PESTICIDE RESIDUES IN FOOD - 1981 Sponsored jointly by FAO and WHO EVALUATIONS 1981 Food and Agriculture Organization of the United Nations Rome FAO PLANT PRODUCTION AND PROTECTION PAPER 42 pesticide residues in food: 1981 evaluations 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 Geneva, 23 November-2 December 1981 FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS Rome 1982 CYHEXATIN Explanation This acaricide was evaluated by the FAO/WHO Joint Meeting in 1970 and 1978.* The estimate of the temporary acceptable daily intake for man, set in 1970, was extended in 1973 and 1978. In 1978 clarification of the no-effect level in the rat in order to elucidate the significance of focal bile duct hyperplasia at low dose levels was required by 1980. A study to elucidate the possible effect on the immune system was desirable. A further evaluation of the focal bile duct hyperplasia findings is presented herewith. In addition, a report of life-time feeding studies of cyhexatin to mice was available. Additional reports of toxicological studies of dogs were submitted. DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Focal bile duct hyperplasia - rats All of the liver slides prepared for microscopic examination from rats of the dietary study with cyhexatin reported by S.D. Warner et al (1977) were re-evaluated by Dr. van der Heijden, pathologist. He clearly states that focal bile duct hyperplasia is a common finding in livers of ageing rats of various strains and is of little pathological significance. However, it appears likely that some environmental factor, e.g. contaminants of food or deficiency, is responsible for the frequently found high incidence. The occurrence of focal bile duct hyperplasia in control and treated rats is considered "spontaneous" and generally not associated with a particular condition or treatment. There is no association between focal bile duct hyperplasia and tumours of the liver or bile ducts and no evidence to relate focal bile duct hyperplasia to any preneoplastic condition (Van der Heijden 1980). * See Annex II for FAO and WHO documentation. Short-term studies Mice Groups of male and female B6C3F1 mice (10/sex/group) received diets containing cyhexatin for 13 weeks in concentrations of about 0, 3, 6 or 10 mg/kg bw/day. Slight, not dose-related, decreases in food consumption occurred during some periods in all treated groups of females. Cyhexatin did not induce dose-related effects on body weight, organ weights including the heart, or gross and microscopic pathology. At the end of the experiment, PCB-values were significantly increased in the male animals of the highest dose level. The no-effect level in this study is about 6 mg/kg bw (McCollister et al 1980). Dog Groups of 8 male beagle dogs were given oral doses of 0, 0.75, 1.50 or 6 mg cyhexatin/kg for 6 months. Treatment-related clinical signs included intermittent loose stools, inappetence, increased physical activity and rough hair. Loose stools were observed in all treatment levels in a dose-response manner. After the test compound was removed from the basal ration and given separately admixed in canned food, food intake was increased, especially at the highest dose level. Increased physical activity was first observed at the 6.0 mg/kg bw dose level, and thereafter also at the 0.75 and 1.50 mg/kg levels. Terminal physical examination did not indicate the presence of any abnormality. In the highest dose groups, body weight and body temperature were decreased. Cyhexatin did not have clear dose-related effects on heart rate, blood pressure, ECG-recording, urinalysis or clinical chemistry. At the end of the study, haematological values (RBC, Hb and PCV) were decreased in the 6 mg/kg group. In all experimental groups, the weight of the heart was not dose-relatedly increased. No gross or microscopic alterations were observed that could be related to the treatment (Gerbig and Warner 1975). In order to study the increased physical activity as found in the previous experiment, 3 groups of male beagle dogs received in their diets 0, 0.4 to 0.75, and 0.4 to 1.5 mg cyhexatin/kg bw during 13 weeks. The daily activity of each dog was recorded by means of actometers. The activity of dogs fed 