affected the fundus, unilaterally or
    bilaterally, and occurred in either the inner corneal layer, the inner
    and outer layers, or all layers of the retina. Based on inhibition of
    brain cholinesterase, the NOAEL was considered to be 1 mg/kg diet,
    equal to 0.05 mg/kg body weight per day (Schmidt & Westen, 1988).

    7.4  Skin and eye irritation and sensitization

    7.4.1  Skin and eye irritation

         Demeton-S-methyl (commercial formulation, 50% of active
    ingredient) was applied (0.5 ml) to the shaved skin of three New
    Zealand white rabbits on a 2.5 × 2.5 cm cellulose dressing for 4 h.
    Mild erythema and oedema were observed, which generally disappeared
    after 3 days (Flucke & Pauluhn, 1983). A 52.5% solution of
    demeton-S-methyl in xylene produced slight skin and eye irritancy in
    New Zealand white rabbits, but this was attributed to the solvent
    (Thyssen, 1981).

         A commercial formulation of demeton-S-methyl (50%) was instilled
    (0.1 ml) either undiluted or as a 0.5% aqueous dilution into the
    conjunctival sac of one eye of groups (n=3) of New Zealand white
    rabbits. Treated eyes were washed with physiological solution after
    24 h. No signs of eye irritation were observed in rabbits treated with
    the 0.5% aqueous solution. The undiluted formulation caused severe
    lacrimation and miosis on application. Mild corneal opacity and
    discrete redness and oedema of conjunctivae were observed and
    recovered in about 7 days (Flucke & Pauluhn, 1983).

    7.4.2  Skin sensitization

         The skin-sensitizing potential of demeton-S-methyl was assessed
    by the Magnusson and Kligman maximization test with Freund's adjuvant
    on guinea-pigs (n=20, Bor:SPF, DHPW strain). The concentrations of
    demeton-S-methyl (96.3% purity, average of three determinations) used
    were: 0.1% for the intra-dermal induction, 10% for the topical
    induction and the first challenge, and 1% for the second challenge.

    All twenty animals reacted positively to the 1st challenge (controls
    4/10), and 16 reacted positively to the 2nd challenge (controls 3/10).
    The results indicate that demeton-S-methyl has a skin-sensitizing
    potential (Heimann, 1987a).

         In another study, the Buehler epidermal patch test was used on
    guinea-pigs (n=12, Bor: SPF, DHPW strain). The concentrations of
    demeton-S-methyl (95.6% purity, average of three determinations) used
    were 10% for topical induction (once a week for 3 weeks) and the first
    challenge, and 20% for the second challenge. The results indicate that
    demeton-S-methyl does not have a skin-sensitizing potential under
    these conditions (Heimann, 1987b).

         It is concluded that demeton-S-methyl might have some
    skin-sensitizing potential, but this is of no relevance in practice.

    7.5  Reproduction, embryotoxicity and teratogenicity

    7.5.1  Reproduction

         A standard two-generation study (two litters/generation) was
    conducted in SPF rats (BOR:WISW) (10 males and 20 females) that were
    given demeton-S-methyl at 0, 1, 5 or 25 mg/kg diet (Eiben et al.,
    1984). The compound was used as a pre-mix in xylene (about 50%). Rats
    in an extra control group were given xylene at 25 mg/kg diet.

         In the F0 generation, none of the animals died. No treatment-
    related signs were observed in any animal. Body weight gain was
    reduced in males (by 10%) and in some females at 25 mg/kg diet. Food
    intake was also reduced (by 7%) in high-dose males. Fertility index
    was not affected by treatment. At 25 mg/kg diet, the viability of pups
    was reduced; it was 89% and 85% in first and second matings,
    respectively. Lactation index was also reduced in the high-dose group
    (85-92%), the control value being 98-99%. Body weight at birth was
    comparable in all groups, but body weight gain was significantly
    reduced (by 8-10%) in pups fed 25 mg/kg diet.

         In the F1b generation, one female was found dead in the 5-mg/kg
    diet group and one in the 25-mg/kg diet group; one male and one female
    in one of the 25-mg/kg diet litters also died. Autopsy did not reveal
    treatment-related alterations. No treatment-related signs were
    observed in any animal. Body weight gain was reduced at times in
    low-dose males and consistently in mid- and high-dose and xylene-
    treated males when compared to untreated animals. When compared to
    xylene-treated animals (which were 5-15% lighter than untreated
    animals), however, only males of the high-dose group had a
    significantly reduced (by about 15%) body weight gain. Females of the
    high-dose and xylene groups had a reduced (by about 10%) body weight,
    compared to controls, the former being at times lighter weight than
    the latter. Fertility index was not significantly affected. The number

    of pups born was reduced in the high-dose group and the viability of
    pups was also reduced in the mid- and high-dose groups in a
    dose-related manner (82-88% and 47-67% of controls, respectively).

         No compound-related malformation was found in animals of any of
    the treatment groups. Demeton-S-methyl intake, as calculated in the
    F0 generation, was found to be (female data in parentheses): 0.07
    (0.08), 0.32 (0.39) and 1.71 (1.90) mg/kg body weight per day in the
    low-, mid- and high-dose groups, respectively, and xylene intake was
    1.66 (1.96) mg/kg body weight per day. Based on the viability of pups
    and body weight in the F1b generation, the NOAEL was 1 mg/kg diet,
    equal to 0.07 mg/kg body weight per day (Eiben et al., 1984).

    7.5.2  Embroytoxicity and teratogenicity

    7.5.2.1  Rat

         Groups (n=25) of fertilized female rats (BAY:FB 30 strain) were
    given daily (0, 0.3, 1 or 3 mg/kg body weight orally) demeton-S-methyl
    (from a 52.6% solution in xylene) dissolved in corn oil from day 6 to
    15 of gestation. At day 20 of gestation, pups were delivered by
    caesarean section. Fetuses were weighed, sexed, inspected for external
    abnormalities and examined for visceral and bone malformations. No
    alteration of physical appearance or behaviour was observed in any
    group. All animals survived until the caesarean section. Body weight
    gain was reduced (by 13%) in the high-dose group. The numbers of live
    fetuses and resorptions, fetal weight, number of fetuses with
    malformations and number of implants were comparable in all groups. No
    treatment-related visceral or skeletal abnormalities were observed
    (Renhof, 1985).

    7.5.2.2  Rabbit

         A formulation of demeton-S-methyl (52.2% a.i. in xylene) was
    administered by gavage to mated chinchilla hybrid rabbits (n=15-16) on
    gestation days 6 to 18 at dose levels of 0, 3, 6 and 12 mg/kg body
    weight per day. Caesarean sections were performed on gestation day 28.
    There were no mortalities. In the high-dose group, diarrhoea was
    observed in all animals after 4 to 10 days of treatment. Beginning 1
    to 2 h after dosing, it persisted for 6 to 24 h. In the high-dose
    group, mean food consumption was decreased by 7% during gestation days
    6 to 18 and by 17% during gestation days 19 to 24 when compared to
    controls. This was associated with decreased mean body weight gain
    (-7%). There were no abortions and no relevant differences between
    test and control groups in the numbers of implantations per dam, pre-
    implantation losses, post-implantation losses, resorptions, living and
    dead fetuses or sex ratios. A decrease in mean fetal body weight,
    compared to the mean control weight, of 6.6% was observed in the
    high-dose group. There was no treatment-related increase in gross,
    skeletal or visceral malformations (Becker, 1983).

    7.6  Mutagenicity and related end-points

         A summary of the studies conducted to assess mutagenicity of
    demeton-S-methyl is given in Table 3.

    7.6.1  DNA damage and repair

         Demeton-S-methyl did not induce DNA damage in the Pol test on
     Escherichia coli either with or without metabolic activation.

    7.6.2  Mutation

         Increased mutation rates were observed in the Ames test and in
    the mouse lymphoma forward mutation assay both with and without
    metabolic activation.

    7.6.3  Chromosomal effects

         In  in vivo tests, no SCEs were found in the bone marrow of
    Chinese hamsters treated with high doses of demeton-S-methyl.

         Bone marrow micronucleus and dominant lethal tests on mice
    treated with demeton-S-methyl gave negative results. Chromosomal
    aberrations were found in the bone marrow of Syrian hamsters treated
    with a commercial formulation of demeton-S-methyl.

         It is concluded that the available information is insufficient to
    permit an adequate assessment of the genotoxic potential of
    demeton-S-methyl.

    7.7  Delayed neurotoxicity

         Adult Leghorn hens (n=20) were given two doses of 100 mg a.i./kg
    body weight (approximately equal to the LD50) of demeton-S-methyl
    (51.2% in xylene) by gavage. The second dose was given 21 days
    after the first one. Positive control animals (n=5) received
    tri- ortho-cresyl phosphate (TOCP) (375 mg/kg body weight by gavage).
    Animals were pretreated with atropine (100 mg/kg body weight
    intramuscularly 10 min before the dose of demeton-S-methyl and
    50 mg/kg body weight subcutaneously 6 h later). Surviving animals
    received atropine (30 mg/kg s.c.) 24, 30 and 48 h later. At the second
    dose, atropine treatment was suspended after 24 h. Hens treated with
    demeton-S-methyl had signs of cholinergic toxicity. The recovery
    started on day 3 and by day 8 all treated animals, except for one,
    were free of signs. After the second dose, the recovery started on day
    2 and by day 5 all treated animals were free of signs. One animal died
    after the second treatment and surviving animals did not develop
    neurological deficits. TOCP-treated animals showed locomotor

        Table 3.  Studies on mutagenicity of demeton-S-methyl
                                                                                                                                               

    Test                Organism                      Purity              Results             LED or HIDa          Reference
                                                                          -S9    +S9
                                                                                                                                               

                        Microorganisms

    Pol assay           Escherichia coli p3478,       93%                 -      -            10 000 µg/plate      Herbold (1983a)
                        W3110

    Reverse             Salmonella typhimurium        unknown             +      n.t.         5 µg/plate           Hanna & Dyer (1975)
    mutation            TA1530, TA1535, his C117,
                        his G46

