CAPTAN JMPR 1973 Explanation This fungicide was evaluated by the 1965 and 1969 FAO/WHO Meetings on Pesticide Residues (FAO/WHO, 1965; FAO/WHO, 1969). A temporary acceptable daily intake of 0-0.125 mg/kg was established but further information on the metabolism, particularly of the trichloromethylthio-moiety, and on the possible teratogenic effect in nonhuman primates was requested. It was considered that evidence on the effects of feeding a low-protein diet on the toxicity of captan was desirable. Further data have been made available and are summarized in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE Biochemical aspects Sixteen male and female rats received 82 mg/kg captan labelled with 14C in the C=O group orally by gavage as an aqueous solution in 1% tragacanth/0.05% Tween-20. Two animals received 14C labelled cis-1,2,dicarboximido-4-cyclohexene orally and others 14C-labelled epoxide of cis-1 2,dicarboximido-4-cyclohexene by the intraperitoneal route. Excretion of activity in urine, faeces and expired air and activity remaining in organs were determined after various periods of time. The results showed that captan was absorbed well from the gastrointestinal tract and that 92% of activity was excreted in 48 hours and 97% in 96 hours. About 85% was excreted in urine and 12% in faeces. Excretion in expired air was <0.1%. After 48 hours the average activity in tissues had declined to 5% of the level at 24 hours and after eight days nearly all tissues contained below an equivalent of 1 ppm captan (Hoffman et al., 1973). Sixteen male and female rats received 100 mg/kg captan labelled with 14C in the trichloromethylthio-moiety and the excretion determined after various periods of time. Four days after receiving labelled captan orally 16% of activity was recovered from faeces, 23% from expired air, 52% in urine and 0.6% in tissues (De Baun et al., 1973). Identification of metabolites in rats receiving captan labelled in various positions showed that the probable metabolic pathway for captan is as shown in Fig. 1 (Hoffman et al., 1973; De Baun et al., 1973). Three goats received daily treatment equivalent to ingesting diets containing 0, 20 or 100 ppm unlabelled captan for seven days and then the same levels of captan labelled with 14C in the C=0 group for three days. Animals were killed six or seven days after the last dose of captan. Over 97% of the 80% of activity which could be accounted for was excreted rapidly within 48 hours of the last dose. Activity was divided evenly between urine and faeces. Milk contained 0.1 to0.2% of the administered dose. At autopsy muscle contained 0.1% of the administered dose of which 95% was in a water soluble form; it was calculated that muscle contained 0.01 ppm or less of captan. Other tissues contained less than 0.02% of the dose. Urine contained no captan while faeces contained captan or tetrahydrophthalimide (Mitoma, 1972). TOXICOLOGICAL STUDIES Special studies on carcinogenicity Mouse. Three groups each of 50 male and 50 female Swiss mice were fed on diets containing 0, 3750 and 7500 ppm technical captan for 18 months. A fourth (positive control) group received diet containing 10 ppm N-nitroso diethylamine. The frequency and total number of deaths was similar in all groups. No abnormal behaviour was noted in treated groups. Abnormalities found in animals of the positive control group consisted of focal hyperplasia and neoplasia in the liver, and neoplasia of the lung and forestomach. No tumours were found in mice of other groups. No other outstanding differences were noted between test and control animals on gross examination at autopsy and histopathological examination of 8-11 animals of each sex from the groups failed to detect other lesions which could be attributed to captan treatment (Reyna et al., 1973a). Rat. Groups of 50 male and 50 female rats were fed for two years on diets containing 0, 1000 and 2000 ppm technical captan. A positive control group of 25 male and 25 female rats received diet containing 10 ppm N-nitroso diethylamine. The mortality rate was high in positive control animals. The rate was similar in males of control and 1000 and 2000 ppm groups, but the rate in females of the test groups was greater than in female controls. This increased mortality in captan-treated females was not considered to be of significance, based on the authors' experience with their strain of laboratory animal. No abnormalities attributable to captan were found on gross examination at autopsy. Lesions seen on