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    PESTICIDE RESIDUES IN FOOD - 1984


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1984




    The monographs



    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985

    DEMETON-S-METHYL

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

         Absorption, distribution and excretion of radioactivity were
    assayed in male Sprague-Dawley rats given single oral doses of 0.1,
    0.5, 5 or 10 mg/kg or intravenous doses of 0.5 or 1 mg/kg of
    14C- demeton-S-methyl. Additional female rats were given a single
    oral dose of 0.5 mg/kg. The test material was very rapidly and nearly
    completely absorbed following oral administration. More than 50
    percent of the administered radioactivity was eliminated in about
    three hours and approximately 90 percent within about eight hours
    following an oral dose of 0.5 or 5 mg/kg. Within 48 hours, radio-
    activity excreted in the urine accounted for 98-99 percent of the
    administered dose. Faeces accounted for 0.5 - 2 percent and exhaled
    air for about 0.2 percent. Radioactivity remaining in the body was
    about 61 percent of the administered dose at two hours (about 39
    percent having been already excreted at that time), about 1.3 percent
    at 24 hours, 0.5 percent at 48 hours and 0.2 percent at ten days.
    Total recovered radioactivity in experiments averaged 90-100 percent.
    Recovery percentages in excreta were largely independent of dose
    level, route of administration and sex of the animal. Rates of
    elimination were dose-proportional. In a separate experiment in which
    0.5 mg/kg of 14C-demeton-S-methyl was intraduodenally administered to
    male rats with bile duct fistulas, about 3 percent of the administered
    radioactivity was excreted in the bile within 24 hours.

         Blood levels of radioactivity peaked at about one hour following
    oral administration of 5 mg/kg of the test material. From zero to six
    hours following administration, the blood half-life was calculated to
    be about two hours. From six to 24 hours post-dosing, the half life
    was about six hours and after 24 hours it was considerably longer.
    Nearly all the radioactivity in blood after 24 hours was accounted for
    by a high retention in erythrocytes which had considerably higher
    levels of radioactivity than other organs and tissues for up to ten
    days. Serum levels after 24 hours were low compared to erythrocytes
    and at ten days were negligible. Distribution of radioactivity in
    various body organs and tissues was relatively uniform at two hours.
    Radioactivity did not concentrate in fat tissue or in the
    reticuloendothelial system (liver, spleen, bone marrow). By two days
    post-administration, radioactivity in most organs and tissues, except
    blood and erythrocytes, had dropped 130 fold. At ten days,
    radioactivity was nearly undetectable in the majority of organs and
    tissues except for blood and erythrocytes.  In a separate experiment,
    whole-body autoradiography confirmed previous findings regarding
    distribution of radioactivity in body tissues, but also indicated some

    localized accumulation or radioactivity in the pineal gland, thyroid
    and in some glands of the genital tract (Cowper's gland, seminal
    vescicle, accessory genital gland) (Weber, Patzschke and Wegner,
    1978).

    Biotransformation

         Rat urine samples from the experiments performed by Weber,
    Patzschke and Wegner in 1978 were collected and subjected to thin
    layer chromatographic and radioactivity counting methods designed to
    identify and quantitate the parent compound and metabolites. 
    Zero-to-eight hour and eight to 24-hour samples were collected from
    male rats given a single oral dose of 5 or 10 mg/kg of 
    14C-demeton-S-methyl. About 92 percent of the administered
    radioactivity was recovered in the urine within eight hours. The main
    route of metabolism of demeton-S-methyl was oxidation of the side
    chain to form the corresponding sulfoxide. Some further slight
    oxidation of the same side chain to form the corresponding sulfone was
    also observed. Three corresponding O-demethylated metabolites of the
    sulfide, sulfoxide and sulfone moieties were also identified in the
    urine, as were two additional metabolites presumably resulting from
    cleavage of the O-methylphosphoric ester group and subsequent
    methylation and sulfoxidation steps. The parent compound, 
    demeton-S-methyl, was nearly completely metabolized and was not
    detected in the urine (<1 percent). Approximately 99 percent of the
    radioactivity in the urine samples, equivalent to about 95 percent of
    the administered oral doses, was identified and quantitated as
    follows: demeton-S-methyl (unchanged parent compound), < 1 percent,
    demeton-S-methyl sulfoxide, 58 percent; demeton-S-methyl sulfone, 6
    percent; O-demethyl-demeton - S-methyl, 6 percent; 
    O-demethyl-demeton-D-methyl sulfoxide, 6 percent; 
    O-demethyl-demeton-S-methyl sulfone, 4 percent; 
    methyl sulfinyl-2-ethyl sulfinyl ethan, 8.4 percent and methyl
    sulfinyl-2-ethyl sulfonyl ethane, 10.4 percent. Another metabolite
    accounting for less than 1 percent of the radioactivity in the urine
    was not further investigated. Treatment of urine with glucuronidase or
    sulfatase did not indicate the presence of any glucuronide or sulfate
    conjugates (Ecker, 1978; Ecker and Colln, 1983).

