INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 133 FENITROTHION This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. First draft prepared by Dr. J. Sekizawa (National Institute of Hygienic Sciences, Japan) and Dr. M. Eto (Kyushu University, Japan) with the assistance of Dr. J. Miyamoto and Dr. M. Matsuo (Sumitomo Chemical Company) Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Orgnization Geneva, 1992 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. WHO Library Cataloguing in Publication Data Fenitrothion. (Environmental health criteria ; 133) 1.Fenitrothion - adverse effects 2.Fenitrothion - toxicity 3.Environmental exposure I.Series ISBN 92 4 157133 0 (NLM Classification: WA 240) ISSN 0250-863X The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 1992 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR FENITROTHION 1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS 1.1. Summary and evaluation 1.1.1. Exposure 1.1.2. Uptake, metabolism, and excretion 1.1.3. Effects on organisms in the environment 1.1.4. Effects on experimental animals and in vitro test systems 1.1.5. Effects on human beings 1.2. Conclusions 1.3. Recommendations 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1. Identity 2.2. Physical and chemical properties 2.3. Conversion factors 2.4. Analytical methods 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Natural occurrence 3.2. Man-made sources 3.2.1. Production 3.2.2. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION 4.1. Transport and distribution between media 4.2. Abiotic and biotic transformation 4.2.1. Abiotic transformation 188.8.131.52 Thermal degradation 184.108.40.206 Photolysis in air 220.127.116.11 Hydrolysis and photolysis in water 18.104.22.168 Photolysis on soil 4.2.2. Biotransformation 22.214.171.124 Biodegradation in soil 126.96.36.199 Biodegradation and bioaccumulation in organisms 188.8.131.52 Abiotic and biological degradation in/on plants 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Air 5.1.2. Water 5.1.3. Soil 5.1.4. Food 5.2. Human exposure 5.2.1. Food 6. KINETICS AND METABOLISM 6.1. Absorption, distribution, metabolic transformation, elimination, and excretion 6.2. Retention and turnover 7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS 7.1. Single exposure 7.2. Skin and eye irritation; skin sensitization 7.2.1. Skin and eye irritation 7.2.2. Skin sensitization 7.3. Short-term studies 7.3.1. Rat 7.3.2. Dog 7.3.3. Rabbit 7.3.4. Guinea-pig 7.4. Long-term and carinogenicity studies 7.5. Reproductive effects, embryotoxicity, and teratogenicity 7.5.1. Reproductive effects 7.5.2. Embryotoxicity and teratogenicity 7.6. Mutagenicity 7.7. Neurotoxicity 7.8. Effects on hepatic enzymes 7.9. Effects on hormonal balance 7.10. Toxicity of metabolites and the S-isomer 7.11. Factors modifying toxicity 7.12. Mechanism of toxicity - mode of action 7.12.1. Mode of action 7.12.2. Selective toxicity 7.12.3. Potentiation of toxicity of other chemicals 8. EFFECTS ON MAN 8.1. General population exposure 8.1.1. Acute toxicity 8.1.2. Poisoning incidents 8.1.3. Contact dermatitis 8.1.4. Possible links with Reye's syndrome 8.2. Occupational exposure 9. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 9.1. Microorganisms and algae 9.2. Aquatic organisms 9.2.1. Fish 9.2.2. Invertebrates 9.2.3. Amphibians and arthropods 9.3. Terrestrial organisms 9.3.1. Terrestrial invertebrates 9.3.2. Birds 9.3.3. Mammals 10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES REFERENCES ANNEX I. TREATMENT OF ORGANOPHOSPHATE INSECTICIDE POISONING IN MAN ANNEX II. NO-OBSERVED-EFFECT LEVELS IN PLASMA, RED BLOOD CELLS, AND BRAIN ChE, IN ANIMALS TREATED WITH FENITROTHION RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS RESUMEN Y EVALUACION, CONCLUSIONES ET RECOMENDACIONES WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TRICHLORFON AND FENITROTHION Members Dr V. Benes, Department of Toxicology and Reference Laboratory, Institute of Hygiene and Epidemiology, Prague, Czech and Slovak Federal Republic Dr C. Carrington, Division of Toxicological Review and Evaluation, Food and Drug Administration, Washington, DC, USA (Joint Rapporteur) Dr W. Dedek, Department of Chemical Toxicology, Academy of Sciences, Leipzig, Germany Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood Experimental Station, Huntingdon, United Kingdom Dr D.J. Ecobichon, Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada Dr M. Eto, Department of Agricultural Chemistry, Kyushu University, Fukuoka-shi, Japan (Vice-Chairman) Dr Bo Holmstedt, Department of Toxicology, Karolinska Institute, Stockholm, Sweden Dr S.K. Kashyap, National Institute of Occupational Health, Ahmedabad, India Dr J. Miyamoto, Takarazuka Research Centre, Hyogo, Japan Dr H. Spencer, United States Environmental Protection Agency, Washington, DC, USA (Chairman) Dr M. Takeda, National Institute of Hygienic Sciences, Tokyo, Japan Observers Dr M. Matsuo, Biochemistry and Toxicology Laboratory, Sumitomo Chemical Co. Ltd, Osaka-shi, Japan (representing GIFAP) Secretariat Dr K.W. Jager, IPCS, World Health Organization, Geneva, Switzerland (Secretary) Dr J. Sekizawa, National Institute of Hygienic Sciences, Tokyo, Japan (Joint Rapporteur) NOTE TO READERS OF THE CRITERIA DOCUMENTS Every effort has been made to present information in the criteria documents as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria documents, readers are kindly requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. * * * A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Palais des Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or 7985850). ENVIRONMENTAL HEALTH CRITERIA FOR FENITROTHION A WHO Task Group on Environmental Health Criteria for Trichlorfon and Fenitrothion met at the World Health Organization, Geneva, from 10 to 14 December 1990. Dr K.W. Jager, IPCS, welcomed the participants on behalf of Dr M. Mercier, Manager of the IPCS, and the three IPCS cooperating organizations (UNEP/ILO/WHO). The Group reviewed and revised the draft and made an evaluation of the risks for human health and the environment from exposure to fenitrothion. The first draft was prepared by Dr J. Sekizawa of the National Institute of Hygienic Sciences of Japan in collaboration with Dr J. Miyamoto and Dr M. Matsuo of Sumitomo Chemical Company, and Dr M. Eto of Kyushu University. Dr J. Sekizawa also prepared the second draft, incorporating comments received following circulation of the first drafts to the IPCS contact points for Environmental Health Criteria. Dr K.W. Jager of the IPCS Central Unit was responsible for the scientific content and Mrs M.O. Head of Oxford for the editing. The fact that Sumitomo Chemical Company Limited, Japan (trichlorfon and fenitrothion) and Bayer AG, Germany (trichlorfon) made available to the IPCS and the Task Group their proprietary toxicological information on the products under discussion is gratefully acknowledged. This allowed the Task Group to make its evaluation on the basis of more complete data. The efforts of all who helped in the preparation and finalization of the document are gratefully acknowledged. 1. SUMMARY AND EVALUATION, CONCLUSIONS AND RECOMMENDATIONS 1.1 Summary and evaluation 1.1.1 Exposure Fenitrothion is an organophosphorus insecticide that has been in use since 1959. It is used in agriculture to control insects on rice, cereals, fruits, vegetables, stored grains, and cotton. It is also used to control insects in forests and for fly, mosquito, and cockroach control in public health programmes. It is formulated as emulsifiable concentrates, ultra-low-volume concentrates, powders, granules, dusts, oil-based sprays, and in combination with other pesticides. Between 15 000 and 20 000 tons of fenitrothion are produced per year. Fenitrothion enters the air by volatilization from contaminated surfaces and may drift beyond the intended target area during spraying. It leaches very slowly from most soils, but some run-off can be expected. Fenitrothion is degraded by photolysis and hydrolysis. In the presence of ultraviolet radiation (UVR) or sunlight, the half-life of fenitrothion in water is less than 24 h. The presence of micro-flora may also accelerate degradation. In the absence of sunlight or microbial contamination, fenitrothion is stable in water. In soil, biodegradation is the primary route of degradation, though photolysis may also play a role. Airborne concentrations of fenitrothion may be as high as 5 µg/m3 directly after spraying, but may decrease markedly with time and distance from the application site. Levels in water may be as high as 20 µg/litre, but decrease rapidly. Bioconcentration factors for fenitrothion with continuing exposure have been estimated to range from 20 to 450 for a number of different aquatic species. Levels of fenitrothion residues in fruits, vegetables, and cereal grains may range from 0.001 to 9.5 mg/kg immediately after treatment, but decline rapidly, with a half-life of 1-2 days. 1.1.2 Uptake, metabolism, and excretion Fenitrothion is rapidly absorbed from the intestinal tract of experimental animals and distributed to various body tissues. The half-life for the dermal absorption of fenitrothion in the monkey was 15-17 h. Fenitrothion has been shown to be metabolized through the major pathways of O-demethylation and by cleavage of the P-O-aryl bond. The nitro group of fenitrothion is reduced by intestinal microorganisms, in ruminants only. The major route of elimination is via the urine, most of the metabolites being eliminated within 2-4 days in the rat, guinea-pig, mouse, and dog. The major metabolites reported are demethyl fenitrothion, demethyl fenitrooxon, dimethylphosphorothioic acid and dimethyl phosphoric acid, and 3-methyl-4-nitrophenol and its conjugates. Differences in the composition of metabolites found among most laboratory test animals and between sexes of the same species appear to be mainly quantitative in nature. Only rabbits appear to excrete fenitrooxon and aminofenitrooxon in small, though quantifiable, amounts in the urine. Evidence from studies on rabbits and dogs showed preferential deposition of fenitrothion in the adipose tissue. Residues found in the milk of cows following exposure to fenitrothion were not detected two days later. Though fenitrothion is readily absorbed via the oral route, it is rapidly metabolized and excreted and is unlikely to remain in the body for any prolonged period. 1.1.3 Effects on organisms in the environment The concentrations of fenitrothion that are likely to be found in the environment do not have any effects on microorganisms in soil or water. Fenitrothion is highly toxic for aquatic invertebrates in both freshwater and seawater with LC50 values of a few µg/litre for most species tested. The no-observed-effect level (NOEL) for Daphnia, in 48-h tests, was < 2 µg/litre; in life-cycle tests, a maximum acceptable toxicant concentration (MATC) of 0.14 µg per litre was established. Field observations and studies on experimental ponds have shown effects on populations of invertebrates. However, most of the changes observed were temporary, even at concentrations considerably higher than those likely to occur after recommended usage. Fish are less sensitive to fenitrothion than invertebrates and show 96-h LC50 values in the range of 1.7-10 mg/litre. The most sensitive life stage is the early larva. Long-term studies have established a MATC at, or above, 0.1 mg/litre for 2 species of freshwater fish. Field studies after application of fenitrothion to forests showed no effects on wild populations of fish or on the survival of caged test fish with measured water concentrations of fenitrothion of up to 0.019 mg/litre. Repeated application of fenitrothion to forests had no effect on fish populations. In laboratory tests, freshwater molluscs showed LC50 values in the range 1.2 to 15 mg/litre. No field effects were seen after forest spraying at 140 g/ha. Fenitrothion is highly toxic for bees (topical LD50, 0.03-0.04 µg/bee). Field effects have been reported with high numbers of honey bees and other species killed locally. However, the total numbers killed represented only a small percentage of the hive population. Acute oral LD50 values for birds range between 25 and 1190 mg/kg body weight and most 8-day dietary LC50s exceeded 5000 mg/kg diet. NOEL values for reproduction were 10 mg/kg body weight for the quail and 100 mg/kg body weight for the mallard. Song-bird deaths occurred soon after application of fenitrothion at a rate of 280 g/ha and were markedly increased at 560 g/ha for species living in the forest canopy. After spraying at 420 g/ha followed by 210 g/ha a few days later, the reproductive success of White-throated Sparrows was reduced. In many studies, song-birds showed inhibition of ChE soon after the fenitrothion spraying of forests. Field observations have not revealed any effects of fenitrothion on populations of wild small mammals. 1.1.4 Effects on experimental animals and in vitro test systems Fenitrothion is an organophosphate and causes cholinesterase activity depression in plasma, red blood cells, and brain and liver tissues. It is metabolized to fenitrooxon, which is more acutely toxic. Its toxicity may be potentiated by some other organophosphate compounds. Fenitrothion is an insecticide of moderate toxicity with oral LD50 values in rats and mice ranging from 330 to 1416 mg/kg body weight. Acute dermal toxicity in rodents ranged from 890 mg/kg body weight to more than 2500 mg/kg body weight. Fenitrothion is only minimally irritating to the eyes and is nonirritating to the skin. The chemical showed dermal sensitizing potential in one of two studies on guinea-pigs. Fenitrothion has been tested in short-term studies on rats, dogs, guinea-pigs, and rabbits and in long-term carcinogenicity studies on rats and mice. In short-term studies on rats and dogs, the no-observed-adverse-effect levels (NOAELs), based on brain-ChE activity, were, respectively, 10 mg/kg diet and 50 mg/kg diet. Long-term studies on rats and mice indicated a NOAEL (based on brain ChE activity) of 10 mg/kg diet. No carcinogenic effects were found in any of the long-term studies reported. Fenitrothion was not mutagenic in in vitro and in vivo studies. Fenitrothion has not been found to be teratogenic at doses of up to 30 mg/kg body weight in rabbits and up to 25 mg/kg body weight in rats. Dose levels exceeding 8 mg/kg body weight were maternally toxic. Developing young rats exhibited behavioural deficits post-natally following in utero exposure. A NOEL for this effect was established at 5 mg/kg body weight per day. Multigeneration reproduction studies on rats did not indicate any morphological effects. A NOAEL of 120 mg/kg diet, based on reproductive parameters, was demonstrated in these studies. Delayed neurotoxicity has not been reported as a result of exposure to fenitrothion. 