                        E. coli WP2, WP2 uvra,        unknown             +      n.t.         5 µg/plate           Hanna & Dyer (1975)
                        CM561, CM571, CM611, WP67,
                        WP12,

                        S. typhimurium TA98, TA100,   50.2%               ++                  300 µg/plate         Herbold (1979)
                        TA1535, TA1537                (formulation)

                        S. typhimurium TA98, TA100,   >98%                ++                  20 µg/plate          Herbold (1980a)
                        TA1535, TA1537

                        Saccharomyces cerevisiae      53.1%                      --           1062 µg/ml           Hoorn (1982)
                        S138 S211ý                    (formulations
                                                      in xylene)

                        Insects

    Recessive           Drosophila melanogaster       unknown             +                   80 mg/kg diet        Hanna & Dyer (1975)
    lethal
                                                                                                                                               

    Table 3.  (con't)
                                                                                                                                               

    Test                Organism                      Purity              Results             LED or HIDa          Reference
                                                                          -S9    +S9
                                                                                                                                               

                        Cultured mammalian cells

    Mutation, tk        Mouse lymphoma L5178Y cells   94%                 ++                  50 µg/ml             Cifone (1984)
    locus

                        Mammals in vivo

    Bone marrow         NMRI mouse                    >98%                -                   2 × 5 mg/kg b.w.     Herbold (1980b)
    micronucleus                                                                              oral

    SCE in bone         Chinese hamster               94%                 -                   20 mg/kg b.w. oral   Herbold (1983b)
    marrow

    Chromosomal         Syrian hamster, female        50%                 +                   2 mg/kg b.w. i.p.    Dzwonkowska & Hübner (1986)
    aberration                                        (commercial)

    Dominant            NMRO mouse                    >98%                -                   5 mg/kg b.w. oral    Herbold (1980c)
    lethal
                                                                                                                                               

    a  LED = lowest effective dose; HID = highest ineffective dose
        impairment beginning on day 10. Histological examination showed
    moderate axonal degeneration in peripheral nerves and medulla in
    TOCP-treated animals but not in demeton-S-methyl-treated or solvent
    control animals (Flucke & Kaliner, 1988).

         Neuropathy target esterase (NTE), the target for organophosphate-
    induced delayed neuropathy, was not inhibited in hen brain and
    spinal cord 1, 2 and 7 days after treatment with demeton-S-methyl
    (80 mg a.i./kg body weight) by gavage. Positive controls (TOCP at
    100 mg/kg body weight) showed NTE inhibition (> 90%) in both brain
    and spinal cord (Flucke & Eben, 1988).

    7.8  Toxicity of metabolites

         Two plant and mammalian metabolites of demeton-S-methyl (namely
    oxydemeton-methyl and demeton-S-methylsulfone) have been studied
    extensively, since they are also the active ingredient of commercial
    pesticides. According to the JMPR, the toxicity of the two compounds
    does not differ substantially, either qualitatively or quantitatively,
    from that of demeton-S-methyl (FAO/WHO, 1990).

    7.9  Mechanism of toxicity - mode of action

         Demeton-S-methyl is a direct cholinesterase inhibitor and
    it causes signs and symptoms of the cholinergic syndrome. The
     in vitro I50 (30 min, 37°C) for sheep erythrocyte cholinesterase
    was 6.5 × 10-5 mol/litre. The I50 of oxydemeton-methyl and
    demeton-S-methylsulfone were of the same order of magnitude
    (2.7 × 10-5 and 4.3 × 10-5 mol/litre, respectively). The half-life
    of recovery of acetylcholinesterase activity after inhibition by
    demeton-S-methyl was 1.3 h, as expected from a dimethyl phosphorylated
    acetylcholinesterase (Heath & Vandekar, 1957).

         The 1973 JMPR (FAO/WHO, 1974) reported that rat brain
    cholinesterase was more sensitive to  in vitro inhibition by demeton-
    S-methyl than by oxydemeton-methyl (I50 values of 9.52 × 10-5 and
    1.43 × 10-3 mol/litre, respectively; time of incubation, temperature
    and pH not reported). It was also reported that demeton-S-methyl was a
    more potent inhibitor of human serum cholinesterase (no details
    given).

         Data on  in vivo inhibition of plasma cholinesterase and
    erythrocyte and brain cholinesterase are reported in section 7.2 and
    7.3.

    7.10  Potentiation

         Male Wistar rats (160-180 g body weight) were given trichlorfon
    (98.6% purity) and demeton-S-methyl (90% purity) in combination by
    gavage. The amount of compound in the mixture was proportional to its

    oral LD50 (302 mg/kg body weight for trichlorfon and 44 mg/kg body
    weight for demeton-S-methyl) in order to obtain equitoxic doses. The
    resulting toxicity was additive (LD50 of the mixture was 223 mg/kg
    body weight against expected 173 mg/kg body weight) (Flucke &
    Kimmerle, 1977).

         Similarly, an additive effect was obtained when demeton-S-methyl
    was given in combination with phenamiphos (ethyl-4-(methylthio)
     m-tolyl-isopropyl-phosphoroamidate). The experimental LD50 of the
    mixture was 55 mg/kg body weight while that estimated from the
    individual LD50s was 50 mg/kg body weight (Kimmerle, 1972).

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

         A 31-year old woman attempted suicide with an unknown amount
    ("1 or 2 mouthfuls") of Metasystox I (25% demeton-S-methyl). On
    admission to hospital she was comatose, sweating and salivating,
    and had pin-point pupils. She stayed in the Intensive Care Unit for 15
    days where she was treated with atropine (up to 97 mg per day, 550 mg
    in 14 days). Oximes (2-PAM) were only given on day 1 (0.5 + 0.25 +
    0.25 g) and there was no apparent clinical improvement. On admission,
    plasma and erythrocyte cholinesterase activities were less than 10% of
    normal control values. The patient was discharged on the 30th day with
    normal plasma cholinesterase values; erythrocyte cholinesterase
    activity was still below the normal values (about 65%), but had
    recovered a month later (Barr, 1966).

         A case of acute poisoning in a 5-month pregnant woman has been
    described (Carrington da Costa et al., 1982). A 41-year-old woman
    attempted suicide by ingesting Metasystox, which resulted in an
    estimated intake of 12 g methyl demeton (it should be noted that in
    the report Metasystox was said to contain methyl-demeton and not
    oxydemeton-methyl as the commercial name implies). On admission, 3.5 h
    after poisoning, blood cholinesterase (it was not specified whether
    pseudo- or acetylcholinesterase) was 10% of normal values. The patient
    became comatose 12 h after admission. She was treated with atropine,
    obidoxime and haemoperfusion 72 h after hospitalization. Artificial
    ventilation was required on the 4th day of hospitalization. The
    patient was discharged after 24 days and 4 months later she delivered
    a healthy female child.

         In a fatal suicidal case with a commercial formulation of
    demeton-S-methyl, the concentration of the compound was measured in
    several organs. It was estimated that death occurred about 6 h after
    poisoning. Highest demeton-S-methyl levels were found in the proximal
    small intestine (166 mg/kg of tissue); in brain, kidney and muscles,
    the levels were 30-80 mg/kg; lowest concentrations were found in liver
    (7 mg/kg tissue) and blood (7-16 mg/litre). Metabolites were not
    measured (Schludecker & Aderjan, 1988).

         In the United Kingdom in 1991 there were five cases of poisoning
    by demeton-S-methyl and in 1994 three cases, none of which were fatal
    (personal communication by G. Volans, Medical Toxicology Unit, London,
    to the IPCS, dated 15 January 1996).

         Hegazy (1965) reported three cases of suspected poisoning with
    demeton-S-methyl in children (6-14 years of age) exposed in a recently
    sprayed field and 1 case after ingestion of contaminated feed.
    Symptoms were mild and the patients recovered fully. Serum
    cholinesterase determinations gave ambiguous results.

    8.2  Occupational exposure

    8.2.1  Acute poisoning

         A worker inadvertently exposed to demeton-S-methyl (no details)
    was monitored for about 100 days. Plasma cholinesterase activity was
    always within the normal values of the laboratory. However, if the
    activity on day 40 and 100 is considered as the normal value for this
    worker, then a 30% inhibition occurred 2-3 days after exposure. The
    activity recovered with an half-life of about 10 days. Erythrocyte
    cholinesterase activity was below the normal value for about 40 days.
    When calculated on the activity of day 100, a 60% inhibition was found
    up to day 10. The activity recovered with a half-life of about 35 days
    (Lewis et al., 1981).

         Two workers in a chemical packaging company, whose job it was to
    fill a concentrate of demeton-S-methyl (500 g/litre of xylene) into
    one-litre containers using a weight-triggered bottle-filling machine
    for 3 to 4 h, were admitted to hospital because of organophosphate
    poisoning and were treated with atropine. Cholinesterase measurement
    made 14 days after exposure (1 worker) showed inhibited erythrocyte
    cholinesterase, but the plasma cholinesterase activity was within the
    normal range. In the second worker, whose symptoms lasted for 3 days,
    erythrocyte cholinesterase activity was below the normal value 5 weeks
    after exposure. These workers wore gloves, overalls and boots, but
    frequent spillage was reported. Normal clothing had been left under
    the filling apparatus and apparently was contaminated. The filling
    system was changed by housing the filling machine in a fume cupboard
    and by providing new protective garments and changing room facilities.
    One more worker was admitted to the hospital and treated with atropine
    because of organophosphate poisoning. This occurred on the morning
    after a day spent fitting the infill seal and screwing on the tops
    of cans. He had reduced erythrocyte and plasma cholinesterase
    (erythrocyte > plasma) activities for several days after exposure.
    Another worker showed a sharp drop in erythrocyte and plasma
    cholinesterase activities associated with abdominal cramps, which
    resolved in about 5 days. Another worker had depressed erythrocyte and
    plasma cholinesterases activities without complaining of any adverse
    effect. It was concluded that absorption of demeton-S-methyl was
    through the skin because of penetration of the protective clothing
    used or because this clothing was not worn properly. It should be
    noted that the active ingredient was dissolved in xylene, which is
    known to attack rubber and plastics, making the penetration of gloves
    possible (Jones, 1982).

