Sponsored jointly by FAO and WHO


    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



         Oxamyl was first evaluated by the Joint Meeting in 1980 1/ and a
    temporary ADI was estimated to be 0-0.01 mg/kg body weight. Additional
    data were submitted in 1983 to the JMPR, but were received too late to
    be evaluated fully. The temporary ADI was extended pending evaluation
    of these data and clarification of the no-effect level in the rat.
    Data on oxamyl and the dimethylcyanoformamide (DMCF) metabolite
    requested by previous joint meetings are reviewed in this monograph




         Twenty male mice (Swiss - Webster) received a dosage of
    oxamyl-1-14C injected intraperitoneally, equivalent to 1.16 mg/kg
    body weight. Pooled urine and faecal samples were collected from
    groups of five mice at 6, 12, 24, 48, 72 and 96 h after dosing. At
    96 h, all mice were killed and blood and other selected tissues were
    analysed. Within 6 h, 72.7 percent and 3.0 percent of the dose were
    excreted in the urine and faeces respectively, and 88.7 percent and
    7.7 percent by 96 h. Parent oxamyl-14C accounted for approximately
    15.5 percent of the organosoluble residue, and DMTO (43 percent) and
    DMOA (20 percent) were the major metabolic forms found in urine.
    Generally, tissue residues were low, ranging from 11 ng/g in testes to
    37 ng/g in liver, identified only as oxamyl-14C equivalents. Results
    from these analyses in mice support previous metabolism studies in
    rats (Chang & Knowles, 1979).

         Additional information concerning the identification of animal
    tissue residues in rats indicated that 14C residues in tissues
    (i.e. hair and skin) were actually derived from metabolic breakdown of
    oxamyl and subsequently reincorporated into natural products, e.g.
    amino acids. Ethyl extraction, including acid hydrolysis, of these
    tissues failed to remove any radioactivity, demonstrating the absence
    of oxamyl, oxamyl oxime, mono-methyl derivatives, DMCF or conjugates
    of these derivatives. Further clarification or identification of these
    fragments is unnecessary.


    1/  See Annex 2 for FAO and WHO documentation.


    Special Study on Teratogenicity


         Groups of rabbits (17 New Zealand Albino Rabbits/group) were
    administered oxamyl orally at dosages of 0, 1, 2 and 4 mg/kg body
    weight from days 6 through 19 of gestation in a standard teratology
    bioassay. On day 29 of gestation, all surviving dams were sacrificed
    and foetuses delivered by Caesarean section.

         There was no mortality attributed to oxamyl and no treatment-
    related clinical observations were noted. There was a statistically
    significant body weight decrease in the mid- and high-dose females
    during the treatment period. However, these females demonstrated
    comparable body weight gains to controls during the post-treatment
    period (days 19 to 29). Food consumption was not significantly
    different between control and treatment groups. Pregnancy rates
    between treated and control groups were comparable (88 vs 100 percent
    except in the high-dose group where marginal effects were observed (76
    percent pregnant). The data related to reproduction (implantations,
    corpora lutea and live young) were comparable, except for resorptions,
    which were slightly increased in mid- and high-dose females. Foetal
    viability was slightly reduced in the high-dose group. Crown-rump
    measurements and mean foetal body weights were not affected by
    treatment. Internal development, including somatic and skeletal
    development, was comparable among all groups. There were no
    teratogenic effects from the administration of oxamyl to pregnant
    rabbits at doses up to and including 4 mg/kg bw during the critical
    period of organogenesis. There were, however, faetotoxic effects at
    the high dose (Hoberman et al., 1980).

    Special Study on Carcinogenicity


         Groups of CD-1 mice (80/sex/group) were administered oxamyl (97.1
    percent a.i.) in the diet at dose levels of 0, 25, 50 and 100 ppm for
    two years. The 100 ppm dose was reduced to 75 ppm after six weeks
    because of increased mortality. Additional animals were added from the
    same shipment group. Animals were 4-1/2 to 5 weeks old at the start of
    the study, except for the animals added. Mice were examined daily for
    signs of mortality, toxicity and behavioral changes; weekly for
    palpable masses; and regularly weighed for body weight changes. Food
    consumption was similarly determined on a routine basis.
    Haematological samples, taken from the orbital sinus, were analysed
    periodically on ten male and ten female mice randomly selected from
    each group. Selected organs weighed from all surviving animals
    included: liver, kidneys, testes, brain and brain stem, and heart.
    Gross necropsy was performed on all animals together with microscopic
    examinations, which included a complete series of organs and tissues.