1.1.5 Effects on human beings Administration of fenitrothion as a single oral dose of 0.042- 0.33 mg/kg body weight and in repeated doses of 0.04-0.08 mg/kg body weight to human volunteers did not cause inhibition in plasma and erythrocyte ChE. The urinary excretion of a metabolite, 3-methyl-4-nitrophenol, was complete within 24 h. Several cases of poisoning have occurred. The signs and symptoms of poisoning were those of parasympathic stimulation. In a few cases, the toxic manifestations were delayed in onset and recurred for up to a few months. It has been suggested that the slow release of the insecticide from adipose tissue can give rise to a protracted clinical course or late symptoms of intoxication. In some cases, contact dermatitis has been attributed to exposure to this insecticide. There is no evidence of delayed neurotoxicity or of an association with Reye's syndrome following exposure to fenitrothion. Within WHO programmes, fenitrothion has been used in a few countries for indoor residual spraying for malaria control (application dose: 2.0 g of active ingredient/m2). No evidence of toxicity was noted in thousands of inhabitants observed, with the exception of one study in which less than 2% inhabitants reported mild complaints. However, approximately 25% of spray operators showed up to 50% inhibition of whole blood ChE activity. Following aerial application of a 50% EC formulation, some workers developed symptoms of poisoning and decreased whole blood ChE activity within 48 h. Occupational exposure for a period of over 5 years of male workers in a production plant and female workers in the packaging unit produced clinical signs and symptoms of poisoning in 15% of male and 33% of female workers. The measured air concentration of fenitrothion in the workplace ranged between 0.028 and 0.118 mg/m3. 1.2 Conclusions * Fenitrothion is a moderately toxic organophosphorus ester insecticide. However, over-exposure from handling during manufacture or use and accidental or intentional ingestion may cause serious poisoning. * Exposure of the general population, resulting mainly from agricultural and forestry practices and public health programmes, should not constitute a health hazard. * With good work practices, hygienic measures, and safety precautions, fenitrothion is unlikely to present a hazard for those occupationally exposed. * Despite its high toxicity for non-target arthropods, fenitrothion has been extensively used for pest control with few, or no, adverse effects on populations in the environment. 1.3 Recommendations * For the health and welfare of workers and the general population, the handling and application of fenitrothion should only be entrusted to competently supervised and well-trained operators who will follow adequate safety measures and use fenitrothion according to good application practices. * The manufacture, formulation, use, and disposal of fenitrothion should be carefully managed to minimize contamination of the environment, particularly surface waters. * Regularly exposed workers should receive periodic health evaluations. * Application rates of fenitrothion should be limited, to avoid effects on non-target arthropods. The insecticide should never be sprayed over water bodies or streams. 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS Fenitrothion was first prepared in Czechoslovakia in 1956 (Drabek, Truchlik, 1957). Later, it was prepared independently by Sumitomo Chemical Co. and by Bayer A.G. in 1959 and later by American Cyanamid Co. Its basic insecticidal activity was described by Nishizawa et al. (1961). 2.1 Identity Primary constituent Chemical formula: C9H12NO5PS Chemical structure: Relative molecular mass: 277.25 Common name: fenitrothion CAS chemical name: O,O-dimethyl O-(3-methyl -4-nitro-phenyl) phosphorothioate IUPAC name: O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate RTECS Registry number: TG0350000 CAS Registry number: 122-14-5 Synonyms: Accothion, Agrothion, Bayer 41831, Bayer S 5660, Cytel, Dybar, Fenitox, MEP, Novathion, Nuvanol, Cyfen, Sumitomo 1102A Technical product (FAO/WHO, 1988b) Major trade names: Metathion, Novathion, Sumithion, Folithion Purity: > 93% (Sumithion) Impurities: O,O-dimethyl O-3-nitro- m-tolyl- phosphorothioate < 1.5% O-methyl O,O-bis(4-nitro- m-tolyl) phosphorothioate < 2.5% O-methyl S-methyl O-(4-nitro- m-tolyl) phosphorothioate(S-isomer) < 0.8% O,O-dimethyl O-2-nitro- m-tolyl phosphorothioate < 3.0% O,O-dimethyl O-6-nitro- m-tolyl phosphorothioate < 2.5% O,O-dimethyl O-2,4-dinitro- m-tolyl phosphorothioate < 2.0% O,O-dimethyl O-4,6-dinitro- m-tolyl phosphorothioate < 1.5% 3-methyl-4-nitrophenol < 0.5% Isomeric composition: S-isomer, < 0.8% 2.2 Physical and chemical properties Some physical and chemical properties of Fenitrothion are given in Table 1. 2.3 Conversion factors 1 ppm = 11.5 mg/m3 (at 20 °C) 1 mg/m3 = 0.087 ppm. 2.4 Analytical methods Methods for the determination of fenitrothion in foods, environmental samples, technical products, and formulations are summarized in Tables 2 and 3. The common procedure for determining residues in foods and environmental media consists of (1) extraction, (2) partition, (3) chromatographic separation (clean-up), and (4) qualitative and quantitative analysis using analytical instruments. Fenitrothion levels in technical products and formulations are usually determined by the diazo method, the colorimetric method, or gas-liquid chromatography. The common procedure consists of: (1) dissolution or extraction, (2) separation of impurities and (3) determination. Granules should be pulverized before analysis. The joint FAO/WHO Codex Alimentarius Commission has given recommendations for the methods of analysis to be used for the determination of fenitrothion residues (FAO/WHO, 1989d). Table 1. Some physical and chemical properties of fenitrothiona Physical state liquid Colour yellow-brown Odour chemical odour Melting point 0.3 °C Boiling point 140-145 °C (decomp.)/0.1 mmHg Flash point 157 °C Vapour pressure 18 mPa at 20 °C; 6 x 10-6 mmHg at 20 °C 25 25 Density d 1.32-1.34; d 1.3227 25 4 n-Octanol/water partition coefficient (log P) 3.16 Solubility in water 14 mg/litre at 30 °C Solubility in organic freely soluble in alcohols, esters, solvents ketones, and aromatic hydrocarbons; > 1000 g/kg dichloromethane, methanol, xylene; 193 g/kg propan-2-ol; 42 g/kg hexane at 20-25 °C Stability hydrolysed by alkali: half-life 4.5 h in 0.01 N NaOH at 30 °C decomposed by heat: 145 °C a From: Martin & Worthing (1981); Worthing & Walker (1983); Meister et al. (1985); Moody et al. (1987a). Table 2. Analytical methods for the determination of fenitrothion in food and environmental samples Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb Residue analysis apple, orange acetone ESd florisil acetone/ GC: FTD, NPD, FPD, 2% 0.1 95-96 (0.1) Ferreira & peach, grape /2%Na2SO4 hexane DC-200 + 3% OF-1, 1.5% 86-97 (0.2) Fernandes tomato, /n-hexane (4/96) OV-17 + 1.95% OF-1, 10% 88-102 (0.5) (1980) cabbage DC-200 86-98 (1.0) 94-95 (2.0) chinese methanol/ benzene GC: FPD, 3% OV-1, 89 (0.5) Talekar cabbage acetone/ 10% DC-200 et al. benzene (1977) (Soxhlet) onion acetonitrile Amberlite methanol GC: FPD, 4% OV-1, 200 °C 99 (0.5) Iwata CH2Cl2/ XAD-8 benzene et al. benzene (1:4) charcoal (1981) apple,lettuce acetone ESd florisil benzene GC: ECD 0.1 70-102 Möllhoff carrot,onion /CH3Cl3 5% SE-30, 190 °C, 6.3 min 64-89 (0.5) (1967) tomato,potato 5% OF-1, 190 °C, 5.6 min 88-114 (1.0) 5% DC-200, 190 °C, 3.4 min 5% E-301, 190 °C, 2.9 min Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb orange,potato ethyl acetonitrile/ florisil petroleum sp/ GC:NPD, 0.001 Mestres acetate petroleum ethyl et al. CH2Cl2 spirit ether or (1974) (4:1) ethyl acetate peach acetone water/ charcoal+ CH2Cl2 GC:NPD Ambrus et al. potato CH2Cl2 MgO 3% OV-22; 3% OV-101; (1981) 1.95% SP-2401/1.5% acetone alumina N hexane SP-2250; 3% NPGS; 3% SE-30 on 100-120 mesh Gas-Chrom Q acetone silica gel benzene 5% water apple acetonitrile ESd HPLC: UV (280 nm) 0.03 81-87 (0.5) Funch (1981) salad 2% Nacl Radpak A with ODS /CH2Cl2 unpolished n-hexane I. n-hexane charcoal/ acetone/ GC: FPD Aoki et al. rice (Soxhlet) /CH3CN avicel n-hexane 10% DC-200 + 15% 76 (0.4) (1975) (1/10) (50/50) wheat OF-1, 180 °C, 7.9 min buck wheat II. CH3CN 2% DEGS + 0.5% H3PO4, 0.0007 92 (0.4) string bean /5% NaCl/ 180 °C, 10.2 min soybean benzene 10% DC-200 + 15% 0.0008 79-101 (0.4) pear OV-17, 190 °C, 9.4 min Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb water melon acetone ESd GC-MS 0.1 91-102 (0.5) Kobayashi tomato NaCl/ 5% OV-1, 150 °C et al. n-hexane (1979) wheat grain methanol GC: AFI, FPD, 5% 0.1 86 (0.5) Smart OV-17 + Epikote 1001 94 (1.0) (1980) apple methanol/ GC: FTD 0.005 80-97 (0.1) Takimoto & strawberry CH3CN/CHCl3 10% DC-200 + 20% OF-1, 97 (0.2) Miyamoto pear, tomato 210 °C (1976b) cucumber potato methanol/ florisil benzene/ GC: FTD, 10% DC-200 0.005 96 (0.01) Takimoto & CH3CN/CHCl3 ethyl + 20% OF-1, 210 °C Miyamoto acetate (1976b) (10/1) soybean methanol/ CH3CN/ silica benzene 0.005 98 (0.2, 0.02) Takimoto & (fresh) CH3CN/ n-hexane gel OF-1, 210 °C Miyamoto CH3Cl3 (1976b) green tea CH3CN/ CH3CN/ florisil benzene/ 0.005 90-93 (0.02) Takimoto & rice grain benzene n-hexane ethyl 92-98 (0.5) Miyamoto acetate/ (1976b) (10/1) Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb milk methanol/ CH3CN/ 0.005 89 (0.1) Takimoto & CH3CN/ n-hexane Miyamoto CHCl3 (1976b) butter hexane I. hexane/ GC: ECD, 5% DC-200, 0.02 95 Gajduskova CH3CN 180 °C (1974) II. aq. Na2SO4 CH3CN/ CH2Cl2 milk acetone I. acetone silica benzene GC: FPD, 10% DC-200, 0.001 96 (0.5), Bowman & CH2Cl2 gel Bcraza II. hexane/ (20% H2O) 180 °C 2.9 min 94 (0.05) (1969) CH3CN meat ethanol/ CH3CN/ TLC benzene/ GC: FTD, 10% DC-200 0.005 95 (0.1), Takimoto & benzene n-hexane ethyl + 20% OF-1 86 (0.2) Miyamoto acetate (1976b) (4/1) lettuce, petroleum- petroleum- TLC methanol Spectrophotometry 0.05- 89-115 Kovac & apple ether ether (A12O3) 400 nm, after hydrolysis 0.1 (0.25-1) Sohler cherries +CH3CN(1:1) (NaOH+ (1965) plums H2O2) Cerna & kohlrabi Benes cauliflower (1972) Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb cabbage citrus, acetone ESd silica hexane/ TLC 3% OV-225 ng Gardner potato CH3CCl3 gel acetone 170-240 °C 0.05 94 (0.5) (1971) (9/1) Martindale (1988) Environmental analysis water amberlite ethyl HPLC: UV (245 nm) RP-8 0.001 94 (0.05- Volpe & XAD-4 acetate CH3CN/H2O (50/50) Mallet (1981) water amberlite CH2Cl2 or GC: FPD, 3.6% OV-101 90 (0.05- Volpe & XAD-4 or 7 ethyl + 5% OV-210 0.005) Mallet acetate (1980) drinking- amberlite acetone/ GC: NPD, -MS, 3% 0.001 104 (0.1), LeBel water XAD-2 hexane OV-17 96 (0.01) et al. (15/85) (1979) water amberlite ethyl GC: FPD, 4% OV-101 + 0.001 91.5 (0.01) Mallet acetate et al. XAD-2 6% OV-210, 195 °C (1978) water uBondapak HPLC: UV (280 0.005 95.6 (0.737) Takaku Phenyl uBondapak Phenyl H2O/ et al. CH3CN (100/0-0/100) (1979a) Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb water petroleum GC: FPD, 5% SE-30, 180 °C 98-102 Grift & ether 5% DC-200, 180 °C (0.005-0.0005) Lockhart (1974) pasture CH3CN/ CH3CN/ florisil benzene/ GC: FTD, 10% DC-200 + 0.005 95 (0.1) Takimoto & ethyl grass benzene n-hexane acetate 20% OF-1, 210 °C Miyamoto (1976b) corn methanol/ silica benzene GC: FPD, 10% DC-200, 0.002 99-100 (5) Bowman & gel Bcraza grass CHCl3 (20% H2O) 180 °C, 2.9 min 98-99 (0.5) (1969) 97-98 (0.05) jack pine ethyl I.carbon/ benzene GC: NPD, 6% SE-30 + 96-100 (0.2) McNeil foliage acetate celite 4% OF-1, 225 °C et al. (1979) (1/6) II. 60% florisil benzene Si600 in hexane water n-hexane GC: FPD, 11% OV-17 + 0.00001 100-108 Ripley OF-1 3.6% OV-101, 225 °C (0.01-0.0001) et al. (1974) Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb fish ethyl ESd florisil benzene/ GC: FPD 0.05 93-110 Grift & ethyl Lockhart acetate CH3CN acetate 5% DC-200, 180 °C (1974) sediment /hexane 5% SE-30, 180 °C 0.05 88-102 (5-0.1) bivalve ethyl bio- CH2Cl2/ GC: FPD, -MS, 3% OV- 0.0009 94.4 (10-0.01) Sergeant acetate beads, cyclohexane 101, 180 °C, 11% OV-17/ et al. (Soxhlet) SX-3 OF-1, 200 °C (1979) (50/50) soil acetonitrile Amberlite ethyl GC: FPD, 3.6% OV-17 +0.05 98-112 (0.5) Hache XAD-2 acetate et al. chicken liver 5% OV-210, 210 °C (1981) wine, clam pine needle soil acetone acetone florisil benzene GC: ECD 0.1 58-100 (0.1) Möllhoff /CHCl3 5% SE-30, 190 °C, 6.3 min 76-98 (0.5) (1967) 5% QF-1, 190 °C, 5.6 min 98-122 (1.0) 5% DC-200, 190 °C, 3.4 min 5% E-301, 190 °C, 2.9 min Table 2 (contd). Sample Sample preparation Determination GLC MDCc Recovery (%), Reference Extraction Partition Clean-up Elution or HPLC conditions; (mg/kg) (fortification solvent column detectora, column, level, mg/kg) temperature, RTb Ambient air vapour trapped on 10% OV-101 on chromosorb GC: FPD, 3% OV-1, 5 x Krzymien aerosol W packed in a glass tube and 205 °C 10-12 (1979) thermally released and carried to GC column aerosol consecutive plates of cascade 5 x 100 (30) Krzymien impactor, plates washed 10-12 (1979) with n-hexane, n-hexane solution injected into GC a Detectors for GC (FPD = flame photometric detector; FTD = flame thermionic detector; ECD = electron capture detector; NPD = NP specific detector; AFI = alkali flame ionization detector), MS = mass spectrometry. b RT = Retention time. c MDC = minimum detectable concentration. d ES = extraction solvent. Table 3. Analytical methods for fenitrothion in technical products and formulationsa Sample Sample preparation Determination Diazo method TG and EC dissolution (ether) reduction (Zn-acetic acid) partition (ether/1% Na2CO3) titration (NaNO2) end-point (potentiometer or iodide-starch paper) Colorimetric method TG and EC dissolution (methanol) addition (1% Na2CO3) determination (free NMC); WP and dust extraction (methanol) 400 nm hydrolysis (5N KOH) determination (total NMC); Granule pulverization extraction (methanol) 400 nm TLC-UV method TG and EC dissolution (CHCl3) determination; 271 nm TLC (benzene/diethyl ether=19/1) WP extraction (methanol) TLC (benzene/diethyl ether=19/1) Dust extraction (CHCl3) TLC (benzene/diethyl ether=19/1) Granule pulverization extraction (CHCl3) TLC (benzene/diethyl ether=19/1) TLC-phosphorus method TG and EC dissolution (CHCl3) TLC digestion (H2SO4 and HNO3) colouring (ammonium metavanadate WP extraction (methanol) TLC and ammonium molybdate) determination; Dust extraction (CHCl3) TLC 420 nm Table 3. (cont'd). Sample Sample preparation Determination Granule pulverization extraction (CHCl3) TLC GC method TG and EC dissolution (IS solution) GC: FID 2% DC-QF-1, 170 °C WP and dust extraction (IS solution) centrifuge Granule pulverization extraction (IS solution) centrifuge a From: Takimoto et al. (1975). TG = technical grade; EC = emulsifiable concentrate; WP = water-dispersible powder; NMC = 3-methyl-4-nitrophenol; IS = internal standard (dibutyl sebacate); GC = gas-liquid chromatography. 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence Fenitrothion is not a natural product. 3.2 Man-made sources 3.2.1 Production The global production volume is not available. However, the global manufacturing capacity has been estimated to be between 15 000 and 20 000 tonnes. Production figures in Japan (a major manufacturing country) are 5346 tonnes in 1982 increasing up to about 10 000 tonnes in 1988 (Japan Plant Protection Association, 1984, 1986, 1988, 1989). Production in India was reported to be 400 tonnes in 1978, 350 tonnes in 1979, and 100 tonnes in 1980 (Battelle, 1982). Production in Czechoslovakia in 1989 was 964 tonnes (Benes, personal communication). Fenitrothion is formulated as an emulsifiable concentrate (50%), an ultra-low-volume concentrate, flowable (20%), a wettable powder (40%), granules (3%), dust (3%), an oil-based liquid spray alone or in combination with other pesticides, e.g., trichlorfon, malathion; BPMC; fenvalerate (insecticide), tetramethrin (house-hold insecticide); IBP, phthalide, thiophanate-methyl (fungicide). 