1.5 mg/kg bw was clearly depressed. No noticeable differences in physical activity occurred between the 0.75 mg/kg group and the controls. The absolute heart weight was not affected, whereas the relative weight was significantly increased (Reuzel 1977). Long-term studies Mice Groups of 60 male and 60 female B6C3F1 mice were maintained on diets formulated to supply 0 (96 males and 96 females), 1, 3 or 6 mg cyhexatin/kg bw for up to 2 years. After one year, 10 male and 10 female mice of each group were killed. In the highest dose level mortality was increased in the males and decreased in the females. The body weight gain in the males was lowered in comparison to controls, whereas in both males and females the food intake was marginally affected. No dose-related effects were observed on behaviour, haematology, clinical chemistry, organ weights or tumour incidence. At the highest dose level of 6 mg/kg bw/day, there were indications that the incidence of a few of the normal changes may have been affected by the treatment, e.g. a decrease in sinusoidal distension and/or increased inflammatory or reticuloendothelial cell activity, a decrease of uterine endometrial hyperplasia in the lymph nodes and a decrease in adenoma formations in the pituitary. Biliary hyperplasia or cyst formation occurred only in a few isolated cases. The no-effect level is 3 mg/kg bw (Keyes et al 1981). EVALUATION COMMENTS A six-month toxicity study in dogs has been received and evaluated. A subjective observation of dose-related increased activity was reported. A second study, measuring activity with an actometer, failed to confirm this observation. A statement from an independent pathologist indicated that the local bile duct hyperplasia noted in an earlier JMPR evaluation is a normal finding in ageing rats and may be considered to be of negligible pathological significance. This statement was confirmed by the Meeting. Two mouse studies, one of 13 weeks and one lifetime study, were evaluated. The lifetime study permitted the estimation of a no-effect level of 3 mg/kg bw/day in this species. The estimated temporary acceptable daily intake for man (0.008 mg/kg bw) was based on the no-effect level (0.75 mg/kg) in 2-year dog feeding studies evaluated in 1970. The receipt of the long- term study in rats and the additional studies in dogs justified the alteration of the temporary ADI to a full ADI. Level causing no toxicological effect Mouse: 3 mg/kg bw/day Rat: 1 mg/kg bw/day Dog: 30 ppm in the diet, adjusted to give 0.75 mg/kg bw/day Estimated acceptable daily intake for man 0 - 0.008 mg/kg bw FURTHER WORK OR INFORMATION Desirable 1. A study to elucidate the possible effect on the immune system. 2. A study to determine the possibility of CNS effects. REFERENCES Gerbig, G.G. and Warner, S.D. Results of a six month oral (dietary) 1975 toxicity study of tricyclohexyltin hydroxide in male beagle dogs (Dow Chemical Company. (Unpublished) McCollister, S.B. et al. Cyhexatin: Results of a 13-week toxicity 1980 study in the diet of B6C3F1 mice. Dow Chemical Company. (Unpublished) Keyes, D.G. et al. Cyhexatin: Results of a two-year dietary toxicity 1981 and oncogenic study in male and female B6C3F1 mice. Dow Chemical Company. (Unpublished) Reuzel, P.G.J. Sub-chronic (13-week) activity study with TCHT in 1977 beagle dogs. Report No. R5464. Central Institute for Nutrition and Food Research, The Netherlands. (Unpublished) Van der Heijden, C.A. Letter d.d. 7-8-1980, to Dow Chemical Europe 1980 Warner, S.D., Ayers, K.M., Gerbig, G.G. and Strebing, R.J. Results of 1977 a two-year chronic toxicity study of tricyclohexyltin hydroxide administered to rats by the dietary route. Report by Dow Chemical Company, U.S.A. (Unpublished)
See Also: Toxicological Abbreviations Cyhexatin (WHO Pesticide Residues Series 4) Cyhexatin (WHO Pesticide Residues Series 5) Cyhexatin (Pesticide residues in food: 1978 evaluations) Cyhexatin (Pesticide residues in food: 1980 evaluations) Cyhexatin (Pesticide residues in food: 1983 evaluations) Cyhexatin (Pesticide residues in food: 1989 evaluations Part II Toxicology) Cyhexatin (Pesticide residues in food: 1991 evaluations Part II Toxicology) Cyhexatin (JMPR Evaluations 2005 Part II Toxicological)