FENTHION JMPR 1978 Explanation Fenthion was reviewed by the 1971, 1975 and 1977 Meetings (FAO/WHO 1973b, 1977b, 1978b). A temporary ADI was established and temporary MRLs were recommended for a range of fruits and vegetables and attention was drawn to various items on which there was a need for further work or information. New data received is evaluated in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special studies Pharmacological study A daily diet containing 300 ppm fenthion was given to 8 groups of Donrya rats: a hare's eye group, a satured eyelid group, a cervical sympathectomy group, a group given antibiotic eye ointment, a group given atropine eyedrops and groups given subcutaneous injections of pralidoxime, atropine and GSH for about one month. All rats given fenthion showed typical symptoms, of organophosphorus intoxication such an nervousness, general spasms, diarrhea, and salivation. Also ophthalmological symptoms, such as eye-ball protrusion, keratoconus, mammiform cornea and corneal turbity were observed. The described pretreatments did not prevent the ocular symptoms (abstract only)(Kawai et al., 1976). Teratogenicity Preliminary studies indicated 100 mg/kg was lethal to non-pregnant female rats in 2-4 days, and that 30 mg/kg induced toxic symptoms. Therefore four groups of 20 pregnant rats were dosed orally at 0, 1, 3 or 10 mg/kg/day on days 6-15 of pregnancy. Day 0 was the day semen was detected). At sacrifice (day 20 of gestation) implantation rate, numbers of live, dead and resorbed foetii, litter weight and placental weights were recorded. After gross examination, approximately 2/3 of the offspring were examined for skeletal malformations (Alizarin stain), and 1/3 for soft tissue malformations. No treatment related effects were noted (Machemer, 1978a). Mutagenicity In a dominant lethal assay 2 groups of 50 male mice (NMRI-strain) were given a single oral dose of 0 or 25, mg fenthion/kg b.w. Additionally a third group of mice was treated with 10 mg fenthion/kg b.w., because 25 mg/kg induced toxic effects in the males (drowsiness, ruffled coat and dilated intestines). The compound was given in a 2% aqueous cremophor E.L. emulsion. After injection each male was caged with a untreated virgin female for a period of 4 days. This procedure was repeated for a total of 12 matings. On day 12-16 of gestation the females were sacrificed and the number of implantations, the live and dead implants (sum of the deciduomata, the resorptions and the dead embryos) counted. Except for an increased pre-implanation loss at the dose level of 25 mg/kg b.w. in the first two mating periods, no other treatment-related effects on fertility, pre- and post implantation loss were observed (Machemer, 1978b). Potentiation In rats no synergistic effects on the acute oral toxicity was noticed of fenthion with edinfenphos and the active ingredient of Bassa. (Thyssen, 1977). Acute toxicity In an attempted suicide 0.5 g of 2% fenthion powder was ingested. The patient felt severe pain in the epigastrium and abdomen 3 hrs after ingestion, then experienced continued vomiting and diarrhea. Upon admission to hospital conspicuous reduction of serum ChE-activity of 0.08 delta pH was observed. She was treated by repeated injections of P.A.M. and atropine (summary only) (Kanda and Matsushima, 1976). Short-term studies Monkey In an interim report data are provided on four groups of 5 male and 5 female Rhesus monkeys which received 0, 0.02, 0.07 or 0.2 mg fenthion/kg body weight as a freshly prepared solution in corn oil, daily by stomach tube for one year. Animals were observed daily for general appearance, etc., body weight and ophthalmological examinations were reported monthly, and clinical chemistry, haematology and urinalysis were performed at 0, 1, 3, 6 and 12 