3.2.2 Uses Fenitrothion is mainly used in agriculture for controlling chewing and sucking insects on rice, cereals, fruits, vegetables, stored grains, cotton, and in forest areas. It is also used for the control of flies, mosquitos, and cockroaches in public health programmes and/or indoor use. 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION 4.1 Transport and distribution between media Several studies were performed to elucidate the mechanism of the apparent rapid disappearance of fenitrothion from the water phase after the field spraying of fenitrothion formulation. The processes most likely to explain the phenomena include sorption by the sediments, photolysis, microbial degradation, hydrolysis, and volatilization. Marshall & Roberts (1977) discounted volatilization as a major pathway for the disappearance on the basis of the calculated half-life of 93 days obtained in a 1-m water column, designed as a simple model for small, well-mixed lentic systems with compartments representing the major pools, i.e., the water, the hydrosol, and the suspended solids, which include both biotic and abiotic material. Maguire & Hale (1980) studied the kinetics of fenitrothion distribution and transformation in water and sediment, both experimentally and after field spraying (see section 5.1.2 for results after field spraying). Laboratory experiments demonstrated that volatilization of fenitrothion from true solutions (5 mg/litre) in distilled water followed first-order kinetics and that the half-life of disappearance at 20 °C was estimated to be 64 ± 5 days. The fact that the half-life was considerably longer (> 180 days) in the presence of 5 mg fulvic acid/litre indicated that the rate would be considerably reduced in natural waters too. In contrast with this, the volatilization of fenitrothion that had been sprayed on the surface of water appeared to be a very fast process in the laboratory (half-life = 18 min for volatilization from the surface of water). Surface volatilization was suggested to play a significant role in the dissipation of fenitrothion from a small pond after spraying the formulation. Metcalf et al. (1980) also reported the significance of volatilization in the disappearance of fenitrothion in a lake by taking account of the effects of winds and water currents on natural water bodies in experiments using various rates of aeration. Observed half-lives of fenitrothion in Palfrey Lake and Brook in Southwestern New Brunswick (water temperature: 11 °C, average pH value in the lake: 6.7) were 6.3 days (bottom) - 7.2 days (surface) and 0.9 days, respectively. In a laboratory leaching study, 14C fenitrothion and its degradation products hardly moved with water in 3 loam soils, whereas, in Muko sand containing 0.2% clay and less than 0.1% organic matter, about 15% of the applied 14C was eluted from the soil column. Preincubation of the fenitrothion in sandy soil for 60 days before leaching decreased the degree of mobility. In the effluent from sandy soil, a trace amount of fenitrothion (0-0.1%) together with water-soluble products, such as 3-methyl-4-nitro-phenol 1 (0.6%) and amino-fenitrothion  (11.3%), were detected (Takimoto et al., 1976, see Fig. 3). Baarschers et al. (1983) examined the adsorption of fenitrothion and 3-methyl-4-nitrophenol  in water-soil suspension systems, using 4 different soils and 1 sediment as adsorbents. The Freundlich k values were 15.5-354.8 for fenitrothion and 2.1-147.8 for 3-methyl-4-nitrophenol . Both of the k values increased when the organic matter content increased from 0.9 to 33.1%. The adsorption characteristics of fenitrothion may be correlated with the lower degree of mobility in the leaching study. 4.2 Abiotic and biotic transformation 4.2.1 Abiotic transformation 184.108.40.206 Thermal degradation Tsuji et al. (1980) examined the mechanisms of thermal degradation of fenitrothion in air and found that 3 major exothermic steps were involved (Fig. 1). The first step was formation of fenitrooxon , and S-methyl fenitrothion  with evolution of sulfur dioxide at 150-160 °C. The second step was formation of fenitrooxon , S-methyl O,O-bis(3-methyl-4-nitrophenyl) phosphorothioate  and polymetaphosphate  with evolution of dimethyl sulfide from S-methyl fenitrothion  at 210-235 °C. The third step was carbonization of the phenolic ring of  and gas evolution from  at 270-285 °C. In a nitrogen atmosphere, the first step did not take place and only the other two steps were involved. S-methyl fenitrothion was produced by heating fenitrothion up to 193 °C. The thermal degradation of fenitrothion in a closed system was more rapid than that in an open system. Maeda et al. (1982) proposed that dimethyl sulfide, which was evolved during thermal degradation of S-methyl fenitrothion , catalysed isomerization of fenitrothion to . In fact, addition of 0.4-1.6% of dimethyl sulfide in a closed system enhanced the degradation of fenitrothion. Although metal salts, such as zinc, aluminum, ferric chloride, and stannic chloride, also accelerated isomerization of fenitrothion, calcium dodecylbenzene sulfonate (surfactant) showed no effect. 1 Chemical structures in Fig. 1-7 are referred to giving the numbers in brackets. 220.127.116.11 Photolysis in air Addison (1981) examined the photolysis of fenitrothion by UV radiation (200-400 nm) from a xenon lamp in the vapour phase (10-15 mg/50-1 reaction chamber) at about 85-90 °C, and computed the half-life of disappearance to be 61 ± 11 min and 24 ± 3 min in the absence or presence of ozone (0.7-0.9 ± 1 mg/m3), respectively. Brewer et al. (1974) also studied the vapour phase photolysis of fenitrothion at 313 nm UV radiation, and detected 3-methyl-4-nitrophenol  and an unidentified product as primary photo-products (Fig. 2). 18.104.22.168 Hydrolysis and photolysis in water Fenitrothion underwent hydrolysis in the absence of light through a pH-independent process below pH 7 and a base-catalysed process above pH 10, while both processes occurred between pH 7 and pH 10. The half-lives of fenitrothion within the pH range of 5-9 (normally found in natural water) were about 200-630 days at 15 °C, 17-61 days at 30 °C, and 4-8 days at 45 °C. The predominant hydrolysis products were 3-methyl-4-nitrophe-nol  above pH 10 and demethylated fenitrothion  below pH 8 (Fig. 2; Mikami et al., 1985a). [Phenyl-14C]-fenitrothion was dissolved at 1.0 mg/litre in aqueous buffer solutions at pH values of 5, 7, and 9 and kept at 25 ± 1 °C in the dark for 30 days, free from microbial contamination. Fenitrothion was less stable at pH 9 with a half-life of 100-101 days, compared with those of 180-186 days and 191-200 days at pH 7 and pH 5, respectively. Cleavage of the P-O-methyl linkage to form demethylated fenitrothion  was predominant at pH 5 and pH 7, while at pH 9 cleavage of the P-O-aryl linkage to form 3-methyl-4-nitrophenol  was the major hydrolytic path-way (Ito et al., 1988). Greenhalgh et al. (1980) and Aly & Badawy (1982) demonstrated that hydrolysis of fenitrothion follows pseudo-first-order kinetics, yielding mainly the phenol  at alkaline pH and the demethylated form  under acidic conditions. The rate of hydrolysis of fenitrothion may be accelerated through the addition of peroxide ion (1.7 x 10-4 mol/litre), particularly under alkaline conditions, since energies of activation were reduced to 7.8 kcal/mol for peroxide hydrolysis from 16.3 kcal/mol for alkaline hydrolysis (Desmarchelier, 1987). The photostability of fenitrothion in water is dependent on both pH and energy of UVR or sunlight (Miyamoto, 1977a). Fenitrothion rapidly decomposed in distilled water under sunlight and in pH 7 and pH 9 solutions at ambient temperatures, but was considerably more stable at pH 3. The half-life of fenitrothion was 10, 50, 20, and 6 h, respectively, in distilled water and in solutions at pH 3, pH 7, and pH 9. Fenitrothion decomposed nearly 8 times faster at pH 9 than at pH 3. Mikami et al. (1985a) determined the quantum yield of the photodecomposition reaction of fenitrothion in distilled water (8.0 x 10-4) and calculated that the half-life of photolysis by sunlight at the 40° north latitude was 7.6, 6.8, 11.3, and 17.0 h in spring, summer, autumn and winter, respectively. The actual half-life in autumn in Takarazuka, Japan, at a latitude of 35° north, was 12 h, agreeing with the above calculation. Photode-composition of fenitrothion in sterile lake water and sea water was also rapid and the half-life in both these solutions was less than 1.1 days. Fenitrothion degraded fairly rapidly under sunlight to form CO2; 14C ring-labelled fenitrothion released 39.4, 40.4, and 45.0% CO2 in 32 days in distilled water, in a buffer solution (pH 7), and in sterilized sea water (pH 7.8), respectively (Mikami et al., 1985a). [Phenyl-14C]-fenitrothion was dissolved at 1.0 mg/litre in aqueous acetate buffer (pH 5.0), free from microbial contamination and irradiated with artificial sunlight (wave length > 290 nm, xenon arc lamp), for 30 days (10 h/day irradiation) at 25 ± 1 °C. Fenitrothion was degraded rather rapidly with a half-life of 3.33-3.65 days (70.8-140.9 days under dark conditions). Photo-degradation reactions were oxidation of the aryl methyl group to a carboxyl group to form compound  (a main product, 8.0-12.4% in 14 days), oxidation of the P=S group to P=O group, cleavage of the P-O-CH3 or P-O-aryl linkage, and further decomposition to 14CO2 (41.2-42.0%) during 30 days (Katagi et al., 1988). Kanazawa (1977) demonstrated that fenitrothion (20 µg/litre) degraded to 8% of the original concentration under greenhouse conditions and only to 55% in the absence of light, in sea water, over 2 weeks. Fenitrothion (about 0.1 mg/litre) degraded in sea waters collected from various coasts of Japan to 44-62% and 63-94%, with and without sediments, respectively, after 2 weeks in the absence of sunlight and aeration (Environment Agency of Japan, 1978). The effects of several factors on the persistence of fenitrothion in sea water were examined using the experimental design with an L16 orthogonal layout (Kodama & Kuwatsuka, 1980). The persistence of fenitrothion was affected mainly by water quality (river water or sea water) and sunlight (exposed or unexposed), but also partially by temperature; it was not affected by the presence of suspended solid or vaporization. After 72 h, the persistence of fenitrothion in sea water was 56-97% of the original concentration under varying conditions, while that in river water was 1-28%. When river water was boiled, the rate of disappearance of fenitrothion was the same as that in sea water, indicating that microbial degradation was one of the most important contributing factors. The photodegradation of fenitrothion (1 mg/litre) in sea water collected along 3 different coastlines of Japan was very rapid with a half-life of about 3 h, twice as fast as that in distilled water (Takimoto et al., 1980). A microcosm study using distilled, estuarine, and lake water revealed that the ionic complement and/or microflora content of estuarine water contributed more to the degradation of fenitrothion than the pH. Sunlight irradiation in the static lake/bay models decomposed 80% of fenitrothion to polar products within 6 h (Weinberger et al., 1982a). Twenty-one out of at least 50 radioactive photoproducts of 14C ring-labelled fenitrothion in water at various pHs were identified. The major photoproducts were O,O-dimethyl O-(3-carboxy-4-nitrophenyl) phosphorothioate  in distilled water and in buffer solutions at pH 3 and 7. A dimeric compound  composed of  and the corresponding amino analogue  was more predominantly formed in buffer solutions at pH 7 and 9, in natural river (pH 7.4) and sea (pH 7.8) water. On prolonged irradiation with sunlight, these photoproducts decreased to less than 4% of the initial concentration with concomitant increases in carbon dioxide (21.5-45%) and the unextractable residues (29.3-51.4%) consisting of polymeric humic acids. Demethylated products [6,7] and hydrolysis products at the P-O-aryl linkage, such as 3-methyl-4-nitrophenol , were of minor importance, independent of pH values. S-Methyl fenitrothion  was occasionally detected in trace amounts (Mikami et al., 1985a). The UV irradiation of fenitrothion in oxygenated hexane solution produced fenitrooxon  and O,O-dimethyl O-(3-formyl-4-nitrophenyl)phosphorothioate  (Greenhalgh & Marshall, 1976). However, these photochemical reactions might not play a major role in the environmental photochemistry of fenitrothion in water. 22.214.171.124 Photolysis on soil When fenitrothion was applied to thin-layer plates with a 2 mm thickness of 7 different types of soil and exposed to sunlight, it took 50-150 days for the 90% disappearance of fenitrothion from the soils (Miyamoto, 1977a). No clear correlation existed between the rate of disappearance of fenitrothion and the physical and chemical parameters of the soils. S-Methyl fenitrothion and aminofenitrothion similarly applied to the soil decreased much more rapidly than fenitrothion. The order of stability was fenitrothion > S-methyl fenitrothion > aminofenitrothion. Under dark conditions, decomposition of these 3 compounds proceeded more slowly, the range of stability among them being the same as that observed under irradiated conditions. At most, 10% of the applied chemical was lost, probably by evaporation, from the soil after 14 days. Fenitrothion was degraded on the soil surface mainly by oxidation of the P = S to the P = O group and cleavage of the P-O- aryl linkage. The rapid photodecomposition of fenitrothion on soil surfaces was also demonstrated by Mikami et al. (1985a). Unlike photolysis in water, the principal products were fenitrooxon  and 3-methyl-4-nitrophenol , amounting to 3.6-9.4% and 20.4-23.1% of the applied 14C, respectively, after 12 days. A photolysis study was conducted with [phenyl- 14C]-fenitrothion applied on the surface of soil at a rate of 23.4 µg/cm2. The samples were continuously irradiated (290 nm) using an artificial light source (xenon arc lamp) over 30 days, the soil temperature being maintained at 25 ± 1 °C throughout the experiment. The rate constant and the half-life of photolysis were determined to be 0.00814/day and 85 days, respectively, while under dark conditions these were 0.0038/day and 182 days. Degradation products identified included fenitrooxon  (2.0% at day 30), demethyl fenitrothion  (2.1%) and 3-methyl-4-nitrophenol  (3.0%) (Dykes & Carpenter, 1988). Sunlight irradiation of fenitrooxon , 3-methyl-4-nitrophenol , or carboxy-fenitrothion  on silica gel TLC plates resulted in degradation and polymerization to humic acids, with half-lives of 3.9, 4.3, and 1.8 days, respectively (Ohkawa et al., 1974). 