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 CAPTAN Explanation Captan has been evaluated by the Joint Meetings on Pesticide Residues in 1969, 1973, 1974, 1977, 1978 and 1982 (FAO/WHO, 1965b, 1970, 1974, 1975, 1979, and 1983). In view of the concerns with respect to carcinogenicity in mice, the inability to demonstrate a no-effect level in the 3-generation reproduction study in rats and the finding of the long-term/carcinogenicity studies in both mice and rats conducted by IBT being invalid, the 1982 Joint Meeting decided that the full ADI be modified to a temporary ADI at 0 - 0.01 mg/kg bw. Further work required by 1984 included the complete report of the new two-year study in rats and mice, and a two-generation reproduction study. New studies were made available to the meeting and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special Study on Reproduction Rat Groups of Charles River CD rats (15 males and 30 females per group) were fed Captan in the diet at dosages of 0, 6, 12.5 and 25 mg/kg/day in a one-generation, one-litter reproduction study. After 102 days of treatment the animals were mated. The F0 adults were necropsied after weaning of the F1 pups. The parental rats and the pups were observed for signs of toxicity, changes in general behaviour, appearance and survival. There were no compound-related effects on survival, appearance, behaviour, body weight or food consumption among the parental animals. Fertility index, length of gestation, and pup viability and weight at birth in all treated groups were comparable to controls. Pup survival during lactation was comparable to controls. There was slight reduction in mean pup body weight and litter weight on lactation days 4, 7 and 14 at the 25 mg/kg level. No other compound-related effects on reproduction were reported (Aldrige, Shardein & Blair, 1982). Special Study on Teratology Hamster The Joint Meeting in 1982 reviewed a teratology study in Golden hamsters in which "non-specified" rat anomalies were reported in treated pups. Additional detail was requested and has been provided. The rib anomalies were primarily bent ribs, confined to the high-dose group and occurred in only one litter. The results of this study indicated that Captan produced maternal deaths and weight loss at doses of 200 and 400 mg/kg and was also foetotoxic at the 400 mg/kg dose. Therefore, these bent rib anomalies may be accounted for by a maternal stress effect upon the foetus rather than a teratogenic effect (Shardein, 1983). Special Studies on Carcinogenicity Mouse Groups of CD-1 (ICR derived) mice (80 males and 80 females per group) were fed Captan (purity 90.7 percent) in their diet at dose levels of 0, 2 000, 6 000 and 10 000 ppm for four weeks, after which these levels were increased to 0, 6 000, 10 000 and 16 000 ppm, respectively, for the remaining 105 weeks of the study. In males there was a statistically significant dose-related trend in mortality. The survival pattern of females is less clear, but still statistically significant, due to higher mortality of the high-dose group. In all treatment groups, average body weights were significantly lower than the controls throughout the study. No significant haematological effects were noted. Gross pathological examination demonstrated the presence of duodenal lesions and gastrointestinal tract abnormalities. There were statistically significant increases in duodenal adenomas and adenocarcinomas in both sexes. The incidence of adenoma and carcinoma in the stomach, duodenum and jejunum-ileum for males was 3.7 percent (control), 23.7 percent (low-dose), 28 percent (mid-dose) and 48.7 percent (high-dose); for females, 3.7 percent (control), 32 percent (low-dose), 26 percent (mid-dose) and 36 percent (high-dose). The high-dose males generally showed proliferative changes of the duodenum earlier than the other groups. The results demonstrate that captan, at dietary concentrations of 6 000, 10 000 and 16 000 ppm induced both benign and malignant duodenal tumours in CD-1 mice (Bradfield, Wong & MacGregor, 1981). Groups of 42-day-old CD-1 mice (100 males and 100 females per group) were administered Captan (purity 89 percent in the diet at dose levels of 0, 100, 400, 800 and 6 000 ppm continuously for 22 months. Cage-side observations for signs of toxic or pharmacologic effects were conducted daily and palpations for tissue masses were performed weekly. Body weight and food consumption were measured regularly throughout the study. Complete gross postmortem examinations were conducted on all animals and microscopic examinations were performed on selected tissues from all animals. The high-dose males exhibited a higher incidence of mortality than controls during the first 14 months of the study. Mortality data in the other treated groups were comparable to controls. The mean body weights of the high-dose males and females were reduced throughout the study and were statistically significant in high-dose males during the first year, and in high-dose females for the first 18 months. Food consumption was variable in control and treated groups. Gross postmortem examinations revealed an increased incidence of lesions of the small intestine (masses, nodules, raised areas) in female mice fed 800 and 6 000 ppm of Captan. Microscopic examination