histological examination of organs from 10 animals of each sex killed after two years' treatment were those common in rats of that age and none could be attributed to ingestion of captan. The tumour incidence was not increased by exposure to captan. Hepatocellular hyperplasia and benign and malignant tumours of the liver and carcinoma of the forestomach seen in positive control rats were attributed to treatment with the nitrosamine (Reyna et al., 1973b). Special studies on mutagenicity Host mediated assays were conducted in mice using Salmonella typhimurium G.46 and Serratia marcescens a21. The animals received a single 500 mg/kg dose of captan. Positive results were attained at this dosage level with these two systems (Buselmaier et al., 1972). Captan was administered to adult male drosophila by topical application and injection and to larvae by leg feeding. The results showed that no mutagenic changes could be produced in these systems (Mollet, 1973, Kramers and Knapp, 1973). Special studies on teratogenicity Rat. Pregnant rats received a single 3500 mg/kg bw dose of captan on one of the days between days 8-15 of gestation. An embryotoxic effect was seen with an increased number of post implantation deaths. No malformations were grossly visible but haematomas occurred in various parts of the body and anophthalmia and microphthalmia, hydrocephalus and intracranial haematomas were seen at autopsy of the fetuses (Mirkova, 1973). Hamster. Groups of two to 10 pregnant hamsters were administered a single dose of between 200 and 1000 mg captan/kg bw on days seven or eight of gestation or dosed daily from the sixth to the tenth day with a total of between 500 and 2500 mg captan/kg bw. They were killed and examined on the fifteenth day of gestation. At the highest dosage levels maternal mortality was increased and some abnormal fetuses were produced but lower dosage levels produced no signs of teratogenic activity (Robens, 1970). Dog. Four groups of six female beagles were mated with a group of six untreated males, each male being mated to one female from each of the four test groups. The females then received control diet providing 30 or 60 mg/kg bw/day or intraperitoneal injections of 0.15 mg/kg of 6-diazo-5-oxo-alpha-norleucine (DON) on days 20, 21 and 22 of gestation. Three females of each group were placed on control diet after whelping, the remainder continuing to receive test material until they were killed eight weeks after whelping. No adult animals died during the test and the growth pattern of females and young was unaffected by treatment. The mortality of progeny of test groups compared favourably with that of controls. Captan did not impair the ability of females to carry the young to parturition or affect the weight, length and growth of young. All progeny from females treated with DON showed cleft palates and clubbing of the extremities but no abnormalities were found in young from captan-treated females. No gross or histologically detectable abnormalities or skeletal abnormalities were observed which could be attributed to treatment with captan (Jackson et al., 1968). Acute toxicity Animal Route LD50 Reference mg/kg Mouse oral 130 Vasikidge and Mandzegamadze, 1973 Rat oral 2650 " Rabbit oral 740 " Short-term studies Mouse. Groups of mice were administered 1.15, 4.0, 5.3 or 10.6 mg captan/kg bw daily by gavage for two months or 6.0, 11.6, 14.7 or 530 mg captan/kg bw daily by gavage for one year. Further details are not available. The abnormalities said to occur were changes in the testes, reduced sperm motility, prolongation of aestrus cycle, increase of serum transaminase activity and reduction of blood prothrombin concentration. Male and female rats were unaffected by 10 and 5 mg/kg levels respectively and male and female mice by 2.6 and 1.0 mg/kg levels respectively. (Vasikidge and Mandzegamadze, 1973). Long-term studies Mouse. (See under "Special studies on carcinogenicity"). Rat. (See under "Special study on carcinogenicity") Comments Extensive investigations have shown that captan is well absorbed from the gastrointestinal trace and rapidly metabolized and eliminated from the body. The probable metabolic pathways of both the tetrahydrophthalimide and trichloromethyl thi-moieties have been elucidated. Although no further study has been carried out on the embryotoxic or teratogenic effects in nonhuman primates it was noted that in one experiment previously reported, and since published, effects were not found in rhesus or stump tall monkeys