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 FENITROTHION Explanation Fenitrothion was evaluated by the Joint Meeting in 1969, 1974, 1976, 1977, 1979 and 1982. 1/ An ADI of 0 - 0.005 mg/kg bw was recommended in 1974 partly supported by studies performed by Industrial Bio-Test Laboratories. No independently obtained validations, replacement studies or other additional information were submitted to the 1982 JMPR concerning these data. Considering the absence of adequate mammalian non-rodent toxicity data and an adequate teratology study, the ADI was retained as a temporary ADI and reduced to 0 - 0.001 mg/kg bw pending receipt of data validation and additional data. New studies have been presented and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special Studies on Teratogenicity Mouse Groups of pregnant ICR-JCL mice (25-27 per group) were orally intubated with 0, 20, 70 and 200 mg/kg bw fenitrothion (97.2 percent purity) in maize oil from day 7 to 12 of gestation. Eighteen dams in each group were sacrificed on day 18 of gestation, foetuses were removed by caesarean section and examined for internal and external abnormalities, as well as skeletal malformations. The remaining dams were allowed to deliver their young naturally at parturition; the young mice were then observed for six weeks for growth and development. No adverse effects of fenitrothion on maternal body weight or physical appearance were noted. No significant differences in the reproductive parameters, such as total implantations, dead and live foetuses, sex ratio or mean body weight of foetuses, were observed between treated and control groups. The anomalies observed in the treated groups included cleft palate and open eyelids. However, no historical data were provided that permitted an evaluation of the significance of these findings. Skeletal variations and ossifications were not significantly different between control and test groups. The teratogenic potential of fenitrothion to pregnant mice could not be determined from this study because the dosing regimen did not cover the whole period of organogenesis (Miyamoto et al., 1975). 1/ See Annex 2 for FAO and WHO documentation. Rat Groups of pregnant Sprague-Dawley rats (22-26 dams/group with 24 control dams) were orally gavaged with 0, 2, 7 and 20 mg/kg bw of fenitrothion 97.2 percent purity) in maize oil from day 9 to 14 of gestation. Eighteen dams in each group were sacrificed on gestation day 20 and foetuses removed by caesarean section. The remaining dams were allowed to deliver their young naturally at parturition; the young mice were then observed for six weeks for growth and development. Foetuses were examined at necropsy for external and internal abnormalities as well as skeletal malformations. A slight reduction in maternal body weight gain as well as clinical signs of toxicity were noted in the high-dose group only. No effects on reproductive parameters such as total implantations, incidence of dead or resorbed foetuses, foetal sex ratio or foetal birth weight were noted between treated and control groups. Although there were no apparent compound related skeletal or visceral anomalies, the teratogenic potential of fenitrothion to pregnant rats could not be determined from this study because the dosing regimen did not cover the whole period of organogenesis (Miymoto et al., 1975). Special Studies on Short-Term Toxicity Dogs Groups of purebred beagle dogs (6 males and 6 females per group), approximately 3 months old, were administered fenitrothion (purity 96.8 percent) in the diet at dose levels of 0, 5, 10 and 50 ppm for 12 months. The dogs were observed for general physical appearance and behaviour signs of overt toxicity, moribundity and mortality. Body weight and food consumption were determined. Opthalmoscopic and physical examinations were also performed. Routine haematological and clinical biochemical parameters were determined as well as urinalysis. All dogs received a complete post-mortem macroscopic examination and selected organs weighed. There was no mortality and no effect on appearance or behaviour. Food consumption and body weight gain were unaffected by treatment. Clinical analysis showed no treatment-related effects on urinalysis, haematological or biochemical parameters, except for cholinesterase values. Plasma cholinesterase was significantly reduced in both sexes at the high dose level. Erythrocyte cholinesterase activity was reduced in high dose males only. Brain cholinesterase was unaffected by treatment. There were no organ weight changes related to treatment and no macroscopic lesions observed. Histopathological examinations were not performed. The demonstrated no-effect level is 10 ppm based on plasma and erythrocyte cholinesterase depression (Griggs et al., 1984). Observations in Humans Twelve adult male volunteers were repeatedly given oral doses of fenitrothion equal to 0.1 or 0.5 mg/kg bw followed by dermal application