         There was no long-term reduction in survival associated with the
    ingestion of oxamyl, although initially (<6 weeks) high dose males
    and mid- and high-dose females experienced high mortality rates. The
    high dose was accordingly reduced from 100 to 75 ppm and replacement
    animals added. Males demonstrated significant reductions in body
    weight throughout the study at 50 ppm. Although 75 ppm male body
    weights were significantly reduced during the first 28 weeks, they
    were not consistently depressed for the remainder of the study.
    Females demonstrated significant but sporadic body weight decreases at
    50 and 75 ppm throughout the study. Food consumption for females was
    equally sporadic, with no dose-related trends throughout the test.
    Males, however, at 50 and 75 ppm showed a consistent pattern of
    decreased food consumption throughout the study. Sporadic changes were
    evident at 25 ppm for the first 28 weeks, but there were uniform
    decreases in food consumption from weeks 38 to 84.

         There were no apparent dose-related changes in the haematological
    parameters, although significant decreases in RBC, HGB and HCT were
    evidenced at four weeks for high dose males. These were not similarly
    effected at other time points. Morphology of peripheral blood did not
    identify any unusual cell types such as reticulocytes, spherocytes,
    Howell-Jolly bodies, etc. These spurious results are not considered to
    be related to treatment. Organ weights, both absolute and relative,
    were not affected by treatment, except for a marginal increase in
    kidney-to-body weight ratio for high dose males. Gross and
    histopathological examinations revealed evidence of glomerulo
    sclerosis and chronic interstitial nephritis among all groups,
    including controls. There was no apparent compound-related effect for
    this response and, therefore, the increase in kidney-to-body weight
    ratio for high-dose males is probably related to the noted decrease in
    body weight and not to a specific target organ effect. The occurrence
    of benign lung adenomas in males was apparently inversely proportional
    to dose. This trend was not evident in females, as low- and high-dose
    groups had a higher incidence than controls, but there was no
    measurable difference between control and mid-dose females. These
    occurrences are considered fortuitous since the incidence is within
    historical control data accumulated from five other studies from the
    same laboratory conducted during the same time period (1978-81).
    Oxamyl was not oncogenic in this strain of mouse at doses up to and
    including 75 ppm. The NOEL was demonstrated at 25 ppm, based on body
    weight depression (Adamik et al., 1981).

         The available data concerning body weight depression in rats were
    re-evaluated in order to clarify an apparent compound-related effect
    at 50 ppm. The two-year rat feeding study and three-generation rat
    reproduction study indicate that this effect is most noticeable in
    males. Body weight effects in the reproduction study were not
    statistically significant at 50 ppm, although slightly lower than
    controls, whereas 100 and 150 ppm did provide measureable body weight
    depression compared to controls. The data from the two-year rat
    feeding study demonstrate that male body weights are depressed
    initially, reach a plateau and remain 15-20 g less than controls for
    the majority of the study. Weight gain for the 50 ppm males actually

    exceeds controls at 12 months and remains greater than controls until
    month 21. Apparently, during the early growth stages where dietary
    intake versus body weight is increased, animals are receiving more
    oxamyl on a mg/kg body weight basis. Such changes are evident until
    the rats are 10 to 14 weeks old, when their food consumption and body
    weight stabilize or reach a plateau. The body weight decrease was
    reversed when rats reached this plateau in their normal growth curve
    and food consumption vs body weight became stabilized. It would appear
    that if rats had received the same amount in the diet on a mg/kg body
    weight basis throughout their normal lifespan, no measureable
    differences would be evident in body weight gain. Furthermore, this
    level produced no measureable adverse effect on longevity, haemotology
    or clinical chemistry and no pathological change was noted. Therefore,
    on a mg/kg bw basis it would appear that 2.5 mg/kg bw is without
    adverse effect on the body weight of rats.

    Special Studies on Mutagenicity

         Oxamyl was negative in a series of mutagenicity studies (see
    Table 1).


         Oxamyl was assigned a temporary ADI in 1980 and additional data
    and information were identified, which have been reviewed in this

         Metabolism studies in mice support previously reviewed studies;
    73 percent of the dose (1.16 mg/kg ip) was excreted in urine within
    six hours. Tissue residues were low, ranging from 11 ng/g (testes) to
    37 ng/g (liver).

         Information presented indicated that residues in skin and hair of
    rats were derived from the metabolic breakdown of oxamyl. The absence
    of toxicity indicates that identification of these fragments is

         A teratology study in rabbits provided no evidence of teratogenic
    effects at doses up to and including 4 mg/kg body weight, although
    faetotoxicity was indicated at this high dose.