4.2.2 Biotransformation 126.96.36.199 Biodegradation in soil The degradation pathways of fenitrothion in soils are shown in Fig. 3. When fenitrothion was incorporated at 10 mg/kg (on a dry-weight basis) in soils with various physical and chemical properties, and kept at 25 °C in the dark, under upland or submerged conditions, the adsorption and decomposition of fenitrothion were quite variable, depending on the properties of the soils and on the incubation conditions (Takimoto et al., 1976; Miyamoto, 1977a). The half-life of fenitrothion was 12-28 days under upland conditions, and 4-20 days under submerged conditions. However, no direct relationship was observed between the decomposition of fenitrothion in soil and any of the physical or chemical properties measured, namely clay content, organic matter content, ion exchange capacity, and pH. Under upland conditions, 3-methyl-4-nitrophenol  was formed at an early stage of incubation, amounting to 10-20% of the applied radioactivity ( m-methyl position). Levels of 3-methyl-4-nitrophenol decreased with longer incubation. Another major decomposition product was radioactive carbon dioxide, which amounted to approximately 40% of the initial fenitrothion after 60 days. No aminofenitrothion  was detected. On the other hand, under submerged conditions, 3-methyl-4-nitrophenol  and carbon dioxide were minor products. The major decomposition product was aminofenitrothion , its formation being parallel to the decrease in fenitrothion. The maximum amounts of aminofenitrothion were 18-66% of the initial fenitrothion. Aminofenitrothion tended to disappear slowly on longer incubation. In soils, 14C-ring-labelled fenitrothion (10 mg/kg) degraded at 25 °C in the dark with a half-life of 2-5 days under upland and submerged conditions; after 8-26 weeks, levels declined to less than 0.1 mg/kg. After one year, the carbon dioxide evolved amounted to 60-70% of the initial radiocarbon under upland conditions and to 23-40% under submerged conditions, while the remaining radiocarbon was mostly incorporated into the organic matter fractions of the soil. When the soils containing the bound residues of the radiocarbon were mixed with fresh soil, the release of radioactive carbon dioxide was accelerated. Under upland conditions, degradation of 3-methyl-4-nitrophenol  was more rapid than that of fenitrothion (Mikami et al., 1985b). Adhya et al. (1981a) also found that fenitrothion was degraded primarily by reduction of the nitro group to aminofenitrothion in flooded soil with lower redox potentials. Sterilization of the prereduced flooded soil samples by autoclaving prevented the rapid decomposition of fenitrothion in soil. Aminofenitrothion was further degraded to demethyl amino-fenitrothion  in typical flooded acid sulfate soils from Kerala, India. Dealkylation also occurred in low sulfate soils under submerged conditions, when supplemented with extraneous sulfate (e.g., ammonium sulfate or ferrous sulfate). Hydrogen sulfide, evolved as an end product of the anaerobic metabolism of sulfate, catalysed the dealkylation of aminofenitrothion (Adhya et al., 1981b). Fenitrothion was stable when incubated in soil suspensions containing streptomycin, cycloheximide, and mineral salts. However, it decomposed rapidly when the soil suspension was added to a culture medium suitable for fungal or bacterial growth (Takimoto et al., 1976). The major decomposition product in the culture was aminofenitrothion , the content of which reached 40-65%, and a maximum 60-80% when formylamino- and acetylamino- fenitrothion  were combined. Demethyl fenitrothion  and 3-methyl-4-nitrophenol  were detected among other products. The dominant species of microorganisms (Fusarium and Bacillus species), isolated from the above soils, metabolized fenitrothion well. When ring-labelled fenitrothion (7.4 mg/kg) was incubated with two kinds of forest soils collected from the State of Maine, USA, the half-life of fenitrothion at 30 °C was about 3 days. In 50 days, 94-97% of the fenitrothion had been decomposed yielding 35% radioactive carbon dioxide, 5-7% 3-methyl-4-nitrophenol , 4% 3-methyl-4-nitroanisole , and approximately 50% of soil- bound radioactivity (Spillner et al., 1979a). It has been reported (National Research Council of Canada, 1975) that several species of soil and water bacteria, including Bacillus subtilis, Escherichia coli, E. freundii, Pseudomonas reptilovora, and P. aeruginosa, can metabolize or inactivate fenitrothion. The fungus Trichoderma viride can also hydrolyse fenitrothion and fenitrooxon, and the hydrolysed product, 3-methyl-4-nitro-phenol, is co-metabolized by this fungus (Baarschers & Heitland, 1986). Flavobacterium sp. ATCC 27551, isolated from paddy field, hydrolysed fenitrothion to yield 3-methyl-4-nitrophenol  in culture solutions containing mineral salts (Adhya et al., 1981c). A crude cell extract from a mixed bacterial culture growing on parathion also hydrolysed fenitrothion to yield 3-methyl-4-nitro-phenol . The chemical hydrolysis of fenitrothion was 3-5 times slower than that of parathion. However, the rate of enzymatic hydrolysis was 24-205 times faster than that of chemical hydroly-sis by 0.1 N sodium hydroxide at 40 °C (Munnecke, 1976). Liu et al. (1981) studied the biodegradability of fenitrothion using a mixed-culture of microorganisms from activated sludge, soil, and sediments, under aerobic and anaerobic conditions. Fenitrothion was more readily degraded under anaerobic co-metabolic conditions (half-time = 1.0 day) than under aerobic conditions (half-time = 5.5 days). When fenitrothion was applied to the medium as the sole source of carbon, its stability was greater under aerobic conditions, 77% of the initial dose being recovered after 164 h incubation. 188.8.131.52 Biodegradation and bioaccumulation in organisms a) Aquatic organisms The accumulation and partitioning of fenitrothion residues among different tissues and organs in wild trout were investigated following 2 applications of the compound to a lake (280 g a.i./ha with a 9-day interval). Fenitrothion residues accumulated fairly rapidly in the tissues of both brook trout and lake trout. Peak levels of fenitrothion were reached 2-4 days after the first application (in lake trout, fat: 280 µg/kg, muscle: 96.8 µg/kg, intestine: 96.3 µg/kg, liver: 16.1 µg/kg, ovary: 48.2 µg/kg) and 8 days after the second application (in lake trout, fat: 665 µg/kg, muscle: 133 µg/kg, intestine: 114 µg/kg, liver: 39.6 µg/kg). These levels were many times higher than those in the surrounding waters of Lac Ste-Anne. Fenitrothion residues continued to persist in lake trout tissues (but not in the tissues of brook trout) up to at least 8 days after the second application, even though the residues in the water had declined to non-detectable levels 4 days earlier (Holmes et al., 1984). When exposed to running water containing 0.1 or 0.02 mg fenitrothion/litre, both underyearling rainbow trout ( Salmo gairdneri) and southern top-mouthed minnow ( Pseudorasbora parva) rapidly absorbed the chemical (Takimoto & Miyamoto, 1976a). The fenitrothion concentration in the fish reached a maximum after 1-3 days of exposure, and then remained virtually constant. The bioaccumulation ratio did not increase on longer exposure and was more or less independent of the fenitrothion concentration in water. The ratio was similar in the 2 fish species, being approximately 250, 230, and 200 (at its maximum) in underyearling trout, yearling trout, and minnow, respectively. Once the fish were transferred from fenitrothion-containing water to fresh water, the levels of fenitrothion in the fish decreased rapidly to about 0.01 mg/kg in 5 days. None of the fish species exhibited noticeable signs of intoxication during the exposure period. In another study, the bioaccumulation ratio for the fresh-water species, top-mouthed minnow, was 246 (Kanazawa, 1981). Killifish (Oryzias latipes) took up fenitrothion in a flow system with bioaccumulation ratios at different developmental stages of: 115 in embryos, 173 in yolk sac fry, 88 in postlarval stages, 441 in juveniles, 520 in adult males, 540 in adult females, and 224 in eggs produced from fenitrothion-exposed adults (Takimoto et al., 1984a). However, the half-lives of disappearance of the compound in clean water were less than 2 days, independent of fat content. Similar results were reported with southern top-mouthed minnows in a static aquarium test; the fenitrothion concentration in water at 23 °C decreased from 0.81 mg/litre to 0.002 mg/litre in 28 days, while the observed maximum concentration of fenitrothion in the fish (162 mg/kg on the 4th day) decreased to 4.9 mg/kg after 28 days (Kanazawa, 1975). With respect to the distribution and metabolism of fenitrothion, autoradiograms of rainbow trout exposed to labelled fenitrothion under static water conditions for 6 h revealed that the concentration of radiocarbon was highest in the gall bladder and intestines; after 24 h, the radiocarbon was present in every tissue, except the brain and heart. Twenty-four hours after the transfer of the fish to fresh water, most of the radioactivity in the tissues had disappeared. Only the gall bladder, intestines, and pyloric caeca still contained an appreciable amount of the radiocarbon. Intact fenitrothion accounted for 90% of the absorbed radioactivity in fish. The remaining 10% comprised fenitrooxon , demethyl fenitrothion , 3-methyl-4-nitrophenol , and its glucuronide . In water, the percentage of these degradation products increased with time and amounted to 25% of the radioactivity. Because fenitrothion is stable in water under the experimental conditions, the degradation products are presumably derived from fish metabolism (Takimoto & Miyamoto, 1976a) (see Fig. 4). All developmental stages of killifish metabolized fenitrothion mainly to 3-methyl-4-nitrophenyl-ß-glucuronide  (comprising 20-40% of 14C), except the embryo, which had the lowest metabolic activity. Yolk sac fry contained the highest concentration (28%) of demethyl fenitrothion . Fenitrooxon  and demethyl fenitrooxon  were present in small amounts, at the most, 0.5%. These metabolites and the intact fenitrothion were eliminated into the surrounding water, when the fish were transferred to fresh water (Takimoto et al., 1984a). Absorption of [methyl-14C]-fenitrothion at 0.1 mg/litre in running water to a similar plateau level in the killifish (Oryzias latipes) was more rapid at 25 °C than at 15 °C; the bioaccumulation ratios of fenitrothion were 235 and 339, respectively. Water of higher salinity (2.3%) resulted in slightly higher accumulation ratios of fenitrothion in both killifish (303) and mullet, Mugil cephalus (179), than fresh water (235 and 30, respectively), but the half-lives were independent of temperature and salinity, with values of 0.24-0.36 day. Fenitrothion was metabolized, primarily through hydrolysis, to  by the killifish, demethylation to demethyl fenitrothion  by the mullet, and conjugation of the liberated phenol with glucuronic acid  by both species. Although the metabolism of the compound in both fish was not affected by the different salinities and temperatures, the glucuronide conjugate was more directly excreted into water under conditions of lower temperature and higher salinity. 14C-labelled compounds were distributed primarily to the gall bladder, as shown by whole-body radioautography (Takimoto et al., 1987a). Bluegill sunfish (Lepomis macrochirus) was exposed to [phenyl-14C] - fenitrothion or non-radiolabelled fenitrothion in a flow-through system at concentrations of 0.049 mg/litre and 0.043 mg/litre, respectively, for a 28-day exposure period. The concentrations of labelled and non-labelled fenitrothion in whole fish reached an equilibrium on days 1-3 of exposure at levels of 5.4 and 1.3 mg/litre, respectively. Mean bioconcentration factors for labelled and non-labelled fenitrothion during the uptake period were respectively 111 and 29 for whole fish, 26 and 10 for the edible portion, and 279 and 36 for the non-edible portion. When the exposed fish were transferred to running fresh water, the concentrations of labelled and non-labelled fenitrothion in the fish decreased rapidly, with biological half-lives of less than 1 day in both the edible and non-edible portions of the fish. A non-linear 2-compartment, kinetic modelling computer programme estimated 81.9 and 111 as the uptake rate constants (K1), 0.69 and 3.72 as the depuration rate constants (K2), and 118 and 30 as the bioconcentration factors (BCF) for labelled and non-labelled fenitrothion, respectively. Fenitrothion was metabolized through the oxidation of P=S to P=O, demethylation of the P-O-alkyl linkage, cleavage of the P-O-aryl linkage, and conjugation of the phenol with glucuronic acid. The major metabolites were demethylfenitrothion  and 3-methyl-4-nitrophenyl-ß-glucuronide , amounting to 29-40% and 11-15% of the recovered 14C from the whole fish, respectively (Ohshima et al., 1988). Freshwater teleosts ( Tilapia mossambica; body weight, 5-9 g; length, 5-7 cm) were exposed to 200 mg fenitrothion/kg body weight for 24 h. Fenitrothion and its metabolites, extracted from the liver, kidney, and brain, were separated and identified using HPLC and preparative silica gel TLC. The metabolites extracted from the liver were identiied as fenitrooxon, N-acetylaminofenitrothion , and fenitrothion. The metabolites from the kidney were identified as demethyl- N-acetylaminofenitrooxon . The metabolites from the brain were identified as 3-methyl-4-nitrophenol  and demethyl- N-acetylamino-fenitrooxon  (Anjum & Qadri, 1986). McLeese et al. (1979) reported that accumulation ratios of fenitrothion were independent of the exposure levels, and were 19-35, 78-130, and 9, in marine clam (Mya arenaria), mussel (Mytilus edulis), and freshwater clam (Anodonta cataractae), respectively. When freshwater snails ( Cipangopaludina japonica and Physa acuta) were exposed to 0.1 mg [methyl-14C]-fenitrothion/litre in a dynamic flow system, the concentrations of fenitrothion and 14C-label in the body reached equilibrium on day one of exposure. The maximum bioaccumulation ratios of fenitrothion were 18 and 53 in C. japonica and P. acuta, respectively. These snails metabolized the compound primarily by demethylation to , hydrolysis to , and reduction to , and . The liberated phenol moiety was conjugated with sulfate  in C. japonica and mainly with glucose  in P. acuta. When the snails were transferred to a freshwater stream, fenitrothion and its metabolites were rapidly eliminated, and the half-life of the parent compound was less than 0.5 days in both snails. In P. acute, fenitrothion and its decomposition products were mainly distributed in the liver as shown by whole-body radioautography (Takimoto et al., 1987b). When the waterflea Daphnia pulex and the shrimp Palaemon paucidens were exposed to 1.0 µg [methyl-14C]-fenitrothion/litre in a flow-through system, the concentrations of fenitrothion and 14C-label in the body reached equilibrium (on day one of exposure) and the maximum bioaccumulation ratios of fenitrothion were 71 and 6 in the daphnia and shrimp, respectively. These crustaceans primarily metabolized the compound through