    TOXICOLOGICAL STUDIES

    Acute Toxicity

    Buffalo Calves

         Single oral doses of Metasystox, containing 25% demeton-S-methyl,
    were administered to seven male buffalo calves (ten to twelve months
    of age) at a dosage level of 180 mg/kg. At the first signs of
    poisoning, 15 to 35 minutes later, two calves were treated repeatedly
    with atropine, D-tubocurarine and glucose. Another two calves were
    treated repeatedly with atropine, gallamine and glucose. Three calves
    were not treated. All calves displayed typical signs of cholinesterase
    poisoning. Treatments delayed but did not prevent deaths which

    occurred at about 2 hours in untreated calves and in about 23 hours in
    treated calves after administration of the test material (Mitra, Sud
    and Bahga, 1978).

    Special Study on Teratogenicity

    Rabbit

         E 154 (demeton-S-methyl, 52.2 percent active ingredient in
    xylene) was orally administered by intubation to mated Chinchilla
    Hybrid rabbits on gestation days 6 to 18 at dosage levels of 0
    (control), 3, 6 and 12 mg/kg/day. Each group consisted of 16 rabbits.
    The dams were observed two times daily for mortality, appearance and
    behaviour. Body weights were recorded daily and feed consumption was
    determined six times during the study. Caesarean sections were
    performed on gestation day 28. Dams were necropsied for gross changes
    and special attention was given to ovaries and particularly to uterine
    contents. All foetuses were counted, weighed, sexed, inspected
    externally and then subjected to thorough and comprehensive visceral
    and skeletal examinations.

         There were no mortalities. Appearance and behaviour were normal
    in all animals at all times in the control, low- and mid-dosage
    groups. In the high-dosage group, diarrhoea was observed in all
    animals after four to ten days of treatment. Beginning one to two
    hours after dosing, it persisted for six to 24 hours. There were no
    relevant differences in mean food consumption between the control,
    low- and mid-dosage animals. In the high-dosage group, mean food
    consumption, compared to control group intake, decreased 7.3 percent
    during gestation days 6 to 18 and 16.6 percent during gestation days
    19 to 24. There were no relevant difference in mean body weight gains
    during gestation between the control, low- and mid-dosage animals. In
    the high-dosage group, mean body weight gain, compared to the control
    gain, was decreased 6.9 percent during gestation days 6 to 18. The
    diarrhoea, decreased mean food consumption and decreased mean body
    weights observed in the high-dosage animals is attributed to the test
    material. The numbers of litters examined were 15, 16, 15 and 16 in
    the control, low- mid- and high-dosage groups respectively. One animal
    in the control group and one in the 6 mg/kg/day group had no
    implantations. There were no abortions. Regarding reproductive
    parameters, there were 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 foetuses or sex ratios. The numbers of foetuses examined were
    124, 129, 126 and 138 in the control, low-, mid- and high-dosage
    groups respectively. Although there were no relevant differences in
    mean foetal body weights between the control, low- and mid-dosage
    groups, a decrease in mean foetal body weight, compared to the mean
    control weight, of 6.6 percent was observed in the high-dosage group.
    This decrease may possibly be related to the maternal toxic effects
    noted at this dosage level or may possibly be a foetotoxic effect
    attributable to the test material.

         External and visceral examinations of foetuses revealed no
    findings attributable to effects of the test material. Two foetuses
    (from the same dam) in the 3 mg/kg/day group and one in the
    6 mg/kg/day group had external or visceral malformations. Skeletal
    examinations revealed two, one and one foetuses with skeletal
    malformations in the low-, mid- and high-dosage groups respectively.
    In addition, isolated instances of irregular ossified sternebrae
    and/or other minor skeletal variations occurred randomly across all
    groups. No teratogenic potential was observed in the rabbits in this
    study at dosage levels up to 12 mg/kg/day. The evidence for a possible
    foetotoxic effect (reduced foetal body weights) at the highest dosage
    level tested, 12 mg/kg/day, is equivocal (Becker,1983).

    SPECIAL STUDIES ON MUTAGENICITY

         For the results of special studies on the mutagenic potential of
    Demeton-S-methyl, please see Table 1.

