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    OXAMYL

    EXPLANATION

         Oxamyl was evaluated by the Joint Meetings in 1980 and 1984
    (Annex 1, FAO/WHO, 1981a, 1985b). A toxicological monograph was
    prepared by the Joint Meeting in 1980 (Annex 1, FAO/WHO, 1981b) and a
    monograph addendum was prepared in 1984 (Annex 1, FAO/WHO, 1985c). A
    full acceptable daily intake of 0-0.03 mg/kg b.w. was estimated in
    1984. Data concerning the dimethylcyanoformamide (DMCF) metabolite
    were inadvertently omitted from the 1984 monograph addendum; they were
    evaluated by the 1985 Meeting and are included in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Toxicological studies

    Special study on mutagenicity of DMCF

         DMCF did not show any mutagenic potential when tested in an Ames
    test with and without metabolic activation (Table 1).

    Special study on acute toxicity of DMCF

         A separate determination of the acute lethal dose (ALD) to rats
    was estimated to be 450 mg/kg b.w. (Ashley, 1974).

    Special study on subchronic toxicity of DMCF

         Groups of ChR-CD rats (16 males and 16 females per group) were
    administered DMCF (100% purity) in the diet at dose levels of 0, 50,
    150, or 450 ppm for 90 days. All animals were observed for overt
    toxicity and behavioural changes daily, while body weight and food
    consumption were recorded weekly. Haematologic, clinical chemistry and
    urinalysis determinations were performed on 10 rats/sex from the
    control, intermediate and high-dose groups after 30, 60 and 90
    continuous days of study. Blood samples were taken from the tail.
    Gross pathological examinations were performed on surviving animals
    (except animals used in a subsequent reproduction study). Ten rats per
    sex in the control and high-dose groups were examined microscopically,
    including target organs from animals in the other dose groups.

        Table 1.  Results of mutagenicity assays of DMCF
                                                                                                   

    Test System      Test Object       Concentration     Purity           Results        Reference
                                       of DMCF Used
                                                                                                   

    Ames Test        S. typhimurium    250, 500,         approx. 100%     Negative.        Summers,
     (both with      TA 98             1000, 2500,                        Positive         1978
     and without     TA 100            3000, 5000,                        responses
     metabolic       TA 1535           5000, 7000,                        with 2-AA,
     activation)     TA 1537           and 10,000                         2-NF, MNNG
                     TA 1538           g/plate                           and 9-AAc.
                                                                                                   

    
         Results from the 90-day study demonstrated decreased food
    consumption and body-weight gain at the high dose for both sexes. On a
    mg/kg b.w./day basis, the average compound ingestion for 50-ppm males
    and females was 4.0 and 4.2 mg/kg b.w., respectively; for 150-ppm
    males and females it was 11.4 and 12.6 mg/kg b.w., respectively; and
    for 450-ppm males and females it was 34.4 and 35.7 mg/kg b.w.
    Hematological examinations demonstrated decreased red blood cells
    (RBC), hemoglobin, hematocrit, white blood cells (WBC), and increased
    eosinophils (%) in males and females given 450 ppm. At 150 ppm, RBC
    and WBC were decreased in females only, and then only at the 90-day
    interval. Urinalysis was unremarkable except for males and females
    given 50 ppm, where both sexes had significantly-increased volumes;
    however, the urine osmolality of males was increased, whereas the
    urine osmolality of females decreased (these were 90-day analyses
    only). Clinical chemistries (alkaline phosphatase, glutamate-pyruvate
    transaminase (GPT), glutamate-oxaloacetate-transaminase (GOT), and
    lactate dehydrogenase (LDH) were similar to controls except for an
    apparent decreased LDH in females at all levels at the 90-day
    interval. This is probably the result of a 2-fold increase in the
    control females' LDH value at the same time interval and not a
    compound-related effect. Males did not demonstrate the same response.

         Organ-weight data were not reported, and gross and histopathology
    were extremely limited (average 10 rats/sex/dose, limited information
    on tissues reported). Examination of eyes from all groups demonstrated
    an increased incidence in localized focus of retinal atrophy in
    females at 150 and 450 ppm, compared to controls (0-1/10, 150-6/10,
    450-4/10); and for males at 150 and 450 ppm (0-0/10, 150-3/10,
    450-1/10). Although not increasing in a dose-related manner, the
    occurence nonetheless appears to be a consequence of compound
    ingestion. The incidence of hydronephrosis in males was also increased
    over controls at 150 and 450 ppm (0-1/10, 150-6/10, 450-7/10). This
    incidence was not similarly apparent in females, although females in
    all groups demonstrated minute foci of mineralization (0-3/10,
    50-6/10, 150-4/10, 450-9/9). These changes were indicated to be common
    findings among ChR-CD rats; however, the incidence appears to increase
    with dose, although not uniformly between sexes. Based on the limited
    data reported, the effects on kidneys and eyes at > 150 ppm, and
    the haematological effects noted at > 150 ppm, the no-observed-
    effect level in this study is considered to be 50 ppm (equal to 4.0
    and 4.2 mg/kg b.w. in males and females, respectively). Insufficient
    data were presented on the reproductive evaluation of DMCF to permit
    an evaluation (Willigan, 1977).

    COMMENTS

         Information presented on the metabolite DMCF demonstrates
    moderate toxicity in rats.

         A subchronic 90-day feeding study in rats using DMCF demonstrated
    no apparent compound-related effects at 50 ppm (equal to 4.0 and
    4.2 mg/kg b.w. in males and females, respectively). Target organs
    appeared to be kidneys and eyes, although limited data were presented.

         A mutagenicity assay using the Salmonella typhimurium test
    system was negative.

         These do not alter previous evaluations for oxamyl, so the ADI
    for oxamyl was reaffirmed.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg b.w.

         Rat: 50 ppm in the diet, equivalent to 2.5 mg/kg b.w.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.03 mg/kg b.w.

    FURTHER WORK OR INFORMATION DESIRED

         Observations in man.

    REFERENCES

    Ashley, W.E. Acute oral test. Haskell Laboratory Report No. 585-74
    1974      (Unpublished report submitted to WHO by E.I. DuPont de
              Nemours & Co.).

    Summers, J.C. Mutagenic activity of 1-cyano-N,N-dimethylformamide in
    1978      the Salmonella/microsome assay. Haskell Laboratory Report
              No. 284-78 (Unpublished report submitted to WHO by E.I.
              DuPont de Nemours & Co.).

    Willigan, D.A. Ninety-day feeding study in rats with 1-cyano-N,N-
    1977      dimethyl-formamide (INN-79) metabolite of Vydate(R). Haskell
              Laboratory Report No. 630-76 (Unpublished report submitted
              to WHO by E.I. DuPont de Nemours & Co.).
    


    See Also:
       Toxicological Abbreviations
       Oxamyl (JMPR Evaluations 2002 Part II Toxicological)
       Oxamyl (Pesticide residues in food: 1980 evaluations)
       Oxamyl (Pesticide residues in food: 1983 evaluations)
       Oxamyl (Pesticide residues in food: 1984 evaluations)