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 FOLPET Explanation Folpet was evaluated by the Joint Meeting in 1969 and 1973 1/ and a full ADI of 0-0.1 mg/kg bw was allocated on the basis of the no-effect levels taken exclusively from studies done by Industrial Bio-Test Laboratories. The Joint Meeting in 1982 was not presented with information on the validation of these studies and no additional data were made available. The meeting was informed, however, that certain replacements or new studies were in progress or were to be initiated. Consequently, the meeting agreed that the ADI should be replaced by a temporary ADI pending evaluation of the new studies. Further work required by 1984 included short-term test in rats, a 12-month study in dogs, long-term studies in mice and rats, a reproduction study in rats and teratology studies in rats and rabbits. Some new studies were submitted and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special Studies on Teratogenicity Rat A pilot study using mated CRL:COBS CD (S.D.) BR female rats (8 per group was performed wherein Folpet was administered via gavage at doses of 0, 20, 80, 320, and 640 mg/kg bw on days 6 through 19 of gestation. No rats died. Clinical signs consisted of rales, excess salivation, chromorhinorrhea, gasping, soft/liquid faeces, decreased motor activity, dyspnea and distended gastrointestinal tract. Reduced maternal body weight gains were recorded in the 80, 320, and 640 mg/kg does groups, as well as reduced food consumption in the 320 and 640 mg/kg dose groups. Reduced average foetal body weight occurred also at 320 and 640 mg/kg. No other compound-related effects or external anomalies were observed (Christian & Hoberman, 1983a). Groups of mated CRL:COBS CD (S.D.) BR rats (25 per group) were administered 0, 10, 60 and 360 mg/kg bw Folpet (89 percent pure) orally via gavage on days 6 through 19 of gestation. Rats were observed for clinical signs of toxicity, abortion, death, body weight change and food consumption. Animals were killed on day 20 and pups delivered by caesarean section. The uterus was weighed and examined for number of live/dead foetuses and early and late resorptions. Clinical signs consisted of excess salivation, chromorhinorrhea, 1/ See Annex 2 for FAO and WHO documentation. decreased motor activity, soft/liquid faeces, dyspnea and urine-stained fur. Three rats in the high dose group dies, two from intubation error. In the surviving rats no gross lesions were attributed to Folpet. Pregnant rats given 10, 60 and 360 mg/kg gained less weight during the dosing period than controls. Food consumption was significantly reduced in the high dose groups only. The number of implantations, live/dead foetuses, foetal viability, resorptions, average foetal body weight per litter, foetal sex ration and number or corpora lutea were comparable to controls. There were no differences in gross external, visceral or skeletal anomalies between treated and control groups and no compound-related effects on ossification were seen (Christian & Hoberman, 1983b). Rabbit Groups of New Zealand white rabbits (20 per group), artificially inseminated, were administered Folpet (89 percent pure) via oral intubation at dose levels of 0, 10, 20 and 60 mg/kg bw on days 6 through 28 of gestation. Rabbits were observed for body weight gain, food consumption and clinical signs of toxicity. Does which died were autopsied. On day 29, does were killed and pups delivered by caesarean section. The death of one doe at 60 mg/kg was considered to be related to ingestion of Folpet. No other compound-related deaths occurred. One doe in each of the low and high dose groups aborted on day 21 and 22 of gestation, respectively. One doe in each of the control and high dose groups naturally delivered a litter on days 28 and 29, respectively. Significant inhibition of maternal body weight gain and food consumption was determined in the mid and high dose groups. Average number of corpora lutea, implantations, resorptions, foetuses per litter, sex ratio and dead/resorbed implantations per litter were comparable among all groups. Male and female mean foetal body weights decreased in the mid and high dose groups compared to the control group. There was a significant increase in the incidence of hydrocephalic foetuses. A total of four foetuses from three different high dose