oxidation of P = S to P = O to form compound , hydrolysis of P-O-aryl linkage to form compound , and demethylation to give compounds  and . The liberated phenol was conjugated with sulfate to form compound  in D. pulex and with glucose to form compound  in the shrimp. When the organisms were transferred to a freshwater stream, fenitrothion and its metabolites were rapidly eliminated from their bodies, and the half-life of the parent compound was less than 0.2 day in both species (Takimoto et al., 1987c) (see Fig. 4). The uptake rate of radiolabelled fenitrothion by the blue crab (Callinectes sapides) increased with temperature and salinity. The highest concentrations of radioactivity were found in the hepato-pancreas and stomach. The blue crab can metabolize fenitrothion to produce fenitrooxon, aminofenitrothion, 3-methyl-4-nitrophe-nol, 3-methyl-4-aminophenol, demethyl fenitrothion, demethyl fenitrooxon, and glycoside and sulfate conjugates of the phenols (Johnston & Corbett, 1986). Aquatic plants were collected and analysed after the aerial application of fenitrothion (280 g/ha) in Manitoba, Canada, (Moody et al., 1978); the fenitrothion residues present in surface- dwelling duckweed, obtained from stagnant water, disappeared rapidly from 1.44 mg/kg after 1 h to 0.03 mg/kg after 192 h, while the submerged hornwort, also from stagnant water, contained rather persistent, but low, residues of fenitrothion ranging from 0.12 to 0.15 mg/kg after 192 h. No fenitrothion was detected in the submerged flowering rush in running water. Chlorella pyrenoidosa exposed to 10 mg radioactive fenitrothion per litre rapidly took up the compound and the 14C level reached equilibrium after 4 h with a bioaccumulation ratio of 417. On transfer to fresh water, the fenitrothion in the chlorella was rapidly desorbed (Weinberger et al., 1982b). Other algae ( Chlamydomonas reinhardii and Euglena gracilis) showed less bioaccumulation of fenitrothion. The aquatic macrophyte, Elodea densa, showed a bioaccumulation ratio of 24-76 (Weinberger et al., 1982b). Three types of algae, Chlorella vulgaris, Nitzschia closterium, and Anabaena flos-aquae, also rapidly absorbed fenitrothion with maximum bioaccumulation ratios of 44, 105, and 53, respectively (Kikuchi et al., 1984). Only A. flos-aquae (blue-green algae) actively degraded fenitrothion. When transferred to a fenitrothion-free medium, these algae released fenitrothion, as well as its metabolites, with half-lives of the compounds of less than 1 day, except in the case of A. flos-aquae when the half-life was 2.6 days (see Fig. 4). Bioaccumulation ratios for fenitrothion in 2 species of blue-green algae (Anabaena sp. and Aulosira fertilissima) were reported to be 42-347 and 136-784, respectively, when exposed to 1, 5, or 10 mg/litre (Lal et al., 1987). In a field test in which fenitrothion was sprayed twice at 210 g/ha, to give a maximum concentration of 0.9 µg/litre in surface water and 0.42 µg/litre in subsurface water (3 m depth), phyto-planktons and zooplanktons contained maximum levels of 0.05 and 0.014 µg fenitrothion/litre, respectively, the concentrations decreasing with time (Lakshminarayama & Bouque, 1980). b) Birds When male Hubbert chickens were intubated with fenitrothion at a dose of 10 mg/kg, twice every other week, for 2-8 weeks, the residue levels in the brain, blood, liver, and adipose tissue were less than 0.071 mg fenitrothion equivalent/kg wet tissue. None of the tissues retained any significant amounts of fenitrothion or its metabolites, and no tendency towards bioaccumulation was observed (Trottier & Jankowska, 1980). White Leghorn hens, dosed with 2 mg fenitrothion/kg body weight for 7 consecutive days, discharged 95% of the radioactivity in the excreta within 6 h following the last administration. The radioactivity in the hen egg-white decreased sharply after the last dosage, with the highest concentration (0.02 mg/kg) recorded on the third day of administration. The egg yolk showed a maximum radiocarbon level of 0.10 mg/kg (fenitrothion, 0.006 mg/kg), 1 day after the last dose, followed by a decline to 0.02 mg/kg after 1 week (Mihara et al., 1979). After oral administration of ring-labelled 14C fenitrothion at 5 mg/kg body weight to female Japanese quails, 99% of the radio-carbon was eliminated during the first 24 h (Miyamoto, 1977a). When [phenyl-14C]-fenitrothion was administered orally to Japanese quails in a single dose of 5 mg/kg body weight or to White Leghorn hens at a daily dose of 2 mg/kg body weight for 7 days, 97-99% of the radiocarbon was eliminated in the mixture of urine and faeces within one day. The radioactivity in the eggs was, at most, 0.2% of the parent compound (0.055 mg/kg). More than 18 metabolites were found in the excreta. The major metabolites were 3-methyl-4-nitrophenol  and its sulfate conjugate , which accounted for 70.5% of the dose in quails and 50.8% in hens. Demethylfenitrothion  and demethylfenitrooxon  were found as minor metabolites; several m-methyl oxidation products were also detected. In vitro studies revealed that the oxidation activity of hen, quail, pheasant, and duck liver enzymes at the m-methyl group of fenitrooxon was higher than that of mammalian liver enzymes, though the avian enzymes had extremely low O-demethylase activity (Mihara et al., 1979) (see Fig. 5). c) Terrestrial organisms Lactating Japanese Sannen goats were treated orally with [phenyl-14C]-fenitrothion at 0.5 mg/kg body weight per day for 7 days. One day after treatment, no residues of intact fenitrothion were found in the organs and tissues, but a small amount of aminofenitrothion  was detected in the digestive tracts (rumen, omasum, and large intestine). The administered radiocarbon was essentially quantitatively eliminated during the week following treatment; 50% of the dose was recovered in the urine, 44%, in faeces, and 0.1%, in the milk with a maximum concentration of 0.011 mg/litre. The major metabolites in the urine, faeces, and milk were aminofenitrothion  and O-methyl O-hydrogen O-(3-methyl-4-acetyl-aminophenyl) phosphate , and O,O-dimethyl O-(3-methyl-4-sulfo-aminophenyl) phosphorothioate (N-sulfo-aminofenitrothion) , respectively. No intact fenitrothion or fenitrooxon was found in the milk, urine, or faeces (Mihara et al., 1978) (see Fig. 6). When 30 calves (1-1.5 years old, average weight, 243 kg) were confined on a pasture sprayed with 378 g fenitrothion/ha (initial residue on grass, 11.8 mg/kg), the meat and fat contained about 0.01 mg fenitrothion residues/kg on the first day. No fenitrothion residues were found in the meat from the third day on, and only 0.004-0.007 mg fenitrothion/kg was found in the fat on the third day; these amounts decreased to almost control levels by the seventh day (Miyamoto & Sato, 1969). Silage prepared from corn treated with 1.1, 2.2, or 3.4 kg fenitrothion/ha was fed to lactating Jersey cattle for 8 weeks. Although traces (0.001-0.005 mg/kg) of aminofenitrothion  were found in the milk of cows fed 3.4 kg fenitrothion/ha silage, no residues (< 0.001 mg/kg) were found in the milk of cows that had consumed the silage treated at lower levels (Leuck et al., 1971). Jersey cows, administered 3 mg fenitrothion/kg body weight for 7 consecutive days, produced milk containing fenitrothion and aminofenitrothion  levels of up to 0.002 and 0.003 mg/kg, respectively. However, levels were undetectable within 2 days of the last dose (Miyamoto et al., 1967). Johnson & Bowman (1972) reported that neither fenitrothion nor its metabolites were detected in the milk of lactating Jersey cows, 7 days after being fed (for 28 days) a diet containing the pesticide at a concentration of 1.84 mg/kg. Topical application of a lethal dose of fenitrothion to spruce budworm ( Choristoneura fumiferana) resulted in the formation of 3-methyl-4-nitrophenol (2-17%) and desmethyl fenitrothion (2-4%). Trace levels (1-2% of the applied dose) of fenitrooxon were also detected (Sundaram, 1988). 184.108.40.206 Abiotic and biological degradation in/on plants The photolysis and metabolic pathways of fenitrothion in plants are illustrated in Fig. 7. One half the amount of fenitrothion applied at 12 mg/kg to rice plants at the preheading stage was lost by evaporation and only 10% was left on the plant surface after 24 h, 50% penetrating into tissues (Miyamoto & Sato, 1969). Although fenitrooxon  was detected at 0.01-0.86 mg/kg in leaf sheaths and blades (not in harvested grains), it disappeared faster than fenitrothion. The half-lives of fenitrothion were 1-3 days on, and in, fenitrothion-treated apples (approx. 4.5 mg/kg) growing on the tree under natural conditions, with fenitrooxon  (0.005 mg/kg) and S-methyl fenitrothion  (approx. 0.005 mg/kg), on the fruit and demethyl fenitrothion  (0.012 mg/kg), 3-methyl-4-nitro-phenol  (0.024 mg/kg), and its glucose conjugate  in the fruit after 21 days (Hosokawa & Miyamoto, 1974). It was concluded that the fruit metabolized the penetrating fenitrothion gradually to 3-methyl-4-nitrophenol , and further to the glucose conjugate (e.g., ) in the tissues; this was combined with the disappearance of fenitrothion on the fruit surface through photodecomposition and volatilization. A number of residue data are available on various feed plants (Sumitomo, 1969; Takimoto & Miyamoto, 1976b). Coastal Bermuda grass and corn treated with fenitrothion at 1, 2, and 3 kg/ha were analysed for residues of the parent compound and some metabolites (Leuck & Bowman, 1969); the residues of fenitrothion diminished rapidly to approximately one hundredth of the initial levels after 14 days. The fenitrooxon  contents were low, declining more rapidly, and none was detected after 21 days. While the amounts of 3-methyl-4-nitrophenol  were highest in the 1- and 7-day samples, the total residues on both crops diminished to less than 1 mg/kg in 28 days. Under operational spraying (280 g/ha) for the control of budworm, fenitrothion deposits (2-4 mg/kg, wet weight) on the foliage of red and white spruce and balsam fir decreased by about 50% within 4 days, and 70-85% within two weeks. In some cases, about 10% of the initial deposit (0.05-0.5 mg/kg) persisted for most of the year following spraying (Yule & Duffy, 1972). To monitor the persistence of fenitrothion in the Canadian forest, LaPierre (1985) measured residues in leaves. Immediately following application (15 min) of fenitrothion to poplar ( Populus tremuloidus) and gray birch trees ( Betula populifolia), fenitrothion levels of 22 and 18 mg/kg, respectively, were detected. Residue levels decreased to less than 1 mg/kg and 0.1 mg/kg, respectively, within 30 and 120 days. No fenitrooxon was detected in any of the samples. The observation, made by McNeil & McLeod (1977), indicating that sawfly populations were depressed by persistent fenitrothion residues in jack pine foliage apparently supported the persistence of fenitrothion within leaf tissues. However, it may be that, in this case, the fenitrothion was rather persistent because of the special circumstances (in micro sink). A complete disappearance of fenitrothion from spruce foliage was observed, within 45 days, following operational spraying with 280 g/ha. The hardwood species within mixed forests, such as red maple, appeared to collect 3-4 times higher deposits on their foliage when exposed to the same operational spraying (National Research Council of Canada, 1975), but the residues decreased rapidly. During environmental surveillance of aerial spraying of fenitrothion, carried out from 1979 to 1982 in Quebec, the insecticide concentrations were measured in foliage samples taken from 1 to 4 h after spraying, when residue levels were likely to have peaked. Over the 4 years studied, the median residue level of fenitrothion found in balsam fir foliage was 3.81 mg/kg (dry weight), with a maximum concentration of 111 mg/kg. On conifer foliage, feni-trothion had a half-life of 2-4 days; 70-95% of the residue dissipated in less than 2 weeks (Morin et al., 1986). Takimoto et al. (1978) examined the stability of fenitrothion (6 and 15 mg/kg) in stored rice grains. The insecticide decomposed after 12 months to 22.0-26.3% and 64.7-65% of the initial dose at 30 and 15 °C, respectively. The major metabolites in rice grains were demethyl fenitrothion  and 3-methyl-4-nitrophenol , which amounted to 10.0-19.2% and 16.0-38.0% of the dose, respectively. In addition, trace amounts of S-methyl fenitrothion , S-methyl demethyl fenitrothion , fenitrooxon , demethyl fenitrooxon , 3-hydroxymethyl-4-nitrophenol , 3-methyl-4-nitroanisole , 1,2-dihydroxy-4-methyl-5-nitro-benzene , and 1,2-dimethoxy-4-methyl-5-nitrobenzene  were detected (see Fig. 7). Fenitrothion and its degradation products were distributed in the outer portions of the endosperm and at 100 µm in depth from the surface of rice grains stored for 12 months, as determined by whole-body autoradiography. On cooking, the unpolished rice grains treated with fenitrothion yielded 3-methyl-4-nitrophenol  and demethyl fenitrothion  as primary degradation products. Abdel-Kader & Webster (1980) and Abdel-Kader et al. (1982) studied the stability of fenitrothion (8 mg/kg) in stored wheat. Very little (< 3%) breakdown of the insecticide residue occurred on wheat stored at -35 or -20 °C for 72 weeks. However, fenitrothion residues decreased as the temperature increased. After 72 weeks, 18, 35, 56, 90, 96% of the initial deposit had degraded in wheat stored at -5, 5, 10, 20, at 20 °C respectively. The major metabolites in wheat stored at 20 °C for 12 months were demethyl fenitrothion , 3-methyl-4-nitrophenol , and dimethyl phosphorothioic acid  (Fig. 7), as determined by GLC. Concentrations of demethyl fenitrothion  and dimethyl phosphorothioic acid , which were highest (2.01 and 0.55 mg/kg, respectively) after 6 months storage, decreased to 0.98 and 0.21 mg/kg, respectively, at the end of storage. The residue level of 3-methyl-4-nitrophenol  gradually increased to 0.96 mg/kg after 12 months. No fenitrooxon  or S-methyl fenitrothion  was detected throughout the experimental period (Abdel-Kader & Webster, 1982). When labelled fenitrothion was applied to bean leaves at a rate of 84.5 µg/12.5 cm2, 26 and 64% of the radioactivity was lost by volatilization after 1 and 3 days, respectively. The decrease of the parent compound was rapid, both on and in the leaf. After 12 days, the major products remaining on the bean leaves were fenitrooxon  (0.1%), carboxy-fenitrothion  (0.1%), and 3-carboxy-4-nitrophenol  (0.1%) (Ohkawa et al., 1974). The residues of fenitrothion in coastal Bermudagrass and corn diminished to less than 0.13 mg/kg in 28 days, with half-lives of less than 1 day, following a spray of the emulsifiable concentrate at 1, 2, or 3 kg a.i./ha. The major metabolite was 3-methyl-4-nitrophenol , with smaller amounts of fenitrooxon . After 28 days, the residues had declined to less than 1 mg/kg for all 3 rates of application (Leuck & Bowman, 1969). In leaves of shrubbery ( Maesa japonica) sprayed twice with fenitrothion at 735 g/ha, fenitrothion was detected at 78.3 mg/kg on the day of application, but 99% had disappeared within a week. Although fenitrooxon  was detected at levels of 