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    FAO/PL:1967/M/11/1
    WHO/Food Add./68.30

    1967 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD

    THE MONOGRAPHS

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Committee on Pesticide Residues, which met in Rome, 4 - 11 December,
    1967. (FAO/WHO, 1968)

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
    WORLD HEALTH ORGANIZATION
    Rome, 1968

    OXYDEMETON-METHYL

    This pesticide was evaluated by the 1965 Joint Meeting of the FAO
    Committee on Pesticides in Agriculture and the WHO Expert Committee on
    Pesticide Residues (FAO/WHO, 1965) under the name of demeton-S-methyl
    sulfoxide, a commercially produced isomer of demeton-S-methyl. Since
    the previous publications, the results of additional experimental work
    have been reported. This new work has been summarized, combined with
    that previously published, and discussed in the following monograph.
    All toxicological studies discussed in this monograph were conducted
    with the commercially produced metabolite, oxydemeton-methyl (the
    currently accepted ISO name of the compound).

    EVALUATION FOR ACCEPTABLE DAILY INTAKES

    Biochemical aspects

    Demeton-S-methyl sulfoxide is produced in plants from the metabolism
    of demeton-methyl. The sulfoxide is further broken down by plants and
    animals. After injection into mice, 97-98 percent is rapidly
    eliminated (Niessen et al., 1963).

    In vitro: Molar concentrations necessary to produce 50 percent
    inhibition of sheep erythrocyte cholinesterase, expressed as I50 in
    30 minutes at 37°C, are as follows (Heath and Vandekar, 1957) :

         demeton-S-methyl P=0 isomer        6.5 × 10-5

         demeton-S-methyl sulfoxide         4.1 × 10-5

         demeton-S-methyl sulfone           2.3 × 10-5

    Acute toxicity

                                                                                  
                                         LD50 mg/kg
    Animal               Route           body-weight        References
                                                                              

    Mouse                Oral                30        DuBois and Plzak, 1962

    Mouse           Intraperitoneal        8-12        DuBois and Plzak, 1962

    Rat                  Oral             30-75        Mühlmann and Tietz, 1956;
                                                       Schrader, 1963

    Rat             Intraperitoneal          20        DuBois and Plzak, 1962

    Rat               Intravenous            47        Heath and Vandekar, 1957

    (cont'd)
                                                                              
                                         LD50 mg/kg
    Animal               Route           body-weight        References
                                                                              

    Guinea-pig           Oral               120        DuBois and Plzak, 1962

    Guinea-pig      Intraperitoneal          30        DuBois and Plzak, 1962
                                                                              
        Short-term studies

    Rat. In groups of 20 rats, administration of the sulfoxide by mouth
    in doses of 5 mg/kg body-weight daily for 3 months caused no signs of
    intoxication or pathological changes, and 10 mg/kg body-weight for 21
    days caused an inhibition of cholinesterase activity after 4-6 days
    (Wirth, 1958).

    Groups of 6 males and 6 females received concentrations of 20 ppm or
    less in the diet for a period of 16 weeks: no significant influence on
    growth-rate or food consumption was observed. Ten ppm or less caused
    no significant depression of erythrocyte cholinesterase activity.
    Gross and microscopic examination of the tissues of rats revealed no
    indication of toxic effects except for fatty changes in the livers of
    some of the rate fed 10 ppm and 20 ppm (Bär, 1963). 50 ppm for 6
    months had no effect on weight gains in a group of 6 rats and showed
    no pathological changes attributable to the action of the compound.
    The brain and blood cholinesterase activity was strongly inhibited.
    Concentrations of 100 and 200 ppm produced signs of intoxication in
    the first 3 weeks of the experiment (Vandekar, 1958).

    In a three-generation reproduction study at dietary levels of 0, 10,
    25 and 50 ppm, groups of 10 males and 20 females of each generation,
    except the third filial, were maintained through two successive
    matings. Second litter animals were used for composing the succeeding
    generation groups. The third filial generation was maintained only to
    weaning age. At 50 ppm in all generations, the number of pregnancies
    and the number of young per litter were significantly reduced.
    Histological examination of the second filial generation animals
    disclosed only reduced oögenesis in 3 of the 10 in the 50 ppm females,
    with no apparent effect at 25 ppm. 10 ppm was without effect on the
    number of pregnancies, the number of young per litter, the number of
    surviving young up to 21 days and microscopic appearance of major
    organs. Erythrocytic cholinesterase activity, expressed in percentage
    of controls, was reduced to 83 per cent in males and 67 per cent in
    females in the third filial generation, after 21 days; and in the
    second generation, after 27 weeks, to 83 per cent in the males and to
    61 per cent in the females. Erythrocytic cholinesterase activity was
    more consistently reduced, in proportion to the test level, at the two
    higher levels. No gross abnormalities nor effect on food consumption
    or body-weight gain were seen at any test level (Taylor, 1967).

    Dog. Diets containing 5, 10 and 20 ppm have been fed to male and
    female beagle dogs for periods of 12 weeks. None of these dose levels
    produced significant changes in food consumption or body-weight or
    gave rise to cholinergic signs. Levels of 10 ppm or less did not cause
    significant inhibition of serum or erythrocyte cholinesterase activity
    (Root et al, 1963).

    Long-term studies

    No data available.

    Comments

    For the establishment of the ADI short term studies on rats and dogs
    can be taken into consideration. In the rat 10 ppm, equivalent to 0.5
    mg/kg/day causes no toxicologically significant inhibition of serum or
    erythrocyte cholinesterase activity and no adverse effect on
    reproduction in three successive generations. In the dogs 10 ppm,
    equivalent to 0.25 mg/kg/day, did not show any effect.

    TOXICOLOGICAL EVALUATION

    Level causing no significant toxicological effect

    Rat 10 ppm in the diet equivalent to 0.5 mg/kg/day

    Dog 10 ppm in the diet equivalent to 0.25 mg/kg/day.

    Estimate of acceptable daily intake for man

    0 - 0.0025 mg/kg body weight.

    Further work desirable

    Observations of the effect in man.

    EVALUATION FOR TOLERANCES

    Not considered at the 1967 Joint Meeting.

    REFERENCES PERTINENT TO EVALUATION FOR ACCEPTABLE DAILY INTAKES

    Bär, F. (1963) Personal communication Unpublished report.

    DuBois, K. and Plzak, G.J. (1962) Toxicol. Appl. Pharmacol., 4, 621

    FAO/WHO. (1965) FAO Mtg. Rpt. PL.1965/10/1; WHO Food Add./27.65

    Heath, D.F. and Vandekar, M. (1957) Biochem. J., 67, 187

    Mühlmann, R. and Tietz, H. (1956) Höfchen-Briefe, 9, 116

    Niessen, H., Tietz, H., Hecht, J. and Kimmerli, G. (1963) Arch.
    Toxikol., 20, 44

    Root, M., Gowan, J. and Doull, J. (1963) Unpublished report.

    Schrader, G. (1963) Die Entwicklung neuer insectizider
    Phosphorsäure-Ester, Verlag Chemie GMBH, Weinheim.

    Taylor, R.E. (1967) Unpublished report submitted by Chemagro
    Corporation

    Vandekar, M. (1958) Brit. J. industr. Med. 15, 158

    Wirth, W. (1958) Arch. exp. Path. Pharmacol., 234, 352
    


    See Also:
       Toxicological Abbreviations
       Oxydemeton-methyl (JMPR Evaluations 2002 Part II Toxicological)
       Oxydemeton-methyl (FAO/PL:1968/M/9/1)