litters also had skull, gastric and lung abnormalities (Feussner et al., 1984). Special Study on Carcinogenicity Mouse Groups of CD-1 (ICR derived) mice (80 males and 80 females per group) were administered Folpet (93 percent pure) in the diet at dose levels of 1 000, 5 000 and 12 000 ppm for 112-113 weeks. An untreated control group consisted of 104 mice of each sex. Animals were observed routinely for food consumption, body weight gain, pharmacological and toxicological effects. Survival was unaffected by treatment. Body weight gain was adversely affected at the mid- and high-dose. Food consumption was sporadic and no dose-related effects were evident. Haematological data at one year revealed no significant differences between groups. However, haematological data at termination demonstrated a possible macrocytic anaemia in high dose males and females. Gross pathology at termination was unremarkable except for duodenal lesions and related gastrointestinal abnormalities. A positive dose-related increase in the incidence of duodenal adenomas and adenocarcinomas was observed for the 5 000 and 12 000 ppm groups, but not in the 1 000 ppm group. The incidence of duodenal tumours in females and males, respectively, were 0 and 1 percent (controls), 2 and 3 percent (low dose), 10 and 12 percent (mid-dose), and 52 and 54 percent (high dose). High dose males also demonstrated an increased incidence of jejunal adenocarcinomas. No other oncogenic or neoplastic changes were evident in other tissues (Eisenlord & Wong, 1982). Short-Term Studies Rat Groups of Sprague-Dawley rats (20 per sex per dose) were administered Folpet in the diet at dosage levels of 0, 300, 1 000, 3 000, and 10 000 ppm for 13 weeks. Technical problems encountered in the diet analysis preclude use of this data since the analysis could not be verified according to currently acceptable standards (Reno et al., 1981). COMMENTS The 1981 JMPR noted that the ADI for Folpet, established originally in 1973, was based exclusively on studies performed by Industrial Bio-Test Laboratories. Information on the validity of these studies has not been provided. The 1982 JMPR required submission, by 1984, of the following studies: a 90-day oral study in rats, long-term oral studies in rats and mice, a 12-month oral study in dogs, a reproduction study in rats and teratology studies in rats and rabbits. The Meeting evaluated the required teratological studies and some additional mutagenicity data. Although teratogenic effects were not observed in rats, the Meeting was unable to evaluate the significance of teratogenicity observed in rabbits. Technical problems with the study precluded the use of data from a new 90-day oral study in rats. In view of the absence of the other required data and because of concern over the possible teratogenicity in the rabbit, the meeting withdrew the temporary ADI. REFERENCES Christian, M.S. & Hoberman, A.M. Teratology study in rats with folpet 1983a technical. Report from Argus Research Laboratories, Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished) Christian, M.S. & Hoberman, A.M. Pilot teratology study in rats with 1983b folpet technical. Report from Argus Research Laboratories Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished) Eisenlord, G.H. & Wong, Z.A. Lifetime oncogenic feeding study of 1982 Phaltan Technical in CD-1(ICR derived). Report from Environmental Health and Toxicology, Chevron Environmental Health Center, submitted by Chevron Chemical Co. to WHO. (Unpublished) Feussner, E.L., Hoberman, A.M., Johnson, E.M. & Christian, M.S. 1984 Teratology study in rabbit with folpet technical. Report from Argus Research Laboratories, Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished) Reno, F.E., Burdock, G.A., Serota, D.G., Voelker, R.W., Alsaker, R.D., 1981 Milad, G.M. & Zurek, E.K. Subchronic toxicity study in rats. Phaltan: Final Report. Report from Hazelton Laboratories America, Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished)
See Also: Toxicological Abbreviations Folpet (HSG 72, 1992) Folpet (ICSC) Folpet (FAO/PL:1969/M/17/1) Folpet (WHO Pesticide Residues Series 3) Folpet (WHO Pesticide Residues Series 4) Folpet (Pesticide residues in food: 1986 evaluations Part II Toxicology) Folpet (Pesticide residues in food: 1990 evaluations Toxicology) Folpet (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)