months. Plasma and erythrocyte cholinesterase were measured at 0, 1, 2, 3 and 4 weeks and thereafter monthly. One monkey/sex from the 0 and 0.2 mg/kg groups were sacrificed at 7 months, 3 weeks. Brain cholinesterase, organ absolute and relative weights, gross and histopathology were recorded. The plasma cholinesterase was depressed in both sexes at 0.2 mg/kg. Plasma cholinesterase depression occurred at 0.07%, but was inconsistent and minimal. No adverse effects were noted on any other parameter (Coulston et al., 1978). Long-term studies Rat In a 2-year toxicity experiment 50 male and 50 female rats per group were fed a diet containing 3, 15 and 75 ppm fenthion. In the control group 100 males and 100 females were used. The rats were weighed weekly during the first 26 weeks and thereafter at 14-day intervals. Food consumption was recorded weekly. Clinical chemistry was performed on 5 male and 5 female rats per group at intervals of 1, 3, 6 and 12 months, and on 10 males and females at the end of the experiment. The clinical chemistry included hematology, liver- and kidney function tests, urinalysis, blood sugar and serum cholesterol determinations. Plasma and erythrocyte cholinesterase activities were determined after 1, 2, 4, 8, 13, 26, 52, 78 and 105 weeks. Brain cholinesterase activity was not measured. At the end of the experiment the rats were examined macroscopically, the organs weighed and studied microscopically. 3 and 15 ppm fenthion did not affect the physical appearance, behaviour, growth and survival rate. The male rats of the 75 ppm group had a significantly lower body weight. A tendency toward increased mortality was observed in the 75 ppm group in both sexes. Hematology, blood chemistry, urinalysis gross macroscopy and histopathology revealed no compound related effects. Dietary concentrations of 15 and 75 ppm fenthion caused dose-dependent depression of plasma and erythrocyte cholinesterase activity. At 3 ppm cholinesterase activity was only slightly depressed in the plasma of the females. A no-effect level of 3 ppm fenthion diet is stated (Bombard and Loser, 1977). OBSERVATIONS IN MAN A prospective study was carried out on 150 cases of anticholinesterase insecticide poisoning to observe the influence of the type of insecticide used on the clinical picture and prognosis. Of the 150 cases, 32 had consumed fenthion, 48 fenitrothion and 50 malathion. Twenty did not know exactly which agent was consumed. Paralytic signs were significantly more frequent with fenthion than with malathion or fenitrothion (being 81.2%, 30% and 23% resp.). These signs occurred later with fenthion and lasted longer. Death occurred significantly more often with fenthion (the mortality rate being with fenthion 35.5%0 with malathion 4% and with fenitrothion 2.1%). Pulmonary oedema was commonest with malathion and not encountered with Fenthion. The cholinesterase depression was most marked with fenthion reaching 0 in 18 of the 27 cases studied (Wadia et al., 1977). Comments The additional data requested by the 1971 and the 1975 Joint Meetings have been partially met, a long-term rodent study having been submitted. Cholinesterase inhibition is the most sensitive criterium. No tumorogenic activity was noted. A long-term nonrodent study is underway, as indicated by the interim report on a monkey study. In addition, special studies in pharmacology, mutagenicity and teratology have been received. Whilst the data reviewed do not increase the concerns relating to fenthion, the continued absence of some previously requested studies precludes the allocation of a firm ADI. However, the data do permit an extension of the existing temporary ADI. TOXICOLOGICAL EVALUATION Level causing no toxicological effect: Rat: 3 ppm in the diet, equivalent to 0.15 mg/kg b.w. Dog: 2 ppm in