    8.2.2  Effects of short- and long-term exposure

         Three volunteers without any protective equipment were exposed
    for two consecutive days to Metasystox (30% demeton-S-methyl, 70%
    demeton-O-methyl) while spraying with a hand-held nebulizer. Exposure

    lasted for 3 and 6 h on the first and second days, respectively. The
    concentrations of the active ingredient (isomers not separated) were
    8.8-27 mg/m3 of ambient air. Plasma and erythrocyte cholinesterase
    activities measured up to 14 days after exposure did not show
    significant decreases when compared to pre-exposure values (Klimmer &
    Pfaff, 1955).

         Volunteers, wearing overalls but not mask protection, were
    exposed to metasystox (30% demeton-S-methyl, 70% demeton-O-methyl)
    while spraying in a greenhouse. They used the splash method
    (0.03-0.05% a.i.), the low volume (0.5% a.i.) or the high volume spray
    method (0.05% a.i.) for 5 to 25 min. There was no effect on plasma or
    erythrocyte cholinesterase activity measured after exposure (Klimmer &
    Pfaff, 1958).

         Six workers engaged in hop cultivation using Metasystox I
    (reported to contain demeton-O-methyl instead of demeton-S-methyl as
    the commercial name implies) were monitored. They sprayed up to
    2400 litres of a 0.1% solution (in water) of the insecticide in one
    day. Protective clothing and masks were not always used. No
    significant inhibition of blood acetyl cholinesterase was observed at
    the end of exposure or 1 or 2 days later. One subject, who was exposed
    twice, showed a 29% decrease in blood acetyl cholinesterase after the
    second exposure. No signs or symptoms were observed in these workers
    (Winkler & Arent, 1970).

         The medical department of a company reported no adverse effect in
    workers employed in the formulation of demeton-S-methyl from 1967 to
    1984 (Faul, 1984).

         Agricultural workers exposed to demeton-S-methyl for 3
    consecutive days were monitored. Pre-and post-exposure urinary levels
    of the metabolite dimethyl phosphorothiolate potassium salt (DMPThK),
    and plasma and whole blood cholinesterase activities were measured.
    Exposed subjects were divided into three groups according to their
    job, i.e. mixers (n=7), sprayers (n=6) and others (n=7) not directly
    involved in handling the pesticide. Higher levels of DMPThK were
    found in mixers, with a medium value of 83 µg/litre and a range of
    0-822 µg/litre (neither corrected for creatinine nor for urine
    volume). Sprayers had a mean value of 30 µg/litre (limit of detection)
    and a range of 0-208 µg/litre; the other subject had a mean value of
    30 µg/litre and a range of 0-100 µg/litre. Whole blood cholinesterase
    activity was not affected by the exposure, while plasma cholinesterase
    activity was slightly (about 10%, statistically significant) reduced
    when compared to pre-exposure levels in mixers. However, no
    correlation was found between DMPThK levels and plasma cholinesterase
    activity (Vasilic et al., 1987).

         Hegazy (1965) reported a study of 121 spraymen exposed to
    Meta-isosystox during spraying of cotton fields in Egypt. The spraymen
    applied Meta-isosystox at a rate of 0.5 litres of concentrate in
    400 litres of spray per 4200 m2 mainly by hand-operated knapsack
    sprayers, or in a few cases by high-pressure motor-powered sprayers
    with a large tank connected by a long hose to a multi-nozzled
    spray-boom. Sprayers were not involved in chemical mixing. Workmen
    washed exposed body parts with soap and water after spraying. Working
    clothes were removed at the end of the day, but the clothes may not
    have been washed before re-use. Not all workers used protective
    clothing and masks. None of the workers were re-exposed to
    Meta-isosystox after the onset of symptoms. Serum cholinesterase
    activity estimates were performed within 24 h after the onset of
    symptoms in some patients and after the cessation of symptoms in some
    others. In most cases they were repeated 2-3 times at various
    intervals up to 40 days from the onset of symptoms. In general, the
    serum cholinesterase activity in spraymen underwent a marked initial
    fall, followed by a rise to above-normal levels after about 30-40
    days. Signs and symptoms of toxicity in spraymen occurred after 1-18
    days of exposure, with a mean time of 3 days. These consisted of
    gastrointestinal disturbances (58% of total), dizziness (23%),
    persistent general weakness and fatigue (19%), respiratory
    manifestations (16%), headache (16%), sweating, salivation or
    lacrimation (12%), tremors of outstretched hands, intention tremors,
    ataxia (4.1%), exaggerated superficial and deep reflexes (5.8%),
    hiccough (2.5%), muscular fasciculations (2.5%), or had apparently
    resolved (30%), at the first determination of serum cholinesterase
    activity (Hegazy, 1965).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Aquatic organisms

    9.1.1  Algae

         Table 4 reports the results obtained when different
    formulations of demeton-S-methyl were tested on the green alga
     Scenedesmus subspicatus (Heimbach, 1985a, 1990b).

    9.1.2  Invertebrates

         The acute toxicity of demeton-S-methyl for molluscs and
    crustaceans is given in Table 5.

         The lowest concentration tested on the water flea  Daphnia 
     magna (10 µg a.i./litre) caused toxic effects (Heimbach, 1985b,c). A
    21-day exposure test on water flea reproduction produced a NOEC of
    > 5.6 µg a.i./litre (Heimbach, 1990d). A study performed with a
    27.3% emulsifiable concentrate formulation (Heimbach, 1985c) yielded
    a NOEC of 3.7 µg/litre (equal to 1 µg a.i./litre) and a LOEC of
    11.7 µg/litre (equal to 3.1 µg a.i./litre).

         Using a commercial formulation of metasystox, the 96-h LC50 for
    the lammellibranch mollusc  Paphia laterisulca was 2 µg/litre (Akarte
    et al., 1986) and that for the freshwater prawn  Donax cuneatus was
    4 µg/litre (Muley et al., 1987).

    9.1.3  Fish

         Table 6 indicates the toxicity of demeton-S-methyl for fish.

    9.2  Terrestrial organisms

    9.2.1  Soil microorganisms

         In a study conducted in silty sand soil or loamy silt soil
    with doses of demeton-S-methyl up to 5 times those recommended
    (2 litres/hectare of a 27% emulsifiable concentrate formulation),
    no influence on soil respiration or nitrification in soil was found
    (Anderson, 1989; Blumenstock, 1989).

    9.2.2  Invertebrates

         When demeton-S-methyl was mixed with an artificial soil where
    earthworms  (Eisenia foetida) were kept for 14 days, the LC50 was
    241 mg/kg of dry substrate of the commercial formulation (a 25%
    emulsifiable concentrate), corresponding to 60 mg a.i./kg (Heimbach,
    1990a).

        Table 4.  Effect of demeton-S-methyl on the green alga Scenedesmus subspicatusa
                                                                                                                                

    Specification of test             EC50 (mg a.i./litre)             NOEC           LOEC         Duration       Conditions
    substance                                                        (mg/litre)     (mg/litre)        (h)
                                                                                                                                

                                 Increase of        Growth rate
                                  biomass
                                                                                                                                

    Technical 97.3% purity             8                 22               1             3              96         pH 7.8 - 8.5
                                                                                                                  23 °C

    EC formulationb                   37               >100              18            32              96         pH 7.6 - 10.4
    (27.3% a.i.)                                                                                                  23 °C

    Pre-solutionc                     13                 37               1            10              96         pH 7.7 - 8.5
    xylene (53.7% a.i.)                                                                                           22 °C
                                                                                                                                

    a  From: Heinbach (1985a, 1990b)

    b  Tests performed with the blank formulation gave the same results as the highest tested concentration.

    c  No test with the blank pre-solution was performed.

    Table 5.  Acute toxicity of demeton-S-methyl for molluscs and crustaceans
                                                                                                                                      

    Species                            Specification of test         Temperature       LC50        Duration of    Reference
                                       substance                        (°C)        (mg/litre)      exposure
                                                                                                      (h)
                                                                                                                                      

    Mollusc                            commercial formulation        ?              0.0042             96         Akarte et al. (1986)
    (Paphia laterisulca)

    Water flea (Daphnia magna)         technical (96.7%)             20 ± 1         >0.1               24         Heimbach (1985b)
                                                                                    0.023              48

                                       pre-solution in xylene        20 ± 1         >0.1               24         Heimbach (1985c)
                                       (53.7%) formulation                          0.022              48

    Clam (Donax cuneatus)              commercial formulation        25-28.5        0.0064             96         Muley et al. (1987)

    Prawn (Macrobrachium lamerrii)     commercial formulation        27 ± 2         1.3                72         Mary et al. (1986)
                                                                                                                                      

    Table 6.  Toxicity of demeton-S-methyl for fish (96-h exposure)
                                                                                                                                     

    Species                                      Mass and length        Temperature      LC50 (mg/litre)          Reference
                                                                        (°C)
                                                                                                                                     

    Rainbow trout (Onchorhyncus mykiss)          4.0 - 5.5 cm           16               4.5                      Grau (1985a)
                                                 1.0 - 1.5 g                             (52.7% of a.i.)

                                                 6.4 ± 1.0 cm           15±2             0.59                     Grau (1990c)
                                                 3.0 ± 0.6 g                             (69.5% of a.i.)

                                                 6.9 ± 1.1 cm           15±2             6.44                     Grau (1990a)
                                                 3.5 ± 1.6 g                             (27.3% of a.i.)

    Golden orfe (Leuciscus idus melamotus)       6.0 - 7.5 cm           21               43                       Grau (1985b)
                                                 2.5 - 4.2 g                             (52.7% of a.i.)

                                                 6.4 ± 0.6 cm           21±2             23.2                     Grau (1990b)
                                                 2.5 ± 0.6 g                             (27.3% of a.i.)

    Goldfish (Carassius auratus)                 6 cm                   18               20-40                    Hermann (1974a)
                                                 1.5 g                                   (28.1% of a.i.)

