FENITROTHION EXPLANATION Fenitrothion was evaluated for acceptable daily intake by the Joint Meetings in 1969, 1974, 1977, 1982, 1984 and 1986. The 1969 monograph (Annex I, FAO/WHO, 1970) was supplemented by addenda (Annex I, FAO/WHO 1975b, 1978b, 1983b, 1985c, 1987a). An ADI of 0.005 mg/kg bw was allocated by the Meeting in 1974. That decision was partially based on studies conducted by Industrial Bid-Test Laboratories (IBT). In 1982 the Joint Meeting replaced the ADI with a Temporary ADI at a lower level (0.001 mg/kg bw). By 1984 a Temporary ADI of 0.003 mg/kg bw was allocated. However, the teratogenicity studies in mice and rats were considered inadequate because the dosing regimen did not cover the whole period of organogenesis. An acceptable rat teratology study was evaluated by the 1986 Joint Meeting, which allocated an ADI of 0.003 mg/kg bw. Some additional teratology and toxicity studies have since been submitted for evaluation by the present Joint Meeting, and are summarized in this monograph addendum. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Toxicological studies Special studies on embryotoxicity/teratogenicity Rats Groups of 20-24 mated female rats (Sprague-Dawley, Crl:CD(SD)BR) were given, by daily gavage, doses of 0, 3, 8, or 25 mg/kg bw of technical fenitrothion (96.6% purity) in corn oil from day 6 through day 15 of gestation. Solutions were freshly prepared each day and doses were based on the animal's body weight on day 6 of gestation. Animals were observed for clinical signs, body weight and food consumption. On day 20 of gestation, the dams were sacrificed and examined grossly for abnormalities of the thoracic, abdominal or pelvic viscera. The usual teratological parameters were then examined. All rats survived to day 20 of gestation. Signs of toxicity (tremors, rhinorrea and rough haircoat, etc.) were present in 18 high-dose animals. A significantly reduced body weight gain was evident in the high-dose group from day 11 through day 19 of gestation. Food consumption was not significantly altered by any of the treatments. The mean numbers of implantations, early and late resorptions, live foetuses per litter, mean foetal weight and sex ratio were similar in all groups. No dead foetuses were observed. Skeletal and visceral variations and malformations were observed in both control and treated groups. The majority of visceral variations were localized in the kidneys and ureters (i.e., renal papilla reduced in size and dilated ureters); the incidence was not dose-related. In the high-dose group there was a statistically significant increased incidence (3.1%) of foetuses with one full and one rudimentary 13th rib. Other skeletal variations included expected degrees of delay in ossification of various bones; these did not occur in a dose-related pattern. The only skeletal malformation (agnathia) was observed in one high-dose foetus. The total number of foetuses with malformations (external, visceral and skeletal) was 1, 0, 1 and 1 in control, low-, mid- and high-dose groups, respectively. In conclusion, no evidence of developmental toxicity was seen under these experimental conditions. The NOAEL in this study was determined to be 8 mg/kg bw/day for dams (Morseth, 1987). Rabbits Inseminated female rabbits (HRA:(NZW)SPF) were given, by gavage, daily doses of technical fenitrothion (96.6% purity) from day 7 through day 19 of presumed gestation. Does were randomly divided in 4 groups (n=16) and administered 0, 3, 10 or 30 mg/kg bw of fenitrothion dissolved in corn oil. The doses chosen followed pilot studies in which daily oral doses of 100 mg/kg bw caused the death of animals by day 3 but daily dose levels up to 20 mg/kg bw to pregnant rabbits did not result in maternal or intrauterine toxicity. Solutions were prepared fresh weekly and dosing was based on the most recently recorded body weight. Animals were observed for clinical signs, body weight and food consumption. On day 29 of gestation, all does were sacrificed and examined grossly for abnormalities of the thoracic, abdominal or pelvic viscera. The usual teratological parameters were examined. One animal of the control group and one of the mid-dose group were anorexic and were found dead on gestation day 8 and 18, respectively. Two animals of the low-dose group died following errors in gavage technique. Six does of the high-dose group were found dead during treatment and three does of the same group aborted or delivered prematurely after the end of treatment. During treatment all animals of the high-dose group showed reduction in motor activity, ataxia, salivation, dyspnea or tremors. These signs were seen only sporadically during the post-treatment interval. Animals treated with lower doses displayed no clinical abnormality. However some animals in all groups