FENITROTHION EXPLANATION Fenitrothion has been evaluated for acceptable daily intake by the Joint Meetings in 1969, 1974, 1977, 1982, and 1984 (Annex 1, FAO/WHO, 1970a, 1975a, 1978a, 1983a, and 1985b). A toxicological monograph was prepared by the Joint Meeting in 1969 (Annex 1, FAO/WHO, 1970b) and monograph addenda were published after the Joint Meetings in 1974, 1977, 1982, and 1984 (Annex 1, FAO/WHO, 1975b, 1978b, 1983b, and 1985c). In 1974 the Meeting allocated an ADI of 0.005 mg/kg b.w., which was partially based on studies conducted by Industrial Bio-Test Laboratories (IBT). Replacement studies, independently-obtained validations, or other additional data had not been submitted for evaluation by the Joint Meeting in 1982, so at that time the ADI was replaced with a temporary ADI at a lower level (0.001 mg/kg b.w.). In 1984 most of the required data were supplied and evaluated by the Joint Meeting, which extended the temporary ADI at a higher level (0.003 mg/kg b.w.). Two teratogenicity studies in mice and rats, however, were considered unsatisfactory, and so an acceptable rat teratology study was required. This teratology study has been submitted for evaluation by the present Joint Meeting, and it is summarized in this monograph addendum. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Toxicological studies Special study on embryotoxicity/teratogenicity Rat Groups of 20 mated female rats (Wistar strain, 12 weeks old) were given fenitrothion (97.6% pure compound; 0.1% 3-methyl-4-nitrophenol) in sunflower oil by gavage at single daily doses of 0, 2, 8, 16, or 24 mg/kg b.w. from days 6 through 16 of presumed (positive sperm smear) gestation. On day 20 of gestation the rats were sacrificed and the number of viable and dead fetuses, resorptions, implantations, and corpora lutea were recorded. Fetuses were subjected to external and internal (skeletal and soft tissue) examination. Clinical signs of maternal toxicity (tremors and chromoda- cryorrea) were observed in 19/20 dams of the group receiving 24 mg/kg b.w./day. In this group, 11/20 dams died between days 10 and 16 of gestation. Statistically-significant decreases in body-weight gain during both the treatment period and the entire gestation period were noted in rats receiving 16 and 24 mg/kg b.w./day, as compared to controls. Food consumption was significantly decreased in the high-dose group during the treatment period, as compared to controls. Embryotoxicity was observed in rats at the highest dose, in which there were an increased total number of resorptions, a statistically- significant reduction in the mean number of live fetuses, and a statistically-significant reduction in the mean weight of placenta as compared to controls. An increased number of resorptions was also present at 2, 8, and 16 mg/kg b.w./day as compared to controls, but these differences were not statistically significant. There was apparently no significant difference between treated and control groups in fertility index, gestation index, and litter size. Sex ratio (number of male fetuses/number of female fetuses) and mean fetal body weight were lower in fetuses of the high-dose group than in controls, but the differences were apparently not statistically significant. A number of skeletal variations and malformations were observed in both control and treated groups. These included: fifth and sixth ribs fused and tibial aplasia in 1 fetus at 2 mg/kg b.w./day and irregular shape of ossification centers in sternebrae in 5 fetuses at 8 mg/kg b.w./day, in 4 fetuses at 24 mg/kg b.w./day, and in 1 control fetus. The authors of the study concluded that "under the conditions of this study, fenitrothion was judged to be non-teratogenic at levels up to and including 24 mg/kg b.w./day when administered orally by gavage to rats during days 6 through 15 of gestation" (Benes & Tejnorvoa, 1986). COMMENTS The teratogenicity study in the rat required by the 1984 JMPR has been submitted and evaluated. In this study fenitrothion was not found to be teratogenic. At doses exceeding 8 mg/kg b.w./day, fenitrothion was maternally toxic and embryotoxic. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg b.w./day Dog: 10 ppm in the diet, equivalent to 0.3 mg/kg b.w./day ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0 - 0.003 mg/kg b.w. STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED EVALUATION OF THE COMPOUND. 1. Observations in man. 2. Submission of ongoing teratogenicity studies. REFERENCE Benes, V. & Tejnorova, I. Fenitrothion: Teratogenicity study in rats. 1986 Unpublished report from Institute of Hygiene and Epidemiology, Prague, Czechoslovakia. Submitted to WHO by Institute of Hygiene and Epidemiology, Prague, Czechoslovakia.
See Also: Toxicological Abbreviations Fenitrothion (EHC 133, 1992) Fenitrothion (HSG 65, 1991) Fenitrothion (ICSC) Fenitrothion (FAO/PL:1969/M/17/1) Fenitrothion (WHO Pesticide Residues Series 4) Fenitrothion (Pesticide residues in food: 1976 evaluations) Fenitrothion (Pesticide residues in food: 1977 evaluations) Fenitrothion (Pesticide residues in food: 1979 evaluations) Fenitrothion (Pesticide residues in food: 1982 evaluations) Fenitrothion (Pesticide residues in food: 1983 evaluations) Fenitrothion (Pesticide residues in food: 1984 evaluations) Fenitrothion (Pesticide residues in food: 1988 evaluations Part II Toxicology) Fenitrothion (JMPR Evaluations 2000 Part II Toxicological)