    Carp (Cyprinus carpio)                       6 cm                   18               40-60                    Hermann (1974b)
                                                 1.6 g                                   (28.1% of a.i.)

    Scardinius erythrophthalmus                  6 cm                   18               30-40                    Hermann (1974c)
                                                 1.3 g

    Cirrhana mrigala (larvae)                    51 ± 3 mg              20               1.45                     Verma et al. (1984)
                                                                                                                                     
             Demeton-S-methyl was applied on fields of winter wheat by
    fixed-wing aircraft using conventional boom-and-nozzle equipment.
    The applied amount was 245 g a.i. per hectare at a volume rate of
    20 litres/hectare. Samples of the soil surface and crop foliage fauna
    were collected 1-2 times before and 4-5 times after application from a
    treated field and from a control untreated field. The number of crop
    foliage but not of soil surface entomophagus invertebrates was reduced
    soon after application of demeton-S-methyl.  Empididai (dance flies)
    was the only group to be significantly reduced in numbers by
    demeton-S-methyl. Predatory  Coleoptera (beatles)  (Carabidae and
     Staphylinidae), Araneae (spiders) and predatory  Diptera (flies)
    (except  Empididae) were not affected by demeton-S-methyl. Among the
    ephytophagus fauna, cereal aphids markedly declined in number soon
    after application, but a rapid increase was observed 2 months later,
    when numbers of  Diptera and  Thripidae (thrips) were also
    increased. Numbers of entomobryid and sminthurid springtails decreased
    soon after the application but were higher than in the control field
    2 months later (Shires, 1985).

         Demeton-S-methyl was slightly toxic to the predatory mite
     Phytoseiulus persimilis since a 70% population reduction was
    obtained with a concentration of 0.025% a.i. (Kniehase, 1984).

         The contact LD50 for bees has been reported to be 0.60 µg/bee
    (Westlake et al. 1985). A field study was conducted on bee
    colonies following application of a 0.2% formulation of Metasystox
    (at 600 litres/hectare) to field beans  (Vicia faba) after bee
    foraging had ceased in the evening. Toxicity to bees was assessed by
    collecting dead insects on canvas sheets in front of the hive
    entrance. Before spraying, the mortality in exposed and control hives
    was comparable. Following spraying, there was a mortality rate of 123
    bees per hive in the exposed and 90 bees in the controls (prior to
    exposure mortality was 98 and 95 respectively). The mortality increase
    persisted for 3 days after the application (Bayer, 1970).

    9.2.3  Birds

         Some oral LD50 values are given in Table 7.
        Table 7.  Acute oral LD50 values for birds
                                                                                       
    Species                  Vehicle           Purity        LD50        Reference
                                                          (mg/kg b.w.)
                                                                                       

    Japanese quail           Cremephor EL      99.7%      44-50           Flucke (1984)
    (Coturnix japonica)

    Canary                   ?                 99.7%      10-20           Grau (1984)
    (Serinus canarius)
                                                                                       
    
         Groups of 10 starlings  (Sturnus vulgaris) were given (by
    gavage) 0, 0.2, 1.5 or 2 mg/kg body weight of demeton-S-methyl
    (technical grade) dissolved in corn oil. Serum butyrylcholinesterase
    and carboxylesterase and brain cholinesterase activities were measured
    at 3 (high-dose only), 6 and 24 h after dosing (n=2 for brain, n=4 for
    serum). The highest dose inhibited brain cholinesterase by about 20%,
    serum carboxylesterase by about 50% and serum butyrylcholinesterase by
    about 80%. The peak effect was at 3 h with some recovery after 24 h.
     In vitro treatment of the enzyme preparation with pralidoxine
    chloride (2-PAM) caused almost complete reactivation of brain
    cholinesterase but had no effect on the other enzymes (Thompson et
    al., 1991).

    9.2.4  Effects in field

         The activities of brain cholinesterase, serum
    butyrylcholinesterase and glutamate oxaloacetate transaminase (GOT)
    were measured in house sparrows  (Passer domesticus) captured 1
    (n=7), 2 (n=6) or 3 (n=6) days after spraying wheat fields with
    demeton-S-methyl (0.485 litres a.i./hectare from an emulsifiable
    concentrate formulation in a xylene solvent base). Liver weight was
    also recorded and histological examination of the liver was performed.
    Serum butyrylcholinesterase was reduced to 64% of that of controls
    (n=5) (statistically not significant) and brain cholinesterase was 82%
    of that of controls (statistically significant) for birds trapped on
    day 2, but serum GOT was not significantly affected in the exposed
    birds. The authors claimed that there was evidence of liver damage
    in exposed birds because of a significant increase of binucleation
    (3.3-5 vs. 1.9 binucleation/10 fields) and inflammatory cell foci
    (more evident after 3 days of exposure) (Tarrant et al., 1992).

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

         The major metabolites of demeton-S-methyl in plant and mammals
    are oxydemeton-methyl and demeton-S-methylsulfone. These two compounds
    are also commercial insecticides. Their mechanism of action
    is the same as that of demeton-S-methyl (i.e. inhibition of
    acetylcholinesterase) and their toxicological profiles have been
    reported to be similar to that of demeton-S-methyl (FAO/WHO, 1990).

    10.1  Evaluation of human health risks

         Sources of exposure of humans to demeton-S-methyl are dietary and
    through dermal absorption and inhalation during the manufacture or use
    of the compound.

         There is very limited information on actual dietary exposure to
    demeton-S-methyl.

         In an early study, during application of a mixture of demeton-S-
    methyl (30%) and its isomer, demeton-O-methyl (70%), an ambient air
    concentration of 8.8-27 mg/m3 of the combined isomers was found. This
    is much higher than the conservative TLV/TWA for methyl-demeton
    proposed by ACGIH (0.5 mg/m3). However, no inhibition of plasma and
    erythrocyte cholinesterase activities was found after exposure.

         Cases of acute intoxication, which required pharmacological
    treatment, have been reported where workers were filling bottles with
    a 50% xylene solution of demeton-S-methyl. Skin absorption was
    considered the cause of poisoning because of inadequate personal
    protection. Agricultural workers exposed to demeton-S-methyl while
    mixing or spraying during three consecutive days did not show
    significant inhibition of either plasma or erythrocyte cholinesterase.
    Agricultural workers exposed to demeton-S-methyl while spraying cotton
    for 1-18 days (average of 3 days) showed signs and symptoms of
    poisoning. Improper working conditions could not be excluded.

         Cases of severe demeton-S-methyl poisoning (suicide attempts)
    have been reported. No delayed toxicity developed in the patients who
    survived.

         No data are available on the effect of repeated human exposure to
    demeton-S-methyl.

         No reproductive, developmental or carcinogenic effects have been
    found in laboratory animals exposed to demeton-S-methyl. NOAEL values
    have been based on inhibition of brain acetyl cholinesterase or, in a
    rat reproduction study, on reduced pup viability and body weight in
    the F1b generation.

         The available information is insufficient to permit an adequate
    assessment of the genotoxic potential of demeton-S-methyl.

    10.2  Evaluation of effects on the environment

         The information on utilization and application rates that
    has been employed for this risk assessment is derived from the
    agricultural use of demeton-S-methyl within the European Union. It
    should be possible to extrapolate this assessment to other
    agricultural uses at similar application rates elsewhere in the world.
    The application rates for demeton-S-methyl can be summarised as
    follows: arable (tractor-mounted/drawn hydraulic spray boom
    applications), 0.32 kg/ha; top fruit (broadcast air-assisted
    applications), 0.49 kg/ha.

         The following risk assessment is based on the principle of
    calculating toxicity-exposure ratios (TERs) (Fig. 3), which follows
    the European and Mediterranean Plant Protection Organisation and
    Council of Europe (EPPO/CoE) Environmental Risk Assessment Scheme
    model and associated trigger values (EPPO/CoE, 1993a,b).

    10.2.1  Aquatic organisms

         The main risk to aquatic organisms from the use of demeton-S-
    methyl is from spray drift during either arable applications
    (0.32 kg/ha) or top fruit air-assisted (0.49 kg/ha). For each of these
    risk scenarios, the predicted environmental concentration (PEC) in a
    30-cm-deep static surface water body, arising from either arable-based
    spray drift at 1 m from the edge of the spray boom or from top fruit
    air-assisted spray drift at 3 m from the point of application (both
    based on Ganzelmeier et al., 1995), was calculated as follows:

         PEC (mg demeton-S-methyl/litre)
         =  max application rate (kg/ha) × A (% spray drift)
                                                             
                                    300

    where

         A =   5 for ground-based hydraulic spray applications 1 m from
               edge of boom

         or 30 for air-assisted application 3 m from point of application

    10.2.1.1  Acute risk

         The acute LC/EC50 values for the most sensitive fish was
    0.59 mg/litre, for the most sensitive aquatic invertebrate (mollusc)
    was 0.0042 mg/litre (0.022 mg/litre for Daphnia), and for the most
    sensitive algal species was 8 mg/litre.

    FIGURE 3

    (a)   Spray drift from ground-based applications

         The acute PEC for spray drift (1 m from the edge of the spray
    boom into a 30-cm-deep static water body at the maximum application
    rate (see PEC assumptions above) is 0.005 mg/litre. Therefore, the
    TERs based on this PEC and the above LC/EC50 toxicity values are:
    fish, 110; aquatic invertebrates, 0.8 (4.1 for Daphnia); and algae,
    1500. Based on the EPPO/CoE risk assessment scheme for aquatic
    organisms, these TERs indicate a low acute risk to fish and algae.
    However, for aquatic invertebrates the TER is less than 10, indicating
    a potential risk to aquatic invertebrates (both molluscs and
    arthropods). In such risk situations the use of a "no-spray"
    restriction zone next to surface waters may reduce the risk to such
    aquatic invertebrates. For example, arable spray drift at 5 m from the
    edge of boom is 0.6% (Ganzelmeier et. al., 1995). Based on this 5 m
    drift data, the PEC is 0.0006 mg/litre and results in a 5 m TER of 7
    for molluscs and 37 for Daphnia. The TER for the most sensitive
    invertebrate (mollusc) is still below the EPPO trigger of 10,
    indicating a borderline risk. However, the Daphnia 5 m TER, which is
    above 10, indicates that the use of a 5 m "no-spray" restriction zone
    next to surface waters would help reduce the acute risk to aquatic
    invertebrates.