the diet, equivalent to 0.05 mg/kg b.w. Monkey: 0.07 mg/kg b.w. by gavage daily Estimate of temporary acceptable daily intake for man: 0 - 0.0005 mg/kg b.w. RESIDUES IN FOOD AND THEIR EVALUATION USE PATTERN Submissions received from Australia and Japan confirmed (see FAO/WHO 1972b) that fenthion is currently used on a wide range of fruits and vegetables, and for the control of insect vectors of farm animals and of pests of public health importance. Use patterns in Japan on rice and potatoes are summarized in Table 1. RESIDUES RESULTING FROM SUPERVISED TRIALS In pears A single application of fenthion at 250 g/100l resulted in 0.08-0.21 mg/kg residues 7 days after treatment. This decreased to less than 0.02 mg/kg 14 days after application (Table 2) (Race, 1978). TABLE 1. Use pattern of fenthion in Japan Crop Formulation Application Use: permitted No. of method period applications allowed Emulsible seed before seeding concentrate immersion spraying up to 30 days before harvest Wettable spraying up to 30 days powder before harvest Rice ULV spraying do up to 30 days concentrate not dilute) before harvest 6 Dust seed dressing before seeding dusting up to 14 days before harvest Granule dusting up to 14 days before harvest Microgranule Emulsible concentrate dusting up to 7 days before harvest - Potato Wettable powder TABLE 2. Residues of fenthion in pears, raspberries, strawberries and radishes in Norway Crop Application rate, Number of Period between Residues, g/ha or g/100l treatments final treatment mg/kg and harvest (days) Pears 250 g/100l 1 7 0.08-0.21 14 < 0.02 21 < 0.02 28 < 0.02 35 < 0.02 Raspberries 250 g/100l 2 1 2.9 - 3.3 5 0.14-0.18 8 0.05-0.06 16 < 0.02 Strawberries 50 g per 1000 m row 1 24-30 <0.05 Radishes 200 g/ha 1 15-16 <0.06 20-22 <0.06 400 g/ha 1 16 <0.06 20-22 <0.06 In raspberries Two applications at 250 g/100l resulted in residues of 2.9-3.3 mg/kg 1 day after the last application. They declined rapidly to 0.14-0.18 mg/kg after 5 days and 0.05-0.06 mg/kg after 8 days. After 16 days, the residues were below the detection limit of 0.02 mg/kg (Norway, Table 2). In strawberries A single application of 50 g per 1000 m row gave residues below 0.05 mg/kg 25-30 days after application (Norway, Table 2). In radishes Application at 200 and 400 g/100l gave residues below 0.06 mg/kg, 15-22 days after application (Norway, Table 2). In rice In Japan, application at 0.5-1.0 kg ai/ha under normal cultivation or with a preharvest interval generally above 25 days gave residues below detection limits in hulled rice (Table 3). In a study with fenthion applied as a dust 4 days before harvest, the residue in hulled rice was still below the limit of detection of 0.001 mg/kg. With good agricultural practice, therefore, the residues in hulled rice would not exceed the MRL. In potatoes In 1974, multiple applications as dust and emulsifiable concentrate at 0.5-2.0 kg ai/ha gave residues below the detection limit. Two applications at 0.5 kg ai/ha with harvesting 7 days after last application gave residues below 0.01 mg/kg (Table 3). RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION In a market basket study in Australia in 1970, fenthion residues were not determined specifically but the total organophosphorus (OF) residues found did not exceed 0.5 mg/kg. Some 240 samples were examined and only 32 contained any OF residues, of which only 3 exceeded 0.2 mg/kg. Traces of fenthion have been detected occasionally in dairy products monitored routinely in a continuous national residues survey programme. For example, in a 12 month period (1977-78), 3 of 335 samples of dairy produce contained fenthion residues in the range 0.1-0.2 mg/kg. TABLE 3. Residues of fenthion in rice and potatoes (Japan 1978) Application Crop Origin Year Formulation Rate No Pre-harvest Residue (kg ai/ha) (days) (mg/kg) Rice Hokkaido 1974 Dust 0.6 4 45 <0.008 (hulled) 0.6 2 48 <0.008 Nigata 0.6 1 83 <0.002 Ibaragi 0.6 6 14 <0.004 Ishikawa 0.6 2 24, 25 <0.01 Shiga 0.8 2 30 <0.01 Shimane 0.8 3 25, 60 <0.004 Aichi 1975 0.6 1 73 <0.01 Shiga 0.8 2 46 <0.003 Wakayama E.C. 0.5-0.9 1-6 51, 68 <0.005 Kochi Dust 0.8 3 4 <0.001 Gumma 1976 E.C. 1 4 29 <0.02 1 5 29 <0.02 Ehime Granule 1 1 57 <0.003 Dust 0.8 1 39 <0.007 0.9 2 36 Potatoes Hokkaido 1974 Dust 2 5 21 <0.008 E.C. 0.5 4 27 <0.008 Gumma 0.5 2 7 <0.01 APPRAISAL Data on residues in pears, raspberries, strawberries, and radishes provided by Norway supported the MRLs established previously and data from Japan show that if good agricultural practice is followed it is unlikely that the MRLs set for hulled rice and potatoes will be exceeded. Fenthion was only occasionally detected in the national residue monitoring programme in Australia. No new data were received on the effects of processing or cooking on residues of fenthion. RECOMMENDATIONS No changes to the existing temporary MRLs are recommended. FURTHER WORK OR INFORMATION Required (1980) 1. Additional report on the on-going non-human primate study. Adequate long-term feeding studies in a non-rodent mammalian species. 2. Investigations on the mechanism of long-lasting cholinesterase inhibition, as previously requested. Desirable 1. Information on the effect of processing and cooking on fenthion residues in fruits and vegetables. REFERENCES Australia Report from the Codex Contact Point, Australia on uses (1978) of fenthion. Bomhard, E. and Loser, E. Chronic toxicity study on rats. Rep. nr. (1977) 6769 from Institut für Toxikologie, Bayer A.G. Unpublished report submitted by Bayer A.G. Coulston, F., Rosenblum, I. and Ford, W. A safety evaluation of (1978) fenthion in Rhesus monkeys (Macaca mulatta). A twelve month interim report from Albany Medical College of Union University, Albany, (N.Y.). Japan Report from the Codex Contact Point, Japan on fenthion in rice (1978) and potatoes. Kanda, M. and Matsushima, S. A case of acute fenthion poisoning. (1974) Annual Rep. Jpn. Inst. Rural. Med. 3: 50-53 (abstract). Kawai, M., Tojo, K., Miyazawa, S., Maruta, H., Naito, M. (1976) Experimental studies on the effects of organophosphorus compounds on the eyes. Natl. Defense Med. J. 23 no. 1: 1-10 (abstract). Machemer, L. S 1752 (Fenthion, Lebaycid-Wirkstoff) Untersuchungen auf (1978a) embryotoxische und teratogene Wirkungen an Ratten nach oraler Verabreihung, Rep. nr. 7580, from Institut für Toxikologie, Bayer A.G. Unpublished report submitted by Bayer A.G. Machemer, L. S 1752 (Fenthion, Lebaycid active ingredient). Dominant (1978b) Lethal study on male mice to test for mutagenic effects. Rep. nr. 7449 from Institut für Toxikologie, Bayer A.G. Unpublished report submitted by Bayer A.G. Race, J. Report from the Codex Contact Point, Norway on fenthion (1978) uses on pears, raspberries, strawberries and radishes. Thyssen, J. Untersuchungen zur Kombinationstoxizität von (1977) Edifenphos, Fenthion und Bassa-Wirkrtoff. Report nr. 7176 from Institut für Toxikologie, Bayer A.G. Unpublished report submitted by Bayer A.G. Wadia, R.S., Bhirud, R.H., Gulavani, A.V. and Amin, R.B. (1977) Neurological manifestations of three organophosphate poisons. Indian J. Med. Res. 66 446-468.
See Also: Toxicological Abbreviations Fenamiphos (ICSC) Fenamiphos (WHO Pesticide Residues Series 4) Fenamiphos (Pesticide residues in food: 1977 evaluations) Fenamiphos (Pesticide residues in food: 1980 evaluations) Fenamiphos (Pesticide residues in food: 1985 evaluations Part II Toxicology) Fenamiphos (Pesticide residues in food: 1987 evaluations Part II Toxicology) Fenamiphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental) Fenamiphos (JMPR Evaluations 2002 Part II Toxicological)