0.1-0.3% of fenitrothion in the leaves, it disappeared after strong rainfall, 35-37 days after application. Fenitrothion was detected in grasses, and the upper and lower layers of the soil, at levels of 0.1, 0.01, and 0.001 mg/kg, respectively, 144 days after application (Ohmae et al., 1981). Hallett et al. (1973) observed the transport of fenitrothion to the embryo, and its metabolism in seed tissues, when pine seeds were germinated for up to 54 days in an aqueous solution or suspension of fenitrothion (10 or 1000 mg/litre). Laboratory studies of fenitrothion on seeds of eastern white pine demonstrated penetration and accumulation of the parent compound, its oxon, and the S-methyl metabolites in the embryo and perisperm. This appeared to alter the amino acid metabolism in the seed but did not affect the later growth of seedlings (Hallett et al., 1974). No significant differences in germination and growth were reported between the seeds of white pine from areas sprayed at 140-280 g/ha and from unsprayed (control) areas (Pomber et al., 1974). Similarly, the seeds of white pine, white spruce, and yellow birch readily absorbed fenitrothion when germinated for up to 21 days in an aqueous solution or suspension of fenitrothion (10 or 1000 mg/litre). Fenitrooxon , demethyl fenitrothion , and S-methyl fenitrothion  were detected as primary metabolites in all 3 species. The highest concentrations of , , and  were 1.4-75 mg/kg, 10-37 mg/kg, and 1-8 mg/kg, respectively. Hallett et al. (1977) proposed that the formation of S-methyl fenitrothion  resulted from the alkylation of demethyl fenitrothion by excess fenitrothion in the conifer seeds. It is probable that  will be formed in plants via the non-enzymatic alkylation reaction, if the concentrations of fenitrothion and  are extremely high. However, formation of  will be extremely low or negligible, when fenitrothion is used at the recommended dosage. Sundaram & Prasad (1975) established the uptake and transportation of fenitrothion in young spruce trees by growing the plants in a nutrient solution containing the insecticide. However, when fenitrothion was applied to the needles of spruce and fir trees, which are the part of the tree most exposed to the insecticide during spraying, the foliar penetration of fenitrothion was found to be extremely small. Furthermore, less than 0.1% of the fenitrothion that had penetrated was translocated laterally and upward to the untreated parts of the foliage. The amounts found in the stems and roots were also negligible (Sundaram et al., 1975). On the other hand, Moody et al. (1977) using an autoradiographic technique, suggested the systemic potential of fenitrothion applied to 4-year-old seedlings of balsam fir and, to a lesser extent, white spruce, and jackpine. Prasad & Moody (1976) also found that, mainly because of volatilization, 70% of the applied fenitrothion was lost one day after treatment, though low levels of the insecticide (0.48 mg/kg after 21 days) persisted in conifer tissues. When labelled fenitrothion was applied to the leaves of Japanese cypress at about 300 µg per leaf, approximately 70-80% of the applied dose disappeared, mainly through evaporation, within 24 h. The major metabolites in the treated leaves were demethyl fenitrothion , 3-methyl-4-nitrophenol  (approx. 2-10 µg), and its glucoside conjugate  (Tabata & Okubo, 1980). Immediately following the application of fenitrothion to poplar ( Populus tremuloidus) and birch trees ( Betula populifolia), levels of 22 and 18 mg/kg, respectively, were detected. Residue levels dropped to under 1 mg/kg within 30 days of treatment, and under 0.1 mg/kg by 120 days. The oxygen analogue, fenitrooxon, was not detected in any of the samples (La Pierre, 1985). 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels 5.1.1 Air In the 1980 spray programme in Canada, fenitrothion was detected occasionally in air, the maximum concentration being 12 ng/m3 (Mallet, 1980), when the compound was sprayed at 140-280 g/ha. Collaborative field studies were initiated in 1978 in Canada to obtain relevant information concerning long-range pesticide drift during the aerial spraying of fenitrothion in forest pest control, using a surrogate (tris(2-ethylhexyl)phosphate) (Crabbe et al., 1980a). At approximately 7.5 km downwind of the spray, the peak treetop concentration of the drifting cloud varied from 1.4 ng/litre in relatively neutral conditions to 5.0 ng/litre in the most stable conditions. The fraction of the tracer material still airborne, 7.5 km from the spray line, was 6 and 16% for the neutral and most stable environmental tests, respectively. In 1980, a study was conducted to measure the atmospheric fenitrothion exposure levels at breathing height near aerial forestry spray operations (Crabbe et al., 1980b). The results revealed an aerial concentration (or dosage) of 40 ng/min per litre1 at the spray line (flight path of aircraft) falling to an average of 8 ng/min per litre, 700 m from the spray line, in the first hour after delivery. During the first hour after spraying, 30% of the material collected in the samplers was vapour and the rest, aerosol. Droplets of approx. 4.0 µm diameter contributed most to the mass of drifting spray cloud at 500 m, about 15% of the airborne aerosol mass consisting of droplets larger than 25 µm in diameter. The peak aerosol concentration at chest height underneath the sprayed swath of forest was approximately 15 ng/litre. One result of considerable interest was the degree of volatilization of fenitrothion from an early morning spray, which resulted in a sustained vapour plume during the afternoon with a concentration 1 The value nanograms/min per litre represents the time integrated aerial concentration of fenitrothion consisting of the mean aerosol cloud concentration of agent (nanograms per litre) divided by the residence time (minutes) of the cloud. of 25 ng/litre at the spray line, falling to approximately 1.0 ng/litre 100 m downwind of the swath at an ambient temperature of 20-25 °C. The vapour plume persisted throughout the day and, in a 10-h period following spraying, was estimated to contribute up to 0.4 µg/person of respirable fenitrothion. A pesticide residue survey was conducted in relation to the 1980 spruce budworm spray programme (210 g a.i./ha applied twice with a 3-day interval) in New Brunswick, Canada. Fenitrothion was detected occasionally in the air, the maximum level being 1.2 µg/m3. Amino-fenitrothion was sometimes present in the air at a maximum level of 12.0 µg/m3 (Mallet & Volpe, 1982). A chemical residue survey was undertaken to determine the extent of the deposition and persistence of fenitrothion in the environment in relation to the 1981 spruce budworm spray programme (210 g a.i./ha applied twice with a 7-day interval) in New Brunswick, Canada. Fenitrothion was only detected twice in the air at levels of 0.08 and 0.04 µg/m3 (Mallet & Cassista, 1984). When a 1.0% emulsion of fenitrothion was applied to a 61.2 m3 room (3.7 ± 0.3 g a.i./room) at 23.5-25.4 °C, using a compressed air sprayer, the airborne concentrations of fenitrothion on days 0 and 3 after application were 3.3 µg/m3 and 0.5 µg/m3, respectively (Wright et al., 1981). 5.1.2 Water In actual field spraying in Canada, concentrations of fenitrothion in stream waters varied greatly, depending on the spray history and the weather. Spraying at 210 g/ha resulted in measurable concentrations (> 0.03 µg/litre) in streams as far as 4 km from the sprayed area. However, at 140-210 g/ha, most peak concentrations were lower than 15 µg/litre and diminished very rapidly in fast-flowing streams. Disappearance was still faster when a rain storm followed spray application (Eidt & Sundaram, 1975). High peak concentrations of fenitrothion were recorded in a few cases, e.g., 64 µg/litre in flowing stream water approximately 1 h after completion of spraying, and 75.5 µg/litre in stagnant water some 17 h after spraying at 140-280 g/ha (Lockhart et al., 1977). Fenitrothion concentrations usually dropped to less than 1 µg/litre within a few days in forest streams and beaver ponds after experimental and operational applications of 140-280 g/ha by aircraft (Flannagan, 1973; Peterson & Zitko, 1974; Sundaram, 1974; Eidt & Sundaram, 1975), and no measurable traces of fenitrothion have been found in water longer than 40 days after spraying. According to Symons (1977), the fenitrothion concentration in water immediately after aerial spray at 140-280 g/ha in Canada seldom exceeded 15 µg/litre. One hour after the first application of fenitrothion (280 g a.i./ha, applied twice with a 9-day interval) to a lake, fenitrothion residues in the water were concentrated near the surface (0.80-0.90 µg/litre), with small amounts (0.06 µg/litre) at the bottom. Six hours later, residues were fairly evenly distributed throughout the water column (0.91-1.49 µg/litre). Residue levels, 97 h after treatment, were similar at all depths at 0.41-0.46 µg per litre, but declined rapidly in the next 48 h to < 0.01-0.06 µg/litre. Similar results were obtained after the second application (Holmes et al., 1984). Sundaram (1973) also reported that concentrations of fenitrothion in aqueous systems diminished rapidly by dilution and by physicochemical and microbial degradation to low levels (0.03 µg/litre) within a period of 40 days. The half-lives were found to be short, ranging from 0.25 to 3.5 days. In the 1980 spruce budworm spray programme in Canada, fenitrothion was usually detected in water in the immediate vicinity of the sprayed sites. The maximum level was 20.0 µg/litre and persistence was usually limited to a few days. Aminofenitrothion  was also found at a maximum of 8.0 µg/litre (Mallet, 1980; Mallet & Volpe, 1982). Water, suspended solids, and sediment samples were collected from a small pond in a spruce-fir forest in New Brunswick, Canada, before and after spraying with a fenitrothion formulation. When an 11% fenitrothion formulation was sprayed on a pond at 1500 g/ha, the initial fenitrothion concentrations in the surface microlayer, subsurface water, and suspended solids (0.25-0.67 h after spraying) were 1.5, 0.015, and 1.9 µg/litre, respectively (Maguire & Hale, 1980). Thereafter, the fenitrothion disappeared exponentially with half-lives of 0.34, 9.8, 1.8, and 3.2 h in the surface microlayer, subsurface water, sediment, and suspended solids, respectively. Residue levels declined rapidly to below detectable levels, 2 days after spraying. The degradation products, 3-methyl-4-nitrophenol  in water and aminofenitrothion  in sediment persisted for less than 2 and 4 days, respectively. The concentration of fenitrothion in rainwater during spraying (140-280 g/ha) in Canada was 77 µg/litre in the sprayed area, 17 out of 43 samples in the neighbouring areas contained levels ranging from a trace to 1.1 µg/litre, while levels were less than 0.01 µg/litre in other regions (Pearce et al., 1979a). No residues of fenitrooxon , aminofenitrothion , or S-methyl fenitrothion  were detected, even in the sprayed area (less than 0.05 µg/litre). In the 1981 spruce budworm spray programme in Canada, the amounts of fenitrothion residues detected in water were low (maximum 1.30 µg/litre) and post-spray samples did not contain detectable amounts (less than 0.01 µg/litre) of fenitrothion. Small amounts of aminofenitrothion  (0.1 µg/litre) were detected in some samples (Mallet & Cassista, 1984). In Quebec, environmental surveillance was performed in the sprayed areas after aerial spraying, carried out from 1979 to 1982. The insecticide concentrations were measured in foliage and water samples taken from 1 to 4 h after spraying, when residue levels were likely to peak. In lentic water, the median residue level was 5.82 µg fenitrothion/litre, with a maximum level of 1114 µg/litre. In lotic water, the median concentration was 2.84 µg fenitrothion per litre, with a maximum level of 127 µg/litre. In aquatic environments, fenitrothion residues disappeared rapidly. Levels of less than 1.0 µg/litre were found 2-8 days after spraying at 140-280 g a.i./ha (Morin et al., 1986). Fenitrothion levels in a mountain stream increased to 20 µg per litre, 6-9 h after spraying, and then decreased to below 1 µg/litre within 24 h (Hatakeyama et al., 1990). 5.1.3 Soil When operationally sprayed twice at 735 g/ha (Japan), fenitrothion levels reached a maximum of 0.13-0.23 mg/kg in soil under shrubbery after 1-8 days and then diminished with half-lives of 2-4 days. Aminofenitrothion  was detected at maximum levels of 1.5-6.5 µg/kg, but only shortly after spraying. Little contamination with fenitrothion due to drift was observed (a maximum of 0.01 µg/m2 per min, 1 h later) in areas that were 1.5 or 3.0 km from the application site (Ohmae et al., 1981). Yule & Duffy (1972) found that an operationally applied dosage of fenitrothion (280 g/ha) produced a deposit of up to 0.04 mg/kg (average depth 15 cm) in forest soil, and that the initial deposit was too small to investigate degradation pathways. Sundaram (1974) found a similar pattern of loss of fenitrothion from the soil after 5 years of repeated annual applications at a rate of 210-350 g/ha in Canada; the insecticide content in the soil samples ranged from traces to 0.1 mg/kg and disappeared within 45 days. No measurable amounts of the breakdown products were found. Despite consecutive annual spraying for up to 5 years at 210-350 g/ha in New Brunswick, Canada, there was no evidence of build-up (< 0.005 mg/kg) in the soil (Yule, 1974). In the 1981 sprucce budworm spray programme in Canada, foilage and soil litter collected after the second spray application contained fenitrothion at levels of 0.2-0.5 and 0.06-0.14 mg/kg, respectively; post-spray samples collected 2 weeks later contained similar levels of fenitrothion. No residual fenitrothion was detected in sediment (Mallet & Cassista, 1984). 