    (b)   Spray drift from broadcast air-assisted top fruit applications

         The acute PEC for spray drift (3 m from the point of application
    into a 30-cm-deep static water body at the maximum application rate
    (see PEC assumptions above) is 0.049 mg/litre. Therefore, the TERs
    based on this PEC and the above LC/EC50 toxicity values are: fish,
    12; aquatic invertebrates, 0.09 (0.4 for Daphnia); and algae, 163.
    Based on the EPPO/CoE risk assessment scheme for aquatic organisms,
    these TERs indicate a low acute risk to fish and algae. However, for
    aquatic invertebrates the TER is less than 1 indicating a high risk to
    aquatic invertebrates (both molluscs and arthropods). In such risk
    situations the use of a "no-spray" restriction zone next to surface
    waters may reduce the risk to such aquatic invertebrates. For example,
    spray drift from broadcast air-assisted applications to top fruit at
    15 m from point of application is 6.0% (Ganzelmeier et al., 1995).
    Based on this 15 m drift data, the PEC is 0.006 mg/litre and results
    in a 15 m TER of 0.7 for molluscs and 3.4 for Daphnia. These TERs at
    15 m for the most sensitive invertebrates are still below the EPPO
    trigger of 10, indicating a potential risk. Therefore, even with a 15
    "no-spray" restriction zone next to surface waters, there is still a
    potential risk to aquatic invertebrates from the broadcast
    air-assisted use of demeton-S-methyl. Table 8 summarizes the acute
    TERs for demeton-S-methyl to aquatic organisms at 1 m for arable and
    3 m for broadcast air-assisted applications.

        Table 8.  Acute toxicity-exposure ratios (TER) for aquatic organisms at 1 m for arable and 3 m for broadcast air-assisted
              applications
                                                                                                                                

    Species                         LC/EC50      PEC (mg/litre) at 1 m      PEC (mg/litre) at 3 m       TER            TER
                                  (mg/litre)          (arable)                 (air assisted)         (arable)    (air assisted)
                                                                                                                                

    Fish                            0.59               0.005                      0.049                 110             12
    (Oncorhynchus mykiss)

    Aquatic invertebrate            0.0042             0.005                      0.049                 0.8           0.09
    (Paphia laterisulca)

    Aquatic invertebrate            0.022              0.005                      0.049                 4.1            0.4
    (Daphnia magna)

    Alga                            8.0                0.005                      0.049                1500            163
    (Scenedesmus subspicatus)
                                                                                                                                
        10.2.1.2  Chronic risk

         No chronic toxicity data are available for fish. However, a
    chronic NOEC of 0.0056 mg/litre has been reported for  Daphnia 
     magna. There are no data reporting the persistence or degradation of
    demeton-S-methyl in water, and so a chronic PEC could not be derived.
    Therefore, owing to the lack of data on chronic fish toxicity and
    environmental fate in water, it is not possible to assess the chronic
    risk to either fish or aquatic invertebrates. There are also no data
    available on either the toxicity of demeton-S-methyl to sediment-
    dwelling invertebrates or fate of demeton-S-methyl in aquatic
    sediments. Therefore, the risk to sediment-dwelling invertebrates
    could also not be assessed. No fish bioaccumulation data are
    available, but, as the log Pow is 1.3 (i.e. < 3), the risk of
    bioaccumulation in fish should be low.

    10.2.2  Terrestrial organisms

         Vertebrates are likely to be exposed to demeton-S-methyl from
    either grazing on treated vegetation or consuming contaminated
    insects. For this risk assessment, typical application rates of
    0.32 kg/ha are used for ground spray application on arable crops and
    0.49 kg/ha for application by air-assisted spraying for fruit.

    10.2.2.1  Birds

         The lowest reported acute oral LD50 for birds is 10 mg/kg body
    weight for the canary. Dietary data are not available.

         Indicator birds for use in the risk assessment are:

    *    Greylag goose  (Anser anser), as a grazing species, with a body
         weight of 3 kg and total daily food consumption of 900 g
         vegetation (dry weight) (Owen, 1975)

    *    Blue tit  (Parus caeruleus), as an insectivorous species, with a
         body weight of 11 g and total daily food consumption of 8.23 g
         (dry weight) (Kenaga, 1973)

     a)  Grazing birds

         Initial residues on short grass or cereal shoots are estimated to
    be 35.8 mg/kg dry weight (based on 112 × application rate) arising
    from application at 0.32 kg/ha to arable crops (EPPO/CoE, 1993a,b) and
    55 mg/kg from application to fruit at a rate of 0.49 kg/ha. This gives
    an estimated total oral intake for the goose of 32.2 mg and 49.5 mg
    for the two application rates assuming that the goose ate exclusively
    food contaminated at this level. This is equivalent to a daily intake
    of 10.7 and 16.5 mg/kg body weight, respectively. TERs can be
    calculated as follows:

                                                                        

    End-point    LD50/LC50      Application rate   Predicted        TER
                 (mg/kg b.w.)   (kg/ha)            concentration
                                                   in food (mg/kg)
                                                                        

    Bird acute   10             0.32 (arable)      35.8             0.93
    oral         (Canary)       0.49 (fruit)       55               0.61

                                                                        

         The calculated TER values fall well below the EPPO/CoE trigger
    values for concern (TER <10) and indicate a high risk to grazing
    birds.

     b)  Insectivorous birds

         Initial residues on small insects are estimated to be 9.3 mg/kg
    dry weight (based on 29 × application rate) arising from application
    at 0.32 kg/ha to arable crops (EPPO/CoE, 1993a,b) and 14.2 mg/kg from
    application to fruit at a rate of 0.49 kg/ha. This gives an estimated
    total oral intake for the blue tit of 0.08 mg and 0.12 mg for the two
    application rates assuming that the blue tit ate exclusively food
    contaminated at this level. This is equivalent to a daily intake of
    6.94 and 10.6 mg/kg body weight, respectively. TERs can be calculated
    as follows:

                                                                        

    End-point    LD50/LC50      Application rate   Predicted        TER
                 (mg/kg b.w.)   (kg/ha)            concentration
                                                   in food (mg/kg)
                                                                        

    Bird acute   10             0.32 (arable)      9.3              1.44
    oral         (Canary)       0.49 (fruit)       14.2             0.94

                                                                        

         The TERs for acute toxicity to insectivorous birds are
    substantially less than the trigger value of <10, indicating high
    acute risk to these birds.

    10.2.2.2  Mammals

         The lowest reported acute oral LD50 for laboratory mammals is
    63 mg/kg body weight for the rat.

         Indicator mammals for use in the risk assessment will be:

    *    Rabbit  (Oryctolagus cuniculus), as a grazing mammal, with a
         body weight of 1200 g and a total daily food consumption of 500 g
         vegetation (dry weight) (Ross, personal communication to the
         IPCS).

    *    Shrew  (Sorex araneus), as an insectivorous mammal, with a body
         weight of 18 g and a total daily food consumption of 18 g
         (Churchfield, 1986)

     a)  Grazing mammals

         Initial residues on short grass or cereal shoots are estimated to
    be 35.8 mg/kg dry weight (based on 112 × application rate) arising
    from application at 0.32 kg/ha to arable crops (EPPO/CoE, 1993a,b) and
    at 55 mg/kg from application to fruit at a rate of 0.49 kg/ha. This
    gives an estimated total oral intake for the rabbit of 17.9 mg and
    27.4 mg for the two application rates, assuming that the rabbit ate
    exclusively food contaminated at this level. This is equivalent to a
    daily intake of 15 and 23 mg/kg body weight, respectively. TERs can be
    calculated as follows:

                                                                        

    End-point    LD50           Application rate   Predicted        TER
    (test        (mg/kg b.w.)   (kg/ha)            concentration
    species)                                       in food (mg/kg)
                                                                        

    Acute oral   63             0.32 (arable)      17.9             4.20
                 (Rat)          0.49 (fruit)       27.5             2.76

                                                                        

         Since the TERs are < 10, this indicates a high risk to grazing
    mammals.

     b)  Insectivorous mammals

         Initial residues on large insects are estimated to be 0.86 mg/kg
    dry weight (based on 2.7 × application rate) arising from application
    at 0.32 kg/ha to arable crops (EPPO/CoE, 1993a,b) and 1.32 mg/kg from
    application to fruit at a rate of 0.49 kg/ha. This gives an estimated
    total oral intake for the shrew of 0.016 mg and 0.024 mg for the two
    application rates, assuming that the shrew ate exclusively food
    contaminated at this level. This is equivalent to a daily intake of
    0.86 and 1.32 mg/kg body weight, respectively. TERs can be calculated
    as follows:

                                                                        

    End-point    LD50           Application rate   Predicted        TER
                 (mg/kg b.w.)   (kg/ha)            concentration
                                                   in food (mg/kg)
                                                                        

    Mammal       63 (Rat)       0.32 (arable)      0.86             72.9
    acute oral                  0.49 (fruit)       1.32             47.6
                                                                        

         These TERs fall outside the trigger for high risk for
    insectivorous mammals but within the range for medium risk.

    10.2.2.3  Bees

         The reported contact toxicity to bees gives an LD50 of
    0.26 µg/bee. Using application rates at 0.32 and 0.49 kg/ha for
    cereals and fruit respectively, hazard quotients are calculated to be
    1231 and 1885 (application (g/ha)/LD50 (µg/bee)). The trigger for
    concern is >50 (EPPO/CoE, 1993a,b) and, therefore, there is
    substantial concern for exposed bees. The compound should not be
    applied to flowering plants, and exposure of flying bees should be
    avoided.