    COMMENTS

         Demeton-S-methyl was rapidly and nearly completely absorbed in
    rats following oral administration. More than 50 percent of single
    doses up to 5 mg/kg was excreted in about three hours and
    approximately 90 percent within eight hours. By 48 hours, only 0.5
    percent remained in the body. Some binding to erythrocytes occurred
    for at least ten days. Excretion was almost entirely via the urine. The
    parent compound was nearly completely metabolized and was not detected
    in the urine (<1 percent). Compounds identified in the urine were
    oxydemeton methyl (58 percent), demeton-S-methyl sulfone (6 percent),
    three O-demethylated metabolites (16 percent) and two additional
    metabolites (19 percent).

         In a teratology study on rabbits, no teratogenicity was observed,
    but a slight decrease in mean foetal body weights was noted at the
    highest dose level, at which maternal toxicity occurred.

         Mutagenicity studies on demeton-S-methyl were equivocal in a
    number of in vitro tests but were negative in in vivo tests.

    FURTHER WORK OR INFORMATION NEEDED BEFORE AN ADI CAN BE ESTABLISHED

    Required:

         Teratology study in a second species.

         Reproduction study.

         Long-term feeding study in rodents.

         Six-month or longer feeding study in dogs.

         Delayed neurotoxicity study in hens.


        Table 1.  Special studies on mutagenicity of demeton-S-methyl

                                                                                                                           

    TYPE OF TEST                  TEST SUBJECT        PURITY                  RESULT                    REFERENCE
                                                                                                                           

    In vitro                                                         Activated      Non-activated

    Reverse Mutation              Saccharomyces
    Induction Assay               cerevisiae                                                            Hoorn, 1983
                                  Strain S138         unknown        negative       negative
                                  Strain S211         "              negative       negative

    Ames Salmonella/              Salmonella
    Microsome Test                typhimurium
                                  Strain TA98         "              negative       negative            Herbold, 1980c
                                  Strain TA100        "              positive       positive
                                  Strain TA1535       "              positive       positive
                                  Strain TA1537       "              negative       negative

    In vivo

    Micronucleus Test             Mouse
    (in bone marrow)              Strain Bor:NMRI     "                     negative                    Herbold, 1980b

    Dominant Lethal               Mouse
    Study                         Strain NMRI         "                     negative                    Herbold, 1980a
                                                                                                                           

    Table 1.  Special studies on mutagenicity of demeton-S-methyl sulphone

                                                                                                                           

    TYPE OF TEST             TEST SUBJECT             PURITY                  RESULT                    REFERENCE
                                                                                                                           

    In vitro                                                         Activated      Non-activated

    Reverse Mutation         Saccharomyces
    Induction Assay          cerevisiae                                                                 De Graff, 1983
                             Strain 8138              unknown        negative       negative
                             Strain S211              "              positive       positive

    Ames Salmonella/         Salmonella
    Microsome Test           typhimurium
                             Strain TA98              "              negative       negative            Herbold, 1980b
                             Strain TA100             "              positive       positive
                             Strain TA1535            "              negative       negative
                             Strain TA1537            "              negative       negative

    In vivo

    Micronucleus Test        Mouse
    (in bone marrow)         Strain Bor:NMRI          "                     negative                    Herbold, 1981

    Dominant Lethal          Mouse
    Study                    Strain NMRI              "                     negative                    Herbold, 1980a

    In vitro

    Primary Rat Hepatocyte   Rat, male                                      negative                    Myhr, 1983
    Unscheduled DNA          Strain Fischer 344       unknown
    Synthesis Assay

    Mouse Lymphoma           Mouse
    Forward Mutation         Strain Fischer L5178Y    "              positive       positive            Witterland, 1984
    Assay

    Human Leucocyte Test     Human                    "                     positive                    Vaidya & Patankar, 1980
                                                                                                                           

    Table 1.  (continued)

                                                                                                                           

    TYPE OF TEST             TEST SUBJECT             PURITY                  RESULT                    REFERENCE
                                                                                                                           

    Sister Chromatid         Lymphocytes,
    Exchange Assay           Human, male              *              positive                           Pandita, 1983

    In vivo

    Micronucleus Test        Mouse
    (in bone marrow)         Strain Bor:NMRI          unknown        negative                           Herbold, 1980a

    Micronucleus Test        Mouse
    (in bone marrow)         Strain Bor:NMRI          "              negative                           Herbold, 1981

    In vivo

    Micronucleus Test        Mouse
    (in bone marrow)         Strain Swiss             unknown        positive                           Vaidya & Patankar, 1980