5.1.4 Food Fenitrothion is used for the pre-harvest treatment of a variety of crops, such as fruits, vegetables, rice, cereals, soybeans and coffee, at the rate of 0.5-2.0 kg a.i./ha. The initial residue levels on fruits, vegetables, rice, and cereals were relatively high (0.001-9.5 mg/kg), but declined rapidly with a half-life of 1-2 days (FAO/WHO, 1970, 1975b). A survey of pesticide residues in crops (total number of samples: 697) collected in the Tokyo Metropolitan Central Vegetable and Fruit Market was carried out from April 1984 to March 1989. Low fenitrothion residues (0.01-0.06 mg/kg) were found in only a few samples (Nagayama et al., 1986, 1987, 1988, 1989). Fenitrothion (EC) was applied 3 times to peach at a rate of 2.0 kg a.i./ha in Japan. The residue levels in peach (pulp) were 0.03-0.07 mg/kg, 7 days after application and decreased to 0.005-0.015 mg/kg after 13-15 days. Peach peel contained most of the residues (1.1-1.6 mg/kg), 7 days after application, but the levels decreased to 0.3-0.6 mg/kg in 15 days. Lettuce, plums, and apples were treated once with 0.2% fenitrothion (EC) at a rate of 0.8 kg. a.i./ha. No increase in 3-methyl-4-nitrophenol indicating the hydrolysis of fenitrothion residues was observed during 8 days following treatment. Levels of 3-methyl-4-nitrophenol did not exceed 10% of the fenitrothion residues (Cerna & Benes, 1972). Strawberries were treated twice with fenitrothion (EC) at a rate of 1.0 kg a.i./ha; the residue levels were 0.02-0.03 mg/kg and 0.005-0.007 mg/kg, 7 and 15 days after treatment, respectively (FAO/WHO, 1975b). Following 3 applications of fenitrothion to tomatoes, a residue of 1.32 mg/kg was detected on the same day as the final application (Kannan & Jayarnama, 1981). The residue level dropped to 0.07 mg/kg, one day later, but there was very little further reduction in fenitrothion levels over a further 2-week period. Fenitrothion (as EC, dust, or WP) was applied to rice plants in Japan at rates of 0.5-1 kg a.i./ha at various time intervals (3-5 times/season) before harvest. Over 120 samples of harvested rice were analysed for residues of the parent compound. The average residue levels ranged from negligible (0.001 mg/kg) to 0.1 mg/kg with a maximum level of 0.3 mg/kg, 11-20 days after the final application, and 0.001 mg/kg, 41-67 days after treatment (Sumitomo Chemical Co. Ltd, 1969). A variety of fenitrothion formulations were applied 1-7 times to rice crops pre-harvest at intervals ranging from 14 to 120 days. Most of the samples of hulled rice did not contain any residues at harvest (limit of determination 0.001 mg/kg), but a few contained low levels (maximum level 0.025 mg/kg) (FAO/WHO, 1978b). Fenitrothion is also used in the post-harvest treatment of stored grain. When grains with a moisture content of 12-13% were treated with fenitrothion at 15 mg/kg (18 mg/kg for brown rice), the residues decreased after 3 and 6 month at 25 °C to 6.8 mg/kg and 3.1 mg/kg, respectively, in barley, 6.9 mg/kg and 4.2 mg/kg in oats, 6.2 mg/kg and 3.5 mg/kg in rice, 11.5 mg/kg and 8.0 mg/kg in brown rice, and to 10 mg/kg and 7.5 mg/kg in polished rice. The rates of decrease of fenitrothion in/on grains in storage can be predicted accurately from the temperature, relative humidity, and dosage level (FAO/WHO, 1978b). When grains were subjected to milling, processing, preparation, and cooking, there was a significant loss of fenitrothion. Fenitrothion was deposited on the epidermis and removed with bran during the milling process, so that the residue level on bran was from 2 to 2.5 times higher than that on whole wheat and about 7 times higher than that on husked (brown) rice. After milling, the residue of fenitrothion in white flour was about 10% or less of the residue in the raw wheat. The residue in the white bread prepared from the white flour was reduced to 1-2% of the residue in the raw wheat. In case of wholemeal bread, however, 20-25% of the initial concentration remained after baking. The residue of fenitrothion in rice was decreased to 4.1 and 1.8% of the initial residue during husking and milling, respectively. The residue in polished rice was also decreased to 30% of original concentration. The concentration of fenitrothion in oats, rice in husk, husked rice, and polished rice decreased to 30-60% of the initial concentration after boiling. The malting process removed substantially all of the fenitrothion residue on raw barley. During the processing of oats for the production of rolled oats and groats, more than 95% of the residues on the raw oats were removed (FAO/WHO, 1977). In the United Kingdom, fenitrothion was found in home-produced and imported wheat at levels of up to 0.2-0.9 mg/kg in 1982 (MAFF, 1986). During the period of 1984-88, residues of fenitrothion were found in haricot and mung beans at levels of up to 0.1 mg/kg, but residues in several other pulses did not exceed 0.05 mg/kg. In retail wheat products, fenitrothion was found at levels of up to 0.05 mg/kg in white bread, 0.3 mg/kg in brown bread, 0.5 mg/kg in bran, and 0.02 mg/kg in cereal-based infant foods, but was not detected in breakfast cereals, wheatgerm products, brown rice, rye products, and processed oats, the level of detection being 0.01-0.1 mg/kg, depending on the commodity and the year of survey (MAFF, 1989). 5.2 Human exposure 5.2.1 Food In the USA, average fenitrothion residues of 0.0001 mg/kg were detected in grains and cereal products in 1979-80, and the average intake for an adult from this source was calculated to be 0.0608 µg/day (or 0.001 µg/kg body weight per day) in 1980 (Gartrell et al., 1985a). For the infant and toddler, maximum daily intakes were estimated to be < 0.001 µg/kg body weight per day and 0.002 µg/kg body weight per day, respectively, during 1977-80 (Gartrell et al., 1985b). 6. KINETICS AND METABOLISM The metabolic pathways of fenitrothion in mammals are shown in Fig. 8.1 6.1 Absorption, distribution, metabolic transformation, elimination, and excretion 32P-fenitrothion administered orally at doses of 15 and 500 mg/kg to rats and guinea-pigs, respectively, was readily absorbed from the gastrointestinal tract and distributed among various tissues. The concentrations of 32P in the blood of rats reached a maximum (15.5 µg/g) 1-3 h after treatment, and diminished to below detectable levels within 4 days (Miyamoto et al., 1963a). Following intravenous injection of 32P-fenitrothion in rats or guinea-pigs at a dose of 15 or 40 mg/kg, fenitrothion disappeared equally rapidly from the blood and tissues (Miyamoto, 1964a, 1969). The radioactivity (32P) was mostly excreted within 2-4 days into the urine (85-97%), up to 10% being eliminated in the faeces, accounting for nearly 100% recovery of the dose. The metabolites in excreta were demethyl fenitrothion , demethyl fenitrooxon , dimethylphosphorothioic acid , and dimethylphosphoric acid . Fenitrooxon  was detected only after intravenous administration of a large amount of fenitrothion and not after oral administration (Miyamoto et al., 1963a; Miyamoto, 1964a). Hollingworth et al. (1967a) studied the metabolism of fenitrothion in white mice. 32P-fenitrothion administered orally to mice at a dose of 3, 17, 200, or 850 mg/kg was rapidly eliminated in the urine and faeces with a recovery of > 90% 72 h after treatment. The isolated metabolites indicated that both the P-O-alkyl and P-O-aryl bonds of fenitrothion and fenitrooxon  were cleaved. No evidence was obtained indicating that the nitro group was reduced to form aminofenitrothion  or that the ring methyl group was oxidized. At the lower dose (17 mg/kg), demethyl fenitrothion , demethyl fenitrooxon , dimethylphosphorothioic acid , and dimethylphosphoric acid  were the major metabolites. At the 200 mg/kg body weight dose, the amounts of dimethylphosphorothioic acid  and dimethylphosphoic acid  decreased, and demethyl fenitrothion  increased. 1 Chemical structures in Fig. 1 to 8 are referred to according to numbers in the brackets. m-Methyl-14C-fenitrothion, administered orally at a dose of 15 mg/kg to Wistar rats, ICR mice, native Japanese rabbits, and Beagle dogs, was readily absorbed from the gastrointestinal tract and distributed to various tissues with maximum concentrations of 0.093 mg/kg (rats) - 0.144 mg/kg (dogs) after 1-3 h of the treatment, and the radiocarbon was rapidly and completely eliminated, mainly in the urine of rats (89-95%), mice (> 90%), rabbits (86-94%), and dogs (88%) (Miyamoto et al., 1976b). Examination of 11 rat tissues, including fat and muscle, revealed that the concentrations of fenitrothion ranged from 0.004 mg/kg to less than 0.001 mg/kg (except in fat-0.034 mg/kg), 24 h after administration. Whole body autoradiography also indicated the rapid disappearance of the radiocarbon from the tissues of mice. The cumulative patterns of elimination were essentially the same among these animals when radioactive fenitrothion was given at 15 mg/kg body weight. Similar patterns were obtained in rats when fenitrothion was administered at 105 mg/kg body weight or 15 mg/kg body weight after a total of 5 pretreatments with non-radioactive fenitrothion at 15 mg/kg body weight every other day. Thin-layer chromatographic analysis of the urinary metabolites showed the absence of intact fenitrothion and the presence of as many as 18 metabolites, of which 17 (92-99% of radioactivity) were identified. The differences in the composition of the metabolites among these animal species and between males and females of the same species were mostly quantitative. The percentage of the metabolites retaining the P-O-aryl linkage varied with animal species, ranging from 8.6% (rabbits) to more than 56.9% (dogs). Most of these metabolites were demethylated products [7,20] at the O-methyl position. Rats and mice tended to eliminate greater amounts (15-26%) of demethyl fenitrooxon  than rabbits and dogs (2-6%). 3-Methyl-4-nitrophenol , free or as conjugates with sulfuric acid  or glucuronic acid , constituted another group of major metabolites. Approximately 50-75% of the urinary radioactivity was accounted for by these three metabolites (  ), except in dogs (36%). The urinary activity in rabbits (64-75%) exceeded that in other animal species (50-60%). A trace amount of the oxidized phenols (0.5-2%) [10,22] was present in rats and rabbits. Rabbits were exceptional in excreting fenitrooxon  and animofenitrothion , though in small amounts (0.1-3.7%). The urine of rabbits and, to a lesser extent, of rats contained several minor metabolites derived from aminofenitrothion  or from 3-methyl-4-aminophenol . The minor products totalled approximately 15% of the excreted radiocarbon in rabbits and about 12% in rats. A few metabolites had unique structures resulting from the reduction of the nitro group and oxidation of the m-methyl group . An appreciable amount of the excreted metabolites from the 4 animal species was in the form of conjugates. It appeared that rabbits were most active in this regard, and dogs least active. In the 4 species treated, higher amounts of sulfate conjugates than glucuronides were excreted. Thus, fenitrothion was metabolized through two major pathways, via O-demethylation and via cleavage of the P-O-aryl bond. Neither S-(3-methyl-4-nitrophenyl) glutathione mediated by glutathione S-aryltransferase nor ring hydroxylation products have been positively demonstrated (Miyamoto et al., 1976b). Although reduction of the nitro group in the fenitrothion molecule, presumably by intestinal microorganisms, was a minor metabolic pathway in the above 4 animal species, it was the major metabolic pathway in ruminants. In fact, a study of female goats revealed that most of the urinary and faecal metabolites of fenitrothion were amino derivatives [13,14,30] and were formed most probably in rumen fluid (Mihara et al., 1978). The metabolism of fenitrothion in Wistar rats with hepatic lesions induced experimentally by dietary administration of diaminodiphenyl-methane (DDM), by feeding a low protein-high fat diet (LPHF), or by intramuscular treatment with carbon tetrachloride, was also investigated. The in vitro rates of degradation of fenitrothion were significantly reduced in all preparations from livers with induced hepatic lesions, with the greatest reduction produced by LPHF followed by carbon tetra-chloride and DDM. The rate of degradation of fenitrothion and fenitrooxon  was less severely affected than the rate of activation of fenitrothion, because of the greater activity of glutathione S-alkyltransferase (Miyamoto et al., 1977a). However, the cumulative excretion patterns of radiocarbon were not altered by these three hepatic lesions after oral administration to the injured rats of either 15 or 50 mg 14C-fenitrothion/kg body weight, or 15 mg/kg body weight of the compound after pretreatment with approx. 2.8 mg/kg body weight per day of nonactive fenitrothion for 4 weeks. Moreover, the injured rats metabolized fenitrothion equally as well in vivo, as the control animals, even though the pathway yielding demethyl fenitrothion  predominated. Higher or short-term doses of fenitrothion tended to reduce the metabolic differences observed between the injured and the control animals (Miyamoto et al., 1977b). These results indicated that even very severe hepatic lesions, such as those described here, hardly influenced the in vivo detoxification of fenitrothion and the excretion of its metabolites. The results also indicated that there was not much possibility of retention or storage of the parent compound and/or its toxic metabolites in the mammalian body under such unfavourable conditions. The dermal penetration of 14C-ring-labelled fenitrothion and aminocarb was determined in male, rhesus monkeys and male, Sprague-Dawley rats. In monkeys, 49 ± 4% of the fenitrothion (urinary excretion half-life = 14 h) was absorbed from the forehead, while 21 ± 10% of the fenitrothion (half-life = 17 h) was absorbed from the ventral forearm. Monkey forehead was 2.3 times more permeable than the forearm. In rats, 84 ± 12% of the fenitrothion (half-life = 20 h) was absorbed from the middorsal region (Moody & Franklin, 1987). The presence of N,N-diethyl-m-toluamide (DEET), used as an insect repellent by workers spraying fenitrothion, increased the absorption of 14C fenitrothion through rat skin (32% DEET; 15% control with acetone) and monkey skin (9.7% DEET; 3.2% control) (Moody et al., 1987b). 6.2 Retention and turnover To evaluate the possible retention of fenitrothion residues in animal tissues, methyl-14C-fenitrothion was administered orally to male Wistar rats at 15 mg/kg body weight per day for 7 days, and then at 30 mg/kg body weight per day for a further 3 days. A measurable amount (0.09 mg/kg) of fenitrothion was found in abdominal fat and athe level increased (2.4 mg/kg) at the later staes of administration. This amount, however, tended to disappear quite rapidly on cessation of the administration (Miyamoto, 1977c). Following administration of 10 or 3 mg fenitrothion/kg body weight per day to male native Japanese rabbits for 6 months, blood, skeletal muscle, and abdominal fat were analysed by gas chromatography for fenitrothion and fenitrooxon. In most cases, blood and muscle did not contain any detectable amounts of either compound (detection limit for fenitrothion 0.005 or 0.002 mg/kg, and that of fenitrooxon, 0.01 mg/kg). Averages of 0.131 mg fenitrothion/kg (0.243 mg/kg maximum) and of 0.045 mg/kg were measured in the fat of rabbits dosed at 10 and 3 mg/kg body weight per day, respectively, while muscle contained a maximum of 0.006 mg fenitrothion/kg. No fenitrooxon was detected (Miyamoto et al., 1976a). Three male beagle dogs were treated orally with 5 mg fenitrothion/kg body weight per day, 6 days per week, for 10 months. After termination of the treatment, only the fat contained trace amounts of fenitrothion (maximum of 0.160 mg/kg) (Tomita et al., 1974). 