demonstrated an increased incidence of duodenal hyperplastic lesions in high-dose male and female mice. The number of benign and malignant duodenal neoplasias were significantly increased in high-dose females only. Although the incidence in low- and high-dose males was increased, it was not statistically significant. The incidence of adenoma and carcinoma in the stomach, duodenum, and jejunum-ileum for males was 0/100, 6/100, 1/100, 1/100 and 5/100; for females 0/100, 1/100, 3/100, 3/100 and 7/100 for 0, 100, 400, 800 and 6 000 ppm groups, respectively. Historic control data derived from concurrent studies in CD-1 mice indicate that 1/718 males developed a duodenal carcinoma, with 0/737 incidence in females (Daly & Knezevick, 1983). Rat Groups of 30-day-old Charles River CD rats (70 males and 70 females per group) were administered Captan (89 percent purity) in the diet at dose levels of 0, 25, 100 and 250 mg/kg bw/day for two years. Animals were observed twice daily for signs of acute toxicity, moribundity and mortality. Individual body weights were regularly determined and food and compound consumption were measured. Ophthalmoscopic, haematologic and clinical biochemical measurements and urinalysis were performed periodically throughout the study. There were no compound-related effects on any of these parameters. The mean body weights for males and females given 100 and 250 mg/kg/day were significantly lower than controls throughout the study. Macroscopic examination at necropsy did not indicate any significant differences between treated and control animals. Microscopically, hepatocellular hypertrophy was significantly increased in high-dose animals only, compared to controls. Male rats demonstrated a statistically significant trend for kidney adenomas (Krus-Kall Wallis test for adjusted trend, p<0.05; Armitage trend test p<0.05). The incidence of kidney adenomas in males was 1/70, 1/70, 3/70 and 4/70 for control, 25, 100 and 250 mg/kg groups, respectively. Although a significant trend is established, the occurrence in the mid- and high-dose groups were not biologically significant in light of the finding of this rare tumour in a control male. Captan was without demonstrated adverse effects in CD rats when administered in the diet for two years at 25 mg/kg bw/day (Goldenthal, 1982). Comments Captan was last considered by the 1982 JMPR. An additional study has confirmed the lack of oncogenicity of Captan in the CD rat. The ability of relatively high doses of Captan to cause duodenal adenocarcinoma in CD-1 mice has also been confirmed. However, duodenal neoplasia occurs in some controls. Data from an additional single generation reproduction study complemented and extended earlier data, establishing that Captan does not adversely affect reproduction of CD rats at 12.5 mg/kg bw/day. The meeting determined that there was no further concern with IBT studies, as these had not been replaced with validated studies. An ADI was therefore estimated. Level Causing no Toxicological Effect Monkey (rhesus, based on reproduction studies): 12.5 mg/kg bw/day. Rat (based on reproduction studies): 250 ppm in the diet equal to 12.5 mg/kg bw. Mouse: 800 ppm in the diet, equivalent to 120 mg/kg bw. Dog: 100 mg/kg bw/day. Estimate of Acceptable Daily Intake for Humans 0 - 0.1 mg/kg bw. FURTHER WORK OR INFORMATION Desired Comparative study of the metabolic fate of Captan in rats and mice. Study of the pathogenesis of gastrointestinal lesions produced by Captan in mice (known to be in progress). Further observations in humans. REFERENCES Aldrige, D., Shardein, J.L. & Blair, M. One-generation reproduction 1982 study in rats with Captan. International Research and Development Corporation, USA. Submitted by Stauffer Chemical Company, USA, to WHO. (Unpublished) Bradfield, L.C., Wong, T.A. & MacGregor, J.A. Lifetime oncogenic 1981 feeding study of Captan Technical in CD-1 mice (ICR derived). Chevron Environmental Health Center, Environmental Health and Toxicology. Submitted by Chevron Chemical Company, Richmond, CA, to WHO. (Unpublished) Daly, I.W. & Knezevick, A.L. A lifetime oral oncogenicity study of 1983 Captan in mice. Bio/dynamics Inc. Submitted by Chevron Chemical Company to WHO. (Unpublished) Goldenthal, E. Two-year oral toxicity/carcinogenicity study of Captan 1982 in rats. International Research and Development Corporation. Submitted by Stauffer Chemical Company, USA, to WHO. (Unpublished) Shardein, J.L. Teratology studying hamsters; amended final report. 1983 International Research and Development Corporation, USA. Submitted by Chevron Chemical Company, Richmond, CA, to WHO. (Unpublished)
See Also: Toxicological Abbreviations Captan (HSG 50, 1990) Captan (ICSC) Captan (PIM 098) Captan (FAO/PL:1969/M/17/1) Captan (WHO Pesticide Residues Series 3) Captan (WHO Pesticide Residues Series 4) Captan (Pesticide residues in food: 1977 evaluations) Captan (Pesticide residues in food: 1978 evaluations) Captan (Pesticide residues in food: 1980 evaluations) Captan (Pesticide residues in food: 1982 evaluations) Captan (Pesticide residues in food: 1984 evaluations) Captan (Pesticide residues in food: 1990 evaluations Toxicology) Captan (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental) Captan (IARC Summary & Evaluation, Volume 30, 1983)