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 OXAMYL Explanation 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 addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Metabolism 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. TOXICOLOGICAL STUDIES Special Study on Teratogenicity Rabbit 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 Mouse 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). COMMENTS Oxamyl was assigned a temporary ADI in 1980 and additional data and information were identified, which have been reviewed in this addendum. 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 unnecessary. 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 ADI. 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 ml). 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 transferase TOXICOLOGICAL EVALUATION 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 FURTHER WORK OR INFORMATION Desirable: Observations in humans REFERENCES 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., 8:499-508. 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. (Unpublished) 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)