were anorexic. Although food consumption was similar in all groups, a lower body weight gain was noted for the high-dose group. The mean numbers of implantations and live foetuses per litter were slightly, not significantly, reduced in the high-dose group. The incidence of foetal resorptions, sex ratio and mean foetal body weight were similar in all groups. The total foetal incidence of external malformations (0-2.9%), visceral variation (1.2-4.8%), visceral malformations (0-2.4%), skeletal malformations (0-7.2%) were not statistically significantly different between treated or control groups. No malformation was observed in the high-dose group. The total incidence of malformations was 2%, 8% and 6% in the control, low- and mid-dose groups, respectively; these incidences were not considered significantly different. Maternal toxicity was seen in the 30 mg/kg group, without effects on foetal growth or development. The NOAEL in this study was thus considered to be 10 mg/kg bw/day for dams (Morseth et al., 1986). Short-term studies Dogs Groups (6 males and 6 females per group) of purebred beagle dogs received a diet containing 0, 5, 10, or 50 ppm of technical fenitrothion (96.8% purity), respectively, for 12 months. Although this study was previously evaluated by the 1984 Joint Meeting, histopathological examinations were not submitted at that time. Physical and ophthalmoscopic examinations did not demonstrate any effect of the test compound. Haematological and clinical biochemical parameters (except for cholinesterase values in the high-dose group), urinalysis, body weight and food consumption were not affected by the treatment. No organ weight changes nor macroscopical lesions related to the treatment were observed. Plasma cholinesterase was significantly reduced (35-55% lower than pretest values) in both sexes at the high-dose level only. Erythrocyte cholinesterase was reduced in high-dose males in 4 of 8 measurements. Brain cholinesterase was unaffected by any of the treatments. Histopathological observations reviewed by the present Meeting showed an increased, but not dose-related, incidence of the following lesions in treated animals as compared to controls: craniopharyngeal pituitary cysts (0/0, 4/6, 2/6 and 3/6 in the 0, 5, 10 and 50 ppm groups, respectively), lymphocytic infiltrates of prostate (3/6 in the high-dose group) and chronic lymphocytic thyroiditis (0/6, 1/6, 1/6 and 3/6 in the 0, 5, 10, and 50 ppm groups, respectively) in males. Haemorrhages in abdominal lymph nodes (2/6 in the mid- and high-dose groups) and lymphoid hyperplasia of mandibular lymph nodes (2/6 in the high-dose group) in females were also found. All lesions observed are considered to be spontaneous and/or incidental in nature. The NOAEL in this study was determined to be 50 ppm (Spicer, 1986). COMMENTS Although an ADI was allocated for fenitrothion in 1986, the Meeting reviewed the additional toxicology studies that had since been completed. Additional data confirmed that fenitrothion was not teratogenic in rats and rabbits. In dogs fenitrothion reduced erythrocyte but not brain acetyl- cholinesterase activity at 50 ppm. No other treatment-related adverse effects were seen at this dose. Upon re-evaluation of previous studies (JMPR 1986) the Meeting utilized available brain acetyl- cholinesterase inhibition data in rats and dogs to establish NOAELs rather than the plasma cholinesterase data previously used. The Meeting also took into account the decreased lactation index noted at 40 ppm in rats by the 1974 JMPR. The ADI was revised accordingly. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 10 ppm in the diet, equivalent to 0.5 mg/kg bw/day (based on brain acetylcholinesterase inhibition and reproduction) Dog: 50 ppm in the diet, equivalent to 1.25 mg/kg bw/day Man: 0.08 mg/kg bw/day (highest dose tested). ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.005 mg/kg bw STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED EVALUATION OF THE COMPOUND Further observations in man. REFERENCES Morseth, S.L. 1987. Teratology study in rats with Sumithion. Report from Hazleton Laboratories America, Inc. submitted by Sumitomo Chemical Co., Ltd. to WHO. Morseth, S.L., Serabian, S.A., Lichtenberger, J.M., Vargas, K.J., Thakur, A.K. & Burley, P.L. 1986. Teratology study in rabbits with Fenitrothion T.G. (Sumithion). Report from Hazleton Laboratories America, Inc. submitted by Sumitomo Chemical Co., Ltd. to WHO. Spicer, E.J.F. 1986. One year dietary toxicity study in dogs with Sumithion technical. Revised report from International Research and Development Corporation submitted by Sumitomo Chemical Co., Ltd. to WHO.
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: 1986 evaluations Part II Toxicology) Fenitrothion (JMPR Evaluations 2000 Part II Toxicological)