         Mutagenicity data were negative, as was a mouse oncogenicity
    study. Reduced food consumption and decreased body weight gains were
    evident at 50 and 75 ppm, but not at 25 ppm.

         The available data concerning body weight depression, primarily
    in rats, were re-evaluated to clarify an apparent compound-related
    effect at 50 ppm. It was determined that oxamyl produced no adverse
    effects on body weight gain at 2.5 mg/kg bw. Accordingly, the meeting
    determined that sufficient toxicity data were available to estimate an

        TABLE 1.  Special Studies on Mutagenicity


    Test system         Test organism       Concentration          Purity     Results                   Reference
                                            of oxamyl used

    Ames Test           S. typhimurium      50, 100, 500,          97.1%      Negative                  Summers,
    (both with          TA 98               1000, 5000, and                                             1981
    without             TA 100              10,000 ug/plate
    metabolic           TA 1535
    activation)         TA 1537

    In Vitro            Chinese             1st trial non-         97.1%      No evidence               Galloway,
    Cytogenetics        Hamster             activation: 2.3,                  of mutagenic              1982
                        Ovary Cells         7.0, 23.3, 70                     or clastogenic
                                            and 700 ug/ml                     potential
                                            2nd trial non-                    due to
                                            activation: 12.5,                 oxamyl.
                                            25, 50, 75 and                    Positive response
                                            100 ug/ml                         with mitomycin C
                                            Activation: 2.3,                  and cyclophosphamide
                                            7.0, 23.3, 70
                                            233, and 700 ug/ml

    Unscheduled         Rat                 1x10-5 1x10-4,         97.1%      Negative.                 Summers,
    DNA Repair          hepatocytes         1x10-3', 1x10-2',                 Positive                  1982a
    Synthesis                               0.1, 10mM oxamyl                  control
                                            with gentamycin                   (1 mM DMBA)
                                            (50 ug/ml) and                    gave expected
                                            tritium labeled                   positive
                                            thymidine (5 uCi/                 response

    TABLE 1.  (continued)


    Test system         Test organism       Concentration          Purity     Results                   Reference
                                            of oxamyl used

    Forward             Chinese             Nonactivation:         97.1%      Oxamyl was                Summers,
    Mutation            Hamster             50, 200, 500 and                  apparently                1982b
                        Ovary Cells         750 uM                            negative in
                        and                 Activation:                       both activated
                        Hypoxanthine-       25, 100, 300,                     and non-
                        guanine             500 and 700 uM                    activated
                        phosphoribosyl                                        systems

    Level Causing no Toxicological Effect

         Dog: 100 ppm in the diet, equivalent to 2.5 mg/kg bw/day;

         Rat: 50 ppm in the diet, equivalent to 2.5 mg/kg bw/day.

    Estimate of Acceptable Daily Intake for Man

         0-0.03 mg/kg bw


    Desirable: Observations in humans


    Adamik, E.R. et al. Long-term feeding study in mice with oxamyl.
    1981      Project #WIL-77033; HLO-252-81 from Wil Research
              Laboratories, Inc., submitted by E.I. DuPont de Nemours to
              WHO. (Unpublished)

    Chang, K-M & Knowles, C.O. Metabolism of oxamyl in mice and two-
    1979      spotted spider mites. Arch. Environ. Contam. Toxicol.,

    Galloway, S.M. Mutagenicity evaluation of H14190 (oxamyl) in an in
    1982      vitro cytogenetic assay measuring chromosome aberration
              frequencies in Chinese hamster ovary (CHO) cells. Report
              from Litton Bionetics, Inc. submitted by E.I. DuPont de
              Nemours to WHO. (Unpublished)

    Hoberman, A.M. et al. Teratology study in rabbits (Project #201-245;
    1980      HLO-0801-80). Report from Hazleton Laboratories America,
              Inc. submitted by E.I. DuPont de Nemours to WHO.

    Summers, J.C. Mutagenicity evaluation in Salmonella typhimurium from
    1981      Report No. 614-81 from Haskell Lab. submitted by E.I. DuPont
              de Nemours to WHO.

    Summers, J.C. Unscheduled DNA synthesis/rat hepatocytes in vitro.
    1982a     Report No. 719-82 from Haskell Lab. submitted by E.I. DuPont
              de Nemours to WHO. (Unpublished)

    Summers, J.C. Chinese Hamster Ovary cell assay for mutagenicity.
    1982b     Report No. 265-82 from Haskell Lab. submitted by E.I. DuPont
              de Nemours to WHO. (Unpublished)

    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: 1985 evaluations Part II Toxicology)