    10.2.2.4  Earthworms

         Earthworms are likely to be exposed to demeton-S-methyl. Based on
    a soil depth of 5 cm and a soil density of 1.5 g/cm3, the soil PEC
    would be 0.43 mg/kg assuming even distribution in the medium. The
    reported LC50 for earthworms  (Eisenia foetida) is 60 mg/kg
    soil giving a TER of 140.6. As this is above the trigger value of
    10 (EPPO/CoE, 1993a,b), the acute risk to earthworms is very low.

    11.  CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
         AND THE ENVIRONMENT

         Demeton-S-methyl causes acute cholinergic toxicity in humans and
    laboratory animals. Carcinogenic, reproductive and developmental
    effects have not been found in laboratory animals. Effects due to
    chronic human exposure are unlikely to occur. Exposure of the general
    population may only occur through food residues. However, the levels
    of exposure are unlikely to cause adverse effects.

         Given the high acute toxicity, as determined in a number of test
    species and the known cases of human poisoning, it can be concluded
    that the risk of occupational poisoning with demeton-S-methyl exists
    when adequate protective measures and good practices are not adopted.
    Therefore, handling and application of demeton-S-methyl should only be
    performed by supervised and trained workers who must adhere to good
    application practices and adopt adequate safety measures.

         Demeton-S-methyl does not persist in the environment and is not
    accumulated by organisms. It has high acute toxicity to aquatic
    invertebrates and is toxic to fish and birds, leading to high or
    moderate risk factors for these organisms. However, significant field
    kills of organisms have not been reported for the compound.
    Precautions should be taken to minimize exposure of non-target
    organisms (e.g., do not spray over water bodies, minimize exposure by
    spray drift).

         In view of the negative results obtained in developmental and
    carcinogenicity studies, it is felt that further clarification of the
    genotoxic potential of demeton-S-methyl is not necessary.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         Demeton-S-methyl was classified as highly hazardous (class Ib) by
    WHO (1996).

         Demeton-S-methyl was evaluated by the Joint FAO/WHO Meeting on
    Pesticide Residues (JMPR) in 1972, 1973, 1979, 1982, 1984, 1989, 1992.
    The 1989 Meeting (FAO/WHO, 1990) evaluated demeton-S-methyl,
    oxydemeton-methyl and demeton-S-methylsulfone and set the following
    NOAEL levels:

    demeton-S-methyl:             mouse:  1 mg/kg diet (equal to
                                  0.24 mg/kg body weight per day)

                                  rat:   1 mg/kg diet (equal to
                                  0.05 mg/kg body weight per day)

                                  dog:  1 mg/kg diet (equal to 0.036 mg/kg
                                  body weight per day)

    oxydemeton-methyl:            mouse:  30 mg/kg diet (equal to
                                  0.03 mg/kg body weight per day)

                                  rat:   0.57 mg/kg diet (equal to
                                  0.03 mg/kg body weight per day)

                                  dog:  0.125 mg/kg body weight per day

    demeton-S-methylsulfone:      rat:   1 mg/litre in drinking water
                                  (equal to 0.06 mg/kg body weight per
                                  day)

                                  dog:  10 mg/kg diet (equal to 0.36 mg/kg
                                  body weight per day)

         The estimated ADI for demeton-S-methyl was established at
    0-0.0003 mg/kg body weight. This ADI applies to demeton-S-methyl
    alone or in combination with oxydemeton-methyl and/or demeton-S-
    methylsulfone because residues are determined after oxidation and are
    expressed as demeton-S-methyl. The 1992 JMPR reviewed the residue data
    on these three related compounds. Updated figures were available only
    for oxydemeton-methyl, which is replacing demeton-S-methyl in most
    registrations. The Meeting decided therefore to change the definition
    of the residues to "the sum of demeton-S-methyl, oxydemeton-methyl and
    demeton-S-methylsulfone expressed as oxydemeton-methyl". The MRLs
    varied from 0.05 to 1 mg/kg commodity and have been obtained from
    supervised trials on oxydemeton-methyl rather than on
    demeton-S-methyl.

         Demeton-S-methyl has not been evaluated by the International
    Agency for Research on Cancer (IARC).

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    RÉSUMÉ ET ÉVALUATION, CONCLUSIONS ET RECOMMANDATIONS

    1.  Résumé et évaluation

    1.1  Identité, propriétés physiques et chimiques

         Le déméton-S-méthyl se présente sous la forme d'un liquide
    huileux jaune pâle à l'odeur pénétrante. C'est un organophosphoré
    agissant par la voie générale et par contact qui est utilisé comme
    insecticide et acaricide sur les fruits, les légumes, les céréales et
    les plantes ornementales pour lutter contre  Acarina, Thysanoptera, 
     Hymenoptera et Homoptera. Sa tension de vapeur est de 63,8 mPa à
    20°C et il est facilement soluble dans la plupart des solvants
    organiques. Il est très soluble dans l'eau (3,3 g/litre à la
    température ambiante) et son coefficient de partage entre l'octanol et
    l'eau (log Pow) est de 1,32. Le déméton-S-méthyl est stable dans les
    solvants non aqueux.

         Pour la recherche et le dosage des résidus et l'analyse des
    échantillons prélevés dans l'environnement, on procède à une
    extraction au moyen d'un solvant organique, suivie d'une oxydation de
    la sulfone correspondante. Le dosage s'effectue ensuite par
    chromatographie en phase gazeuse avec un détecteur spécifique du
    phosphore.

    1.2  Sources d'exposition humaine et environnementale

         Jusqu'en 1957, le déméton-méthyl a été commercialisé sous la
    forme d'un mélange de deux isomères, le déméton-S-méthyl et le
    déméton-O-méthyl. La formulation commerciale est un concentré
    émulsionnable que l'on utilise en pulvérisations sur les céréales, les
    fruits, les légumes et les plantes ornementales. On est en train de le
    remplacer par l'oxydéméton-méthyl qui est un métabolite produit par
    les plantes et les mammifères ou qui résulte du séjour du
    déméton-S-méthyl dans le sol.

    1.3  Transport, distribution et transformation dans l'environnement

         La décomposition par hydrolyse du déméton-S-méthyl dépend du pH
    de la solution. A 22°C, sa demi-vie est de 56 jours à pH 7 et de 8
    jours à pH 9. Dans le sol, sa voie de décomposition principale est la
    biodégradation, avec une demi-vie d'environ 4 h. Au bout de 24 h, il y
    a encore dans le sol une proportion d'oxydéméton-méthyl qui représente
    20 à 30% de la dose initiale de déméton-S-méthyl. Le coefficient de
    sorption dans le sol (Kd) du déméton-S-méthyl est de 0,68 à 2,66,
    selon la composition du sol.

         Dans l'environnement, l'une des principales voies de dégradation
    du composé est la photolyse. La métabolisation par le blé de printemps
    est rapide et elle analogue à celle qui se produit dans le sol et chez
    les mammifères.

    1.4  Niveaux d'exposition environnementale et humaine

         La population générale est principalement exposée au
    déméton-S-méthyl par l'intermédiaire des résidus qui subsistent sur
    les cultures vivrières. La réunion conjointe FAO/OMS sur les résidus
    de pesticides (JMPR) a recommandé une dose journalière admissible
    (DJA) de 0,0003 mg/kg de poids corporel. Il s'agit d'une DJA
    collective qui englobe le déméton-S-méthyl, l'oxydéméton-méthyl et la
    déméton-S-méthylsulfone, étant donné que les méthodes habituelles
    d'analyse ne distinguent pas ces différents composés. Il est arrivé
    qu'une exposition excessive au déméton-S-méthyl par la voie
    transcutanée entraîne une intoxication de type cholinergique chez des
    ouvriers mal protégés qui procédaient au conditionnement du concentré.

         En revanche, des volontaires qui s'étaient prêtés à l'épandage
    simulé d'un mélange de déméton-S-méthyl et de déméton-O-méthyl (30 et
    70% respectivement) et avaient été exposés à des concentrations de 8,8
    à 27 mg/m3 des deux matières actives, n'ont présenté aucune réduction
    de leur activité cholinestérasique plasmatique ou érythrocytaire.

    1.5  Cinétique et métabolisme

         Chez le rat, le déméton-S-méthyl est rapidement et presque
    complètement résorbé au niveau de l'intestin et il se répartit
    uniformément dans les tissus (exception faite des hématies dans
    lesquelles il se concentre plus fortement). Il est rapidement
    métabolisé et excrété dans les urines. Sa concentration sanguine
    diminue avec une demi-vie qui est initialement de 2 h environ. Au 
    bout de 24 h, il reste environ 1% de la dose dans l'organisme. La
    principale voie métabolique du déméton-S-méthyl consiste en une
    oxydation de la chaîne latérale qui conduit à la formation du
    sulfoxyde correspondant (oxydéméton-méthyl) et, dans une moindre
    proportion, après une oxydation plus poussée, à la sulfone.
    L'O-déméthylation constitue une autre voie métabolique importante.

    1.6  Effets sur les animaux de laboratoire et les systèmes d'épreuve
         in vitro

    1.6.1  Exposition unique

         Le déméton-S-méthyl provoque des intoxications de type
    cholinergique. Chez les mammifères, la DL50 varie de 7 à 100 mg/kg
    p.c. selon la voie d'administration et l'espèce.

    1.6.2  Exposition de courte durée

         Une des premières études, comportant une exposition par la voie
    alimentaire, a montré que des rats qui recevaient le composé à raison
    de 50 mg/kg de nourriture, avaient une activité cholonestérasique
    cérébrale sensiblement réduite au bout de 26 semaines de ce régime.

    Des signes d'intoxication de type cholinergique ont été observés au
    bout de 5 semaines de traitement chez des rats recevant 200 mg de
    composé par kg de nourriture.

         Lors d'une étude d'alimentation d'un an effectuée sur des chiens,
    on a obtenu une dose sans effet nocif observable (NOAEL), basée sur
    les effets cholinergiques, de 1 mg/kg de nourriture, soit l'équivalent
    quotidien de 0,036 mg/kg de poids corporel.