which had been exposed to up to 75 mg captan/kg bw daily during days 21-34 of gestation. No effects were seen in the progeny of dogs exposed to twice the dosage levels which increased fetal mortality in rhesus monkeys. It was not, however, certain that the fetuses of this species were exposed to captan or its metabolites. Rats exposed to a single high dose of captan during pregnancy produced young with haematomas in various parts of the body as well as anomalies of the eye and brain. The Meeting felt that these embryotoxic effects should be further investigated in view of the known association between agenesis of a particular region of the body and haematoma formation. A teratogenicity study in hamsters showed that malformations occurred at dosage levels causing mortality while at lower dosage levels malformations were not observed even though fetal and maternal morbidity was increased. Two further long-term studies have failed to demonstrate any carcinogenic potential in captan. Captan gave positive results for mutagenicity in a host mediated assay, but negative results were seen in a dominant lethal test using mice and in a test for mutagenicity in which drosophila were exposed to high dosage levels. No studies are reported on the acute effects of the fungicide in protein-deficient animals but the further extensive studies reported allow estimation of an acceptable daily intake. TOXICOLOGICAL EVALUATION Level causing no significant toxicological effect Mouse: 7500 ppm in diet equivalent to 1070 mg/kg bw/day Rat: 2000 ppm in diet equivalent to 100 mg/kg bw/day Dog: 100 mg/kg bw/day Monkey: 12.5 mg/kg bw/day Estimate of acceptable daily intake for man 0-0.1 mg/kg FURTHER WORK OR INFORMATION Desirable 1. Investigation of the significance of haematoma information in the fetus in relation to fetal death and malformation. 2. Information on the nature, level, and fate of residues following washing, blanching, storage, and thermal processing of treated crops. 3. Residue data obtained by the newer methods of analysis on the main commodities for which tolerances have been recommended. 4. Information on the fate of captan in the soil. REFERENCES Buselmaier, W. von, Rohrborn, G. and Propping, P. 1972 Mutagenitäts Untersuchungen mit Pestiziden in Host-mediated Assay und mit dam Dommanten Letaltest an der Maus, Biol. Zbl. 91: 311-325 De Baun, J. R., Miaullis, J. B., Knarr, J., Mihailovski, A. 1973 and Menn, J. J. The metabolic rate of captan (trichloromethylthio-14C) in the rat. Unpublished report of Stauffer Agricultural Research Center submitted by Stauffer Chemical Co. Hoffman, L. J., De Baun, J. R., Knarr, J. and Menn, J. J. 1973 Metabolism of N-(trichloromethylthio)-1,2- dicarboximido 14C-4-cyclohexene (captan) in the rat. Unpublished report of Stauffer Agricultural Research Center submitted by Stauffer Chemical Co. Jackson, G., Kodras. R. and Fancher, O. E. Progeny study of 1968 captan (SX-114) in beagle dogs. IBT No. J5438. Unpublished report of Ind. Bio-Test Labs submitted by Chevron Chemical Co. Kramers, P. G. N. and Knapp, A. G. A. C. Mutagenicity tests 1973 with captan and folpet in Drosophila melanogaster. Mutation Research, 21: 149-154 Mitoma, C. Pilot study to determine the nature and magnitude 1972 of the residues from ingestion of captan in a ruminating animal. Unpublished report of Stanford Research Institute submitted by Chevron Chemical Co. and Stauffer Chemical Co. Mirkova, E. The effect of captan on the Embryogenesis of 1973 albino rats. Unpublished report, Research Institute of Hygiene and Occupational Health, Sofia Mollet, P. Untersuchungen Über Mutagenität und Toxizität 1973 von captan bei Drosophila. Mutation Research, 21: 137-138 Reyna, M.S. Kennedy, G.L. and Keplinger, M. L. 18-month 1973a carcinogenic study with captan technical in Swiss white mice. Unpublished report of Ind. Bio-Test Labs submitted by Chevron Chemical Co. Reyna, M. S., Kennedy, G. L. and Keplinger, M. L. Two-year 1973b carcinogenic study with captan technical in albino rats. Unpublished report of Ind. Bio-Test Labs submitted by Chevron Chemical Co. Robens, J. F. Teratogenic activity of several phthalimide 1970 derivatives in the golden hamster. Toxicol. Appl. Pharmacol, 16: 24-34 Vasikidge, V. I. and Mandzegamadze, P. N. Captan toxicity and 1973 its hygienic standardization in foodstuffs. Unpublished report
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 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: 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)