    Micronucleus Test        Mouse
    (in bone marrow)         Strain Swiss             *              positive                           Pandita, 1983

    Sister Chromatid         Chinese Hamster          unknown        negative                           Herbold, 1983
    Exchange (in bone marrow)

    Dominant Lethal          Mouse
    Study                    Strain NMRI              "              negative                           Herbold, 1980c
                                                                                                                           

    *  Test material was Metasystox R Insecticide

    Table 1.  Special studies on mutagenicity of oxydemeton-S-methyl

                                                                                                                           

    TYPE OF TEST             TEST SUBJECT             PURITY                  RESULT                    REFERENCE
                                                                                                                           

    In vitro                                                         Activated      Non-activated

    Reverse Mutation         Saccharomyces
    Induction Assay          cerevisiae                                                                 Jagannath, 1980
                             Strain S138              unknown        negative       negative
                             Strain S211              "              negative       negative

    Salmonella               Salmonella
    typhimurium              typhimurium
    Microsome Test           Strain TA98              *              positive       positive            Pandita, 1983
                             Strain TA100             *              positive       positive

    Ames Salmonella/         Salmonella
    Microsome Test           typhimurium
                             Strain TA98              unknown        negative       negative            Herbold, 1980b
                             Strain TA100             "              positive       positive
                             Strain TA1535            "              positive       positive
                             Strain TA1537            "              negative       negative

    Recombination            Bacillus
    Assay                    Subtilis
                             Strain H17               "              negative       negative            Jagannath, 1980
                             Strain M45               "              negative       negative
                                                                                                                           
    

    Desirable:

         Observations in humans.

    REFERENCES

    Becker, H. Embryotoxicity and teratogenicity study on E 154 in
    1983      rabbits. Research and Consulting Company Ltd. Itingen,
              Switzerland. Report No. R2422. Submitted by Bayer AG to WHO.

    Ecker, W. Biotransformation of (ethylene-1-14C) Demeton-S-methyl in
    1978      rats. Bayer AG, Institute for Pharmacokinetics. Pharma
              Report No. 7458. Submitted by Bayer AG to WHO.

    Ecker, W. and Colln, R. Biotransformation of Demeton-S-methyl in rats.
    1983      (final report). Bayer AG, Sparte Pharma. PF Report No. 1759,
              Pharma Report No. 11431(F). Submitted by Bayer AG to WHO.

    Herbold, B. E 25/154 (Demeton-S-methyl; Metaisosystox (i) active
    1980a     ingredient: dominant lethal study on male mouse to test for
              mutagenic effects. Bayer AG, Institute for Toxicology.
              Report No. 9336. Submitted by Bayer AG to WHO.

    Herbold, B. E 25/154 (Studien Nr.: E 25/154/004): Mikronucleus-Test an
    1980b     der Maus zur Prüfung auf mutagene Wirkung. Bayer AG,
              Institute for Toxicology, Report No. 8932. Submitted by
              Bayer AG to WHO (in German).

    Herbold, B. E 25/154 (Studien Nr.: E 25/154/002):
    1980c     Salmonella/Mikrosomen, Test zur Untersuchung auf
              punktmutagene Wirkung. Bayer AG, Institute for Toxicology.
              Report No. 8809. Submitted by Bayer AG to WHO (in German)

    Hoorn, A.J.W. Mutagenicity evaluation of E 154 50 VL (in xylene) batch
    1983      no. 808 204 103, content 53.1% in the reverse mutation
              induction assay with Saccharomyces cerevisiae strains S138
              and S211a, (final report). Veenendaal, The Netherlands,
              Litton Bionetics. Bayer Study No. T 5006333, Report No. R
              2372. Submitted by Bayer AG to WHO.

    Mitra, P.K., Sud, S.C. and Bahga, H.S. Acute oral toxicity of
    1978      Metasystox in buffalo calves. Indian J. Exp. Biol. 16(7):
              813-815. Submitted by Bayer AG to WHO.

    Weber, H., Patzschke, K. and Wegner, L.A. (14C)Demeton-S-methyl
    1978      (Metasystox i Active Ingredient):  biokinetic studies on
              rats. Bayer AG, Institute for Pharmacokinetics. Pharma
              Report No. 7491. Submitted by Bayer AG to WHO.


    See Also:
       Toxicological Abbreviations
       Demeton-s-methyl (EHC 197, 1997)
       Demeton-s-methyl (ICSC)
       Demeton-s-methyl (Pesticide residues in food: 1979 evaluations)