    1.6.3  Exposition de longue durée

         Des souris ont reçu pendant 21 mois des rations contenant
    respectivement 0, 1, 15 ou 75 mg de déméton-S-méthyl par kg de
    nourriture. La NOAEL, a été trouvée égale à 1 mg/kg de nourriture,
    soit l'équivalent quotidien de 0,24 mg/kg de poids corporel en prenant
    comme base l'inhibition de la cholinesterase cérébrale.

         Chez des rats ayant reçu une alimentation contenant
    respectivement 0, 1, 7 ou 50 mg/kg de déméton-S-méthyl, la NOAEL,
    basée sur l'inhibition de la cholinestérase cérébrale, s'est révélée
    égale à 1 mg/kg de nourriture, soit l'équivalent quotidien de
    0,05 mg/kg p.c.

         Chez aucune espèce il n'a été constaté d'augmentation de
    l'incidence des tumeurs.

    1.6.4  Irritation et sensibilisation cutanée ou oculaire

         Le déméton-S-méthyl est légèrement irritant pour l'oeil et la
    peau. Le test de Magnusson et Klingman a donné des résultats positifs
    chez des cobayes. En revanche, le test de sensibilisation de Buehler
    (application d'un timbre cutané) n'a pas fourni d'indice d'une
    sensibilisation cutanée, ce qui donne à penser que, dans la pratique,
    l'usage du déméton-S-méthyl ne devrait pas poser de problème de
    sensibilisation.

    1.6.5  Effets sur la reproduction, embryotoxicité et tératogénicité

         Lors d'une étude sur deux générations de rats, au cours de
    laquelle les animaux ont été exposés au composé par la voie
    alimentaire, on a constaté une réduction de la viabilité et du poids
    corporel des ratons (uniquement la génération F1b) à la dose de
    5 mg/kg de nourriture. La NOAEL était de 1 mg/kg de nourriture, soit
    l'équivalent quotidien de 0,07 mg/kg de poids corporel.

         Le déméton-S-méthyl ne s'est révélé ni embryotoxique, ni
    tératogène chez le rat et le lapin.

    1.6.6  Mutagénicité et points apparentés d'aboutissement des effets
           toxiques

         Le déméton-S-méthyl produit des mutations ponctuelles
     in vitro. On n' a mis en évidence des effets chromosomiques
     in vivo qu'avec des formulations du commerce. Les données
    disponibles sont insuffisantes pour que l'on puisse procéder à une
    évaluation satisfaisante du pouvoir génotoxique de ce composé.

    1.6.7  Neurotoxicité retardée

         Le déméton-S-méthyl n'a produit ni polyneuropathie, ni inhibition
    de l'estérase cible correspondante (NTE) lorsqu'on l'a administré à
    des poules en dose égale à la DL50 par voie orale.

    1.6.8  Toxicité des métabolites

         Deux métabolites du déméton-S-méthyl produits par des
    plantes et des mammifères, à savoir l'oxydéméton-méthyl et la
    déméton-S-méthylsulfone, sont également des pesticides du commerce et
    ont été très largement étudiés. Il ressort de ces travaux que le
    profil toxicologique de ces composés ne diffère pas sensiblement,
    quantitativement ou qualitativement, de celui du déméton-S-méthyl.

    1.7  Mécanisme de la toxicité - Mode d'action

         Le déméton-S-méthyl est un inhibiteur direct de la cholinestérase
    et sa toxicité est liée au fait qu'il inhibe l'acétylcholinestérase
    (AChE) au niveau des terminaisons nerveuses. Une fois inhibée par le
    déméton-S-méthyl, l'acétylcholinestérase se réactive spontanément avec
    une demi-vie  in vitro de 1,3 h environ, comme on peut s'y attendre
    pour une AChE diméthylphosphorylée.

    1.8  Effets sur l'homme

         On a signalé quelques cas d'intoxication aiguë avec syndrome
    cholinergique, consécutifs à des tentatives de suicide. Aucun effet
    retardé n'a été observé chez les survivants, dont une femme enceinte.

         A la suite d'une exposition subie par négligence lors du
    conditionnement de formulations du commerce, quelques employés ont
    présenté des troubles d'origine cholinergique qui ont nécessité un
    traitement pharmacologique. Le composé avait probablement pénétré par
    la voie transcutanée. De même, il est possible que des conditions de
    travail laissant à désirer aient entraîné une absorption excessive de
    déméton-S-méthyl au cours de l'épandage de ce composé sur des champs
    de coton.

    1.9  Effets sur les autres êtres vivants au laboratoire et dans leur
         milieu naturel

         Pour les algues vertes, la CE50 à 96 h va de 8 à 37 mg/litre. On
    a mesuré une CL50 allant de 0,004 à 1,3 mg/litre chez une série
    d'invertébrés aquatiques. Chez les poisson, la toxicité est variable,
    avec une CL50 à 96 h qui peut aller de 0,59 mg/litre pour la truite
    arcen-ciel à environ 40 mg/litre pour l'orfe, le cyprin doré et la
    carpe.

         Chez la caille japonaise et le canari, on a obtenu une DL50
    (effet aigu, voie orale) de 10-50 mg/kg de poids corporel. Chez des
    étourneaux, une dose unique par voie orale de 2 mg/kg p.c. a provoqué
    une inhibition de l'acétylcholinestérase cérébrale 3 h après le
    traitement.

         Pour les lombrics terricoles, la CL50 du déméton-S-méthyl est de
    66 mg/kg sur 14 jours. Pour les abeilles, on a obtenu des valeurs de
    la DL50 de contact et par voie orale (effet aigu) respectivement
    égales à 0,21 et 0,6 par insecte. En traitant du blé d'hiver à la dose
    recommandée, on a constaté une réduction sensible du nombre
    d'invertébrés présents sur les feuilles (principalement des diptères
    du genre  Empididae) sans effet sur les invertébrés entomophages
    présents à la surface du sol.

    2.  Conclusions

         Le déméton-S-méthyl est un insecticide organophosphoré fortement
    toxique (classe Ib de la classification de l'OMS) (OMS, 1966). Son
    action toxique s'explique par l'inhibition de l'acétylcholinestérase
    au niveau des terminaisons nerveuses. L'exposition de la population
    générale résulte principalement des résidus présents dans les denrées
    alimentaires provenant des cultures traitées.

         Moyennant de bonnes pratiques agricoles et le respect des règles
    d'hygiène et de sécurité, la manipulation du composé lors de sa
    fabrication ou de son épandage ne devrait entraîner aucun effet
    indésirable. Des effets résultant d'une exposition chronique sont
    improbables.

         Le déméton-S-méthyl ne persiste pas dans l'environnement et il ne
    s'accumule pas chez les êtres vivants. Il est très toxique pour les
    invertébrés aquatiques et présente une toxicité notable pour les
    poissons et les oiseaux, aussi doit on considérer que pour ces
    organismes, le facteur de risque est élevé ou modéré. Néanmoins, on
    n'a pas signalé de mortalité importante dans la nature du fait de ce
    composé. Des précautions sont à prendre pour réduire au minimum
    l'exposition des organismes non visés (par ex. ne pas le pulvériser
    sur des étendues d'eau et veiller à ce que les gouttelettes
    d'insecticide ne soient pas entraînées vers les zones à respecter).

    3.  Recommandations

         Afin de protéger la santé et le bien-être des travailleurs et de
    la population dans son ensemble, il ne faut confier la manipulation et
    l'épandage du déméton-S-méthyl qu'à des opérateurs dûment formés et
    encadrés, qui auront le souci de respecter les mesures de sécurité et
    d'épandre le produit selon les règles.

    RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES

    1.  Resumen y evaluación

    1.1  Identidad, propiedades físicas y químicas, y métodos analíticos

         El demeton-S-metilo, un líquido oleoso de color amarillo pálido y
    olor penetrante, es un insecticida y acaricida organofosfatado
    sistémico y de contacto que se utiliza para combatir  Acarina, 
     Thysanoptera y  Homóptera en frutas, cereales, plantas ornamentales
    y hortalizas. Tiene una presión de vapor de 63,8 mPa a 20°C, es
    fácilmente soluble en la mayoría de los disolventes orgánicos, tiene
    una gran solubilidad en agua, de 3,3 g/litro a temperatura ambiente, y
    un coeficiente de reparto octanol/agua (log Pow) de 1,32. El
    demeton-S-metilo es estable en disolventes no acuosos.

         Los análisis de residuos y ambientales se realizan por extracción
    con un disolvente orgánico y oxidación a la sulfona correspondiente.
    Las mediciones se efectúan por cromatografía de gases utilizando un
    detector específico del fósforo.

    1.2  Fuentes de exposición humana y ambiental

         Antes de 1957, el metildemeton se comercializaba como mezcla de
    los isómeros demeton-S-metilo y demeton-O-metilo.

         El demeton-S-metilo se utiliza desde 1957. Su presentación es la
    de un concentrado emulsionable y se aplica por rociamiento a los
    cereales, frutas, plantas ornamentales y hortalizas. Se está
    sustituyendo por el oxidemetonmetilo, que es un metabolito del
    demeton-S-metilo producido en las plantas, el suelo y los mamíferos.

    1.3  Transporte, distribución y transformación en el medio ambiente

         La degradación hidrolítica del demeton-S-metilo depende del pH de
    la solución; a 22°C la semivida es de 63 días con un pH de 4, de 56
    días con un pH de 7 y de 8 días con un pH de 9. La principal vía de
    degradación en el suelo es la biodegradación. La semivida del
    demeton-S-metilo en el suelo es de unas 4 horas. Sin embargo, al cabo
    de 24 horas, el oxidemetonmetilo representa aún el 20-30 % de la dosis
    aplicada de demeton-S-metilo. El coeficiente de sorción (Kd) del
    demeton-S-metilo en el suelo oscila entre 0,68 y 2,66, dependiendo de
    la composición del suelo.

         La fotolisis no es uno de los principales mecanismos de
    degradación del demeton-S-metilo en el medio ambiente.

         Su metabolismo en el trigo de primavera es rápido y similar al
    que se produce en el suelo y en los mamíferos.