of 0.1 mg/kg to arms and face. The study lasted nine days. There was no evidence of dermal irritation and no apparent differences in cholinesterase activity observed (Shelanski et al., 1977). Fenitrothion was measured in the serum of nine workers, engaged in the spraying of a wettable powder formulation, for three consecutive days. No material was identified in the serum samples and neither cholinesterase nor glutamic oxalacetic transaminase or glutamic pyruvic transaminase activities were adversely affected by exposure (Usutani et al., 1978). During a 30-day spraying operation of fenitrothion in south Iran for malaria control, a group of 28 pest control operators and 925 inhabitants were monitored with respect to clinical observations and cholinesterase activity. Mild clinical symptoms (e.g. nausea, dizziness) were observed in 8/20 spray operators, who also demonstrated depressed whole blood cholinesterase activity. Among the inhabitants very mild complaints, namely dizziness and nausea, were reported (Motabar et al., 1973). A large-scale spray operation was monitored by WHO in Kisumu, Kenya, involving 35-40 spray operators who used fenitrothion 5 h per day, five days per week intermittently for two years. Numerous clinical parameters were measured in exposed operators and matched controls. Clinical examination of operators and control subjects did not reveal any significant difference between the groups. In a similar indoor village-scale trial of fenitrothion, used in Central Java for four weeks (involving 978 houses), there were no complaints or clinical symptoms of organophosphorus toxicity among the spray operators or the inhabitants of the sprayed area. However, cholinesterase activity, determined by the tintometric method, was reduced in 4/12 spraymen to 40-60 percent of the pre-exposure values after the third week of spraying. COMMENTS Fenitrothion was last evaluated in 1982 when, in view of the absence of 1) replacement studies for those performed previously by Industrial Bio-Test Laboratories (IBT), (2) adequate mammalian non-rodent toxicology data and (3) an adequate teratology study, the ADI was replaced by a temporary ADI. Most of the additional data required have now been supplied and evaluated. Teratogenicity studies in the mouse and rat showed no embryotoxic or teratogenic effects at doses up to 20 mg/kg in rats and 200 mg/kg in mice, but these studies were considered unsatisfactory as dosing did not cover the whole period of organogenesis. The previously evaluated rabbit teratology study was validated. A one-year toxicity study in dogs showed changes in cholinesterase activities as the only toxic manifestations; plasma cholinesterase was depressed in both sexes at 50 ppm, erythrocyte cholinesterase was slightly depressed only in males and the no-effect level was 10 ppm. Further observations of occupationally exposed humans showed no skin irritation, no tendency to accumulation and no evidence of liver damage or other toxicity, except slight nausea and decreased plasma cholinesterase activities. In addition, WHO has undertaken extensive monitoring over a period of two years of spray operators applying fenitrothion indoors; except for mild inhibition of whole blood cholinesterase activity and slight alterations of some other biochemical and haemotological parameters, there were no significant adverse effects. As some information on teratology was available from two three- generation studies, the temporary ADI was extended at a higher level. TOXICOLOGICAL EVALUATION Level Causing no Toxicological Effect Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg bw Dog: 10 ppm in the diet, equivalent to 0.3 mg/kg/ bw Estimate of Temporary Acceptable Daily Intake for Man 0 - 0.003 mg/kg/ bw Further Work or Information Required (by 1986) An acceptable rat teratology study. Desirable Observations in humans. REFERENCES Griggs, L.M.P., Jefferson, N.D., Blair, N., Kopplin, J.R., Richter, 1984 W.S., Spicer, E.J.F. One-year dietary toxicity study in dogs. Report from International Research and Development Corporation submitted by Sumitomo Chemical Co., Ltd. to WHO Miyamoto, J., Kohda, H. & Kadota, T. Teratogenic studies with 1975 Sumithion in ICR-JCL mice and Sprague Dawley rats. Report submitted by Sumitomo Chemical Co., Ltd. to WHO. (Unpublished) Motabar, M., Sanai, G.H. & Heidari, A.A. Toxicological evaluation of 1973 Sumithion (OMS-43) on operators and inhabitants in the Mamasani area Southern Iran. Iranian J. Pharm. Health, 2: 40-49. Shelanski, M.V., Levenson, T. & Karras, C. Report from Product 1977 Investigations Inc. submitted by Sumitomo Chemical Co., Ltd. to WHO. (Unpublished) Usutani, S., Nishiyama, K., Sato, I., Matsuura, K. & Sawada, Y. 1978 Studies on the amount of exposure to pesticides and blood levels or organophosphorus pesticides of farmers engaging in joint control works over apple orchards. J. Jap. Assoc. Rural Med., 27: 79-88.
See Also: Toxicological Abbreviations