    1.4  Niveles ambientales y exposición humana

         La exposición primaria de la población humana en general se
    produce a través de los residuos de demeton-S-metilo en los cultivos
    alimentarios. En la reunión conjunta FAO/OMS sobre residuos de
    plaguicidas (JMPR) se recomendó una ingesta diaria admisible (IDA) de
    0,0003 mg/kg de peso corporal. Se trata de una IDA colectiva para el
    demeton-S-metilo, el oxidemetonmetilo y el demeton-S-metilsulfona, ya
    que los métodos habituales de análisis no diferencian entre estos tres
    compuestos.

         La exposición excesiva al demeton-S-metilo y su absorción cutánea
    produjeron toxicidad colinérgica en trabajadores insuficientemente
    protegidos durante el envasado de la formulación concentrada.

         Tras haber expuesto a voluntarios participantes en una simulación
    de rociamiento con una mezcla de demeton-S-metilo y demeton-O-metilo
    (30 y 70% respectivamente) a 8,8-27 mg/m3 de ambos componentes
    activos combinados, no se observaron efectos adversos en la actividad
    de la colinesterasa en el plasma ni en los eritrocitos.

    1.5  Cinética y metabolismo

         El demeton-S-metilo se absorbe rápida y casi completamente por el
    tracto intestinal en las ratas y se distribuye uniformemente a los
    tejidos (excepto una concentración elevada en los eritrocitos). Se
    metaboliza rápidamente y se excreta por orina. La concentración en la
    sangre disminuye, con una semivida inicial de unas 2 horas.
    Aproximadamente el 1% de la dosis oral sigue presente en el organismo
    24 horas después del tratamiento. La principal ruta metabólica del
    demeton-S-metilo en las ratas es la oxidación de la cadena lateral,
    que da lugar a la formación del sulfóxido correspondiente
    (oxidemetonmetilo) y, en menor medida, a la sulfona, tras una
    oxidación mayor. Otra ruta metabólica importante es la O-demetilación.

    1.6  Efectos en mamíferos de laboratorio y en sistemas de ensayo
         in vitro

    1.6.1  Exposición única

         El demeton-S-metilo produce toxicidad colinérgica. Los valores de
    la DL50 para los mamíferos oscilan entre 7 y 100 mg/kg de peso
    corporal, dependiendo de la vía de administración y de la especie.

    1.6.2  Exposición breve

         Un estudio alimentario inicial reveló que las ratas alimentadas
    con 50 mg de demeton-S-metilo por kg de la dieta habían sufrido una
    reducción notable de la actividad de la colinesterasa cerebral y

    eritrocitaria tras una exposición de 26 semanas. Se observaron
    síntomas colinérgicos en ratas alimentadas con 200 mg/kg de la dieta
    durante las 5 primeras semanas de exposición.

         En un estudio alimentario de un año de duración efectuado en
    perros se estableció un nivel sin efectos adversos observados (NOAEL)
    de 1 mg/kg de la dieta (equivalente a 0,036 mg/kg de peso corporal por
    día) sobre la base de los efectos de la colinesterasa cerebral.

    1.6.3  Exposición prolongada

         Se administró durante 21 meses a ratones una dieta que contenía
    0, 1, 15 ó 75 mg/kg de demeton-S-metilo. El NOAEL, determinado sobre
    la base de la inhibición de la colinesterasa cerebral, fue de 1 mg/kg
    de la dieta (equivalente a 0,24 mg/kg de peso corporal por día).

    En ratas cuya dieta contenía 0, 1, 7 ó 50 mg/kg de demeton-S-metilo,
    el NOAEL, determinado sobre la bases de la inhibición de la
    colinesterasa cerebral, fue de 1 mg/kg de la dieta (equivalente a
    0,05 mg/kg de peso corporal por día).

         La incidencia de tumores no aumentó en ninguna de esas especies.

    1.6.4  Irritación y sensibilización de la piel y los ojos

         El demeton-S-metilo es un irritante cutáneo y ocular leve. La
    prueba de maximización de Magnusson y Klingman dio resultados
    positivos en cobayos. Sin embargo, la prueba del parche cutáneo de
    Buehler no mostró indicios de sensibilización cutánea, lo que parece
    indicar que el uso práctico del demeton-S-metilo no debería acarrear
    problemas de sensibilización.

    1.6.5  Reproducción, embriotoxicidad y teratogenicidad

         En un estudio alimentario llevado a cabo en dos generaciones de
    ratas, se observó una reducción de la viabilidad y del peso corporal
    de los cachorros (generación F1b solamente) con una dosis de 5 mg de
    demeton-S-metilo por kg de la dieta. El NOAEL fue de 1 mg/kg de la
    dieta, equivalente a 0,07 mg/kg de peso corporal por día.

         El demeton-S-metilo no resultó embriotóxico ni teratogénico en
    ratas ni en conejos.

    1.6.6  Mutagenicidad y parámetros conexos

         El demeton-S-metilo produce mutaciones puntuales in vitro. Se han
    demostrado efectos cromosómicos in vivo con formulaciones comerciales
    solamente. La información disponible es insuficiente para realizar una
    evaluación adecuada del potencial genotóxico del demeton-S-metilo.

    1.6.7  Neurotoxicidad retardada

         El demeton-S-metilo no causó polineuropatías retardadas ni
    inhibición de la Esterasa Diana de Neuropatía en pruebas con gallinas
    a un nivel igual a la DL50 oral.

    1.6.8  Toxicidad de los metabolitos

         Las plantas y los mamíferos producen dos metabolitos del
    demeton-S-metilo (el oxidemetonmetilo y el demeton-S-metilsulfona) que
    también son plaguicidas comerciales y han sido ampliamente estudiados.
    Se ha señalado de que el perfil toxicológico de estos dos compuestos
    no difiere de manera significativa, cuantitativa ni cualitativamente,
    del demeton-S-metilo.

    1.7  Mecanismo de toxicidad: modalidad de acción

         El demeton-S-metilo es un inhibidor indirecto de la colinesterasa
    y su toxicidad que está relacionada con la inhibición de la
    acetilcolinesterasa en las terminales nerviosas. La
    acetilcolinesterasa inhibida por el demeton-S-metilo se reactiva
    espontáneamente, con una semivida in vitro de aproximadamente
    1,3 horas, como cabe esperar en la acetilcolinesterasa dimetil
    fosforilada.

    1.8  Efectos en el ser humano

         Se han notificado varios casos de intoxicación aguda con
    síndrome colinérgico tras intentos de suicidio. Los pacientes que
    sobrevivieron, inclusive una mujer embarazada, no presentaron efectos
    retardados.

         Tras una exposición laboral por inatención durante el envasado de
    la formulación comercial, algunos trabajadores desarrollaron una
    toxicidad colinérgica que precisó tratamiento farmacológico. El
    demeton-S-metilo se absorbió probablemente a través de la piel.
    Análogamente, condiciones de trabajo inapropiadas podrían haber sido
    la causa de una absorción cutánea excesiva durante la aplicación del
    demeton-S-metilo en algodonales.

    1.9  Efectos en otros organismos en el laboratorio y sobre el terreno

         Las CE50 96-h para las algas verdes se sitúan entre 8 y
    37 mg/litro. Las CL50 para diversos invertebrados acuáticos se
    encuentran entre 0,004 y 1,3 mg/litro. La toxicidad para los peces
    varía; la CL50 96-h oscila entre 0,59 mg/litro para la trucha
    arcoiris y unos 40 mg/litro para  Leuciscus idus, Carassius auratus 
    y la carpa.

         La DL50 oral aguda para la codorniz japonesa y el canario es de
    10-50 mg/kg de peso corporal. En el estornino, una dosis oral única de
    2 mg/kg de peso corporal produjo inhibición del 20% de la AChE
    cerebral 3 horas después del tratamiento.

         La CL50 del demeton-S-metilo en el suelo para las lombrices
    de tierra es de 66 mg/kg para un período de 14 días. La DL50 aguda
    oral y de contacto del demeton-S-metilo fue de 0,21 y 0,6 g/abeja
    respectivamente. Después de haber sido aplicado al trigo de invierno
    según la proporción propuesta, el demeton-S-metilo redujo
    significativamente el número de invertebrados en el follaje de los
    cultivos (principalmente Empididae), pero no el número de
    invertebrados entomófagos de la superficie del suelo.

    2.  Conclusiones

         El demeton-S-metilo es un éster organofósforado sumamente tóxico
    (pertenece a la clase Ib de la clasificación de la OMS) (OMS, 1996)
    utilizado como insecticida. La acción tóxica consiste en la inhibición
    de la acetilcolinesterasa en las terminales nerviosas. La exposición
    de la población en general se produce principalmente a causa de los
    residuos presentes en los productos agrícolas.

         Con buenas prácticas laborales y medidas de higiene y de
    seguridad, el demeton-S-metilo no debería producir efectos adversos
    durante la fabricación o la aplicación. Es poco probable que aparezcan
    efectos debidos a la exposición crónica.

         El demeton-S-metilo no es persistente en el medio ambiente y no
    se acumula en los organismos. Tiene una toxicidad aguda elevada para
    los invertebrados acuáticos y es tóxico para los peces y las aves,
    llevando aparejados factores de riesgo agudo o moderado elevados para
    esos organismos. Sin embargo, no se han comunicado muertes masivas
    significativas de organismos en el campo a causa de este compuesto.
    Habría que tomar precauciones para reducir al mínimo la exposición de
    organismos no combatidos (por ejemplo, no rociar sobre masas de agua y
    reducir al mínimo la exposición por desviación del rociado).

    3.  Recomendaciones

         Para la salud y el bienestar de los trabajadores y del público en
    general, el manejo y la aplicación del demeton-S-metilo deberían
    encomendarse exclusivamente a personal bien adiestrado y supervisado
    que aplique las medidas de seguridad necesarias y buenas prácticas de
    aplicación.





    See Also:
       Toxicological Abbreviations
       Demeton-s-methyl (ICSC)
       Demeton-s-methyl (PDS)
       Demeton-s-methyl (Pesticide residues in food: 1979 evaluations)
       Demeton-S-methyl (Pesticide residues in food: 1984 evaluations)