7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS A more complete treatise on the effects of organophosphorus insecticides in general, especially their short- and long-term effects on the nervous system, can be found in Environmental Health Criteria 63: Organophosphorus insecticides - A general introduction (WHO, 1986). No-observed-effect levels on the ChE in the plasma, erythrocytes, and brain of animals treated with fenitrothion under various conditions are summarized in Annex II. 7.1 Single exposure As with other organophosphorus insecticides, a large dose of fenitrothion produces toxic signs and symptoms in various animals by the inhibition of acetylcholinesterase (AChE) in the nervous system, with the consequent accumulation of excessive levels of acetylcholine. The major toxic signs in experimental animals are salivation, tremor, exophthalmos, urinary incontinence, piloerection, and dyspnoea, which are similar to the toxic signs elicited by other organophosphorus insecticides (Namba, 1971). The acute toxicity of fenitrothion varies according to the species of the test animal, its sex, the route and method of administration and/or the solvent used, as shown in Table 4. The acute oral LD50s in mammals range from 330 mg/kg in the rat to 1850 mg/kg in the guinea-pig, the dermal LD50s range from 890 mg/kg in the rat to > 2500 mg/kg in the mouse. Groups of 8 male and 8 female Sprague-Dawley rats were exposed to fenitrothion mists dissolved in a mixture of deodorized kerosene and xylene (particles mostly less than 3 µ in diameter) to assess inhalation toxicity at aerial concentrations of 10, 70, and 186 mg/m3 for 2, 4, or 8 h. No significant toxic signs were observed in the rats exposed to an aerial concentration of 10 mg/m3 for 2 and 4 h. With longer exposure and/or higher fenitrothion concentrations, toxic symptoms developed including salivation, urinary incontinence, tremor, lacrimation, muscular fibrillation, and dyspnoea, and, after 8 h exposure to 186 mg fenitrothion/m3, 2 out of 8 males died. A transient body weight decrease was observed after 8 h exposure to 10 and 70 mg fenitrothion/m3. A marked body weight decrease was observed at a concentration of 186 mg/m3. The LC50 value for fenitrothion in rats exposed for 8 h, was estimated to be more than 186 mg/m3 (Kohda & Kadota, 1979). Table 4. Acute toxicity of fenitrothion Animal Strain Sex Route LD50 (mg/kg) Vehicle Reference Mouse male oral 1336 Carshalton (1964) female oral 1416 dd male oral 1030 10%Tween 80 aq. Miyamoto & Kadota (1972) dd female oral 1040 10%Tween 80 aq. dd male dermal > 2500 Undiluted Kadota et al. (1972) female dermal > 2500 Undiluted Rat Sherman male oral 740 Peanut oil Gaines (1969) Sherman female oral 570 Peanut oil Sprague-Dawley male oral 330 10%Tween 80 aq. Miyamoto & Kadota (1972) Sprague-Dawley female oral 800 10%Tween 80 aq. Wistar male oral 940 Benes & Cerna (1970) Wistar female oral 600 Sprague-Dawley male dermal 890 Undiluted Kadota et al. (1972) Sprague-Dawley female dermal 1200 Undiluted Guinea-pig male oral 500 DuBois & Puchala (1960) oral 1850 Sorpol 2001 Miyamoto et al. (1963b) Dog Beagle male/ oral > 681 Gelatin capsule Mastalski (1971b) female Hen White Leghorn oral 500 10%Tween 80 aq. Kadota et al. (1975b) The pulmonary toxicity of fenitrothion was evaluated following a single exposure of caged rats (n = 160) placed in a field oversprayed by aircraft during an operational forest treatment. Depending on the position of the cages, the air concentrations of fenitrothion measured in the first 30 min after spraying, were 6.19 and 33.2 µg/m3. Plasma pseudocholinesterase activity and pulmonary alveoli ultrastructure were used as indices of fenitrothion exposure. Although a few signs of toxic lung injury were observed on days 3 and 7, there were no cholinergic signs or effects on pseudocholinesterase activity within 12 h in exposed animals, compared with controls. The alveolar toxic reaction was limited to small and discrete foci, and was entirely reversible within a period of 2 months (Coulombe et al., 1986). Rat lungs were examined with light and electron microscopes, 3-60 days after exposure to fenitrothion. Groups of 9 male, Sprague-Dawley rats were exposed by a "nose-only" apparatus for 1 h to an aerosol of fenitrothion (15%) mixed with non aromatic hydrocarbon solvent and oil diluent at 2 or 500 mg/m3. Only minor modifications of lung alveolar tissue were observed after exposure to the higher concentration. At 3 days, discrete foci of mild inflammation were detected, including interstitial oedema, cellular infiltration, and an increased number of alveolar macrophages. At 7 days, signs of irritation were diminished, and, at 21 and 60 days, alveolar tissues were essentially normal. Exposure to the lower concentration induced more limited changes at 3 days; no modification was seen at later examinations. It was considered that a single exposure to this fenitrothion mixture at 500 mg/m3 did not present a serious hazard to the lung (Chevalier et al., 1984). Alveolar irritation was also seen in the solvent- exposed control animals. When Holstein milk cows and sheep (male) were administered fenitrothion orally at 500 and 770 mg/kg body weight, respectively, they showed signs of poisoning, such as paralysis of the hindlegs and salivation, but gradually recovered 4 h after treatment (Namba et al., 1966). Pigs given a single oral dose of 310 mg/kg body weight showed typical signs of ChE inhibition, but the toxic signs disappeared within 48 h. When cows and sheep were given fenitrothion at 3 mg/kg body weight per day, for 90 and 60 days, respectively, the ChE activity in the plasma decreased in both species early in the test period, but recovered fully after 30 days. 7.2 Skin and eye irritation; skin sensitization 7.2.1 Skin and eye irritation One tenth ml of fenitrothion (technical) was applied to one eye of 9 male, New Zealand White rabbits. The untreated eye served as a control. The treated eyes of 6 animals remained unwashed. The treated eyes of the other 3 animals were flushed for 1 min with about 300 ml lukewarm water, 30 seconds after application. Slight hyperaemia in the conjunctiva was observed 1 h after application in the unwashed eyes. This change had disappeared 48 h after application. No irritating reactions were induced in any washed eyes. The irritating potency of fenitrothion in eyes was judged to be minimal for the unwashed group, and negative for the washed group (Hara & Suzuki, 1981). A half ml of fenitrothion (technical) on a 1 x 1 inch lint patch was applied to abraded and intact parts of the back skin of 6 New Zealand White rabbits. No irritating reactions, such as erythema and oedema, were noticed in the animals. The irritating potency of the material was estimated to be negative (Hara & Suzuki, 1981). 7.2.2 Skin sensitization The Landsteiner-Draize test with fenitrothion (technical) was conducted on 6 male, Hartley guinea-pigs using 2,4-dinitrochloro-benzene (DNCB) as a positive control, to examine possible skin sensitization activity. Fenitrothion dissolved in corn oil at concentrations of 1 or 5% was applied intradermally every other day, 10 times. The animals were treated for a challenge with intradermal injection and dermal application 2 weeks after the last sensitizing treatment. Allergic reactions were not observed in any animals treated with fenitrothion, while reactions, such as swelling and hyperaemia, were clearly noticed in the animals treated with DNCB. It was concluded that fenitrothion (technical) was not a skin sensitizer (Kohda et al., 1972). The maximization test was undertaken to study the allergenicity of fenitrothion. Ten young adult, female, Hartley guinea-pigs weighing from 300 to 500 g were studied, induction and challenge being undertaken according to the original method. The concentrations of the compounds for the induction were 5 and 25% for intradermal and topical treatment, respectively. Challenge concentrations of 0.05% showed the potential for allergenicity in this test (Matsushita et al., 1985). 7.3 Short-term studies 7.3.1 Rat Male rats were given daily oral doses of 13 mg fenitrothion/kg body weight for 28 days. Erythrocyte ChE activity was severely depressed, but recovered 30 days after withdrawal of fenitrothion (Kimmerle, 1962a). Oral administration of fenitrothion at 7.25 or 14.5 mg/kg body weight per day to male, Wistar rats (5/group) for 28 days resulted in increases in plasma corticosterone and glucose levels, 7 days after the start of treatment, and in the relative adrenal weight, 2 weeks after the start of treatment (Yamamoto et al., 1982b). Groups of 36 male, CD rats received technical fenitrothion by oral gavage (2.5, 5.0, 10.0, or 20.0 mg/kg per day) for 30 consecutive days. No significant treatment-related changes were observed by serum biochemistry or by light microscopy of liver. However, a dose-dependent decrease was noted in the brain, plasma, and erythrocyte ChEs as well as tissue esterase activities. Eight out of 36 animals died at the 20.0 mg/kg level (Trottier et al., 1980). Male rats were fed 5, 10, or 20 mg fenitrothion/kg diet for 5 weeks. The activity of brain and erythrocyte ChE was normal in the 5 mg/kg group, whereas the 10 mg/kg group showed a slight depression of erythrocyte ChE activity after 5 weeks and recovery 2 weeks after withdrawal. The 20 mg/kg group showed some depression of activity in both erythrocyte and brain ChE and the recovery in brain ChE remained incomplete 2 weeks after withdrawal (Carshalton, 1964). The neurobehavioural effects were examined in male, Sprague-Dawley rats (6/group) of fenitrothion administered orally at doses of 10, 20, or 40 mg/kg body weight, daily, for a period of 40 days. At the 2 higher doses, mortality was more than 50%, while only one animal died at a dose of 10 mg/kg. Toxic signs, such as cholinergic signs, loss of reflexes, and changes in motor activity and indices of ataxia, were observed markedly at the 2 higher doses, and slightly at the lowest dose. However, these effects tended to recover gradually later in the study (Rondeau et al., 1981). Groups of male, Wistar rats (16 or 17 in number) were fed 0, 32, 63, 125, 250, or 500 mg fenitrothion/kg diet for 90 days. Mortality, food intake, growth, general behaviour, urinalysis, average organ weights, and histopathology in the groups fed 32, 63, 125, and 250 mg/kg diet were comparable to those in the controls. All animals fed 500 mg/kg diet showed clinical signs of anticholinesterase poisoning and there were minimal toxic signs in 4 animals in the 250 mg/kg diet group. In the 500 mg/kg group, the average weights of the testes and brain were increased in comparison with those of the control group. On monthly interim sacrifice of 4 rats from each group, the cholinesterase (ChE) activity of plasma, erythrocyte, brain cortex, liver, and kidney showed a dose-dependent depression, the lowest activity being in the brain. The ChE activity in the 32 and 63 mg/kg diet groups generally increased by day 60 of feeding to a level within the normal limits (Misu et al., 1966). Fenitrothion (60% water miscible concentrate) was given to groups of 12 Wistar rats/sex at dose levels of 0, 20, 92.8, 430.7, or 2000 mg/kg diet in the feed or 0, 10, 46.4, 215, or 1000 mg/litre in drinking-water, for 90 days. The levels causing no appreciable effect on the ChE activity of plasma, erythrocyte, and whole blood were 20 mg/kg diet and 10 mg/litre drinking-water. The above mentioned levels and 92.8 mg/kg diet and 46.4 mg/litre and 215 mg/litre in drinking-water did not cause any effects on food or water intake, weight gain, average organ weights, haemogram, and blood biochemistry. However, 92.8 mg fenitrothion/kg diet and 46.4 mg/litre in the drinking-water moderately depressed the activities of whole blood and erythrocyte ChE and had a more marked depressive effect on plasma ChE. The ChE activity recovered between 30-40 days after withdrawal of fenitrothion. The levels of 430 mg/kg diet and 1000 mg/litre drinking-water caused a depression in body weight gain (Cooper, 1966). Two groups of male rats (20 each) were dosed by stomach tube with fenitrothion (50% formulation) at 10 mg/kg or 11 mg/kg body weight, for 6 days per week, over 6 months. During the first weeks, the rats showed a temporary deterioration in general condition and loss of weight. Haematology and urinalysis during the study and gross and microscopic pathology at its termination did not reveal any abnormalities (Klimmer, 1961). Groups of rats (15 males and 15 females) were fed fenitrothion at 0, 10, 30, or 150 mg/kg diet for 6 months. In all groups, growth, food and water consumption, mortality, blood and urinalysis, and blood biochemistry were comparable with those of the controls. The ChE activities in the brain, erythrocytes, and plasma were depressed in both sexes in the 150 mg/kg diet group and in females in the 30 mg/kg diet group. In the 10 mg/kg diet group, only the plasma ChE of females was depressed. Absolute and relative organ weights were within normal limits. No histopathological changes were found in the organs examined. Based on brain acetylcholinesterase inhibition, a NOAEL of 10 mg/kg diet was concluded (Kadota et al., 1975a). Groups of 8 male and 8 female rats were fed diets containing 0, 10, 50, or 250 mg fenitrothion/kg for 34 weeks. In another test, groups of 16 rats of each sex were fed fenitrothion at 0, 5, 25, or 125 mg/kg diet over the same period. The feeding of fenitrothion at 250 mg/kg diet resulted in a decrease in body weight gain in females. In the 125 mg/kg diet group, a lower relative weight of spleen was found in both sexes. The ChE activities in both the plasma and erythrocytes, measured at intervals, showed a dose-dependent decrease in all test groups, except for males at 5 mg/kg diet whose plasma ChE activity was not suppressed. In females, the depression was slight. The ChE activity in the brain was decreased only in the 250 mg/kg diet group (Benes & Cerna, 1970). Groups of 9 and 10 male Sprague-Dawley rats were fed 0, 25, 100, or 400 mg fenitrothion/kg diet for 63 weeks. A positive control group was fed 800 mg malathion/kg. At the 400 mg/kg level of fenitrothion, body weight gain was decreased and only a few animals survived the 63-week period. At this level, there was also a 100% depression of erythrocyte ChE. At the 100 mg/kg level, a slight ChE depression (10-30%) occurred in the brain and a moderate depression (30-65%) in the erythrocyte and plasma. At 25 mg/kg diet, fenitrothion had a slight effect on plasma ChE activity, but did not cause any effects on other parameters (food intake, body weight gain, brain and erythrocyte ChE) evaluated (Ueda & Nishimura, 1966). Groups of male, Wistar rats (60/group with 120 controls) were administered fenitrothion, by gavage, at 0, 0.5, 1, 5, or 10 mg/kg body weight per day, for 12 months. Each month, 10 controls and 5 rats from each group were sacrificed. After 12 months, administration was stopped and survivors were held for an additional 2 months to monitor recovery from the biological effects of the treatment. No changes attributable to treatment with fenitrothion were observed in haematology or blood biochemistry, except in esterase activities. Marked reductions in hepatic ChE, and brain and erythrocyte AchE activities, observed at doses of 5 and 10 mg/kg body weight per day, within 1 month of treatment, persisted for the duration of the treatment. Two months after treatment was terminated, the esterase activities in all treated rats were comparable to those in the controls. Little change was measured at 0.5 and 1 mg/kg per day (Ecobichon et al., 1980). Groups of Wistar rats (26 males and 27 females) were fed a diet containing 0, 1, 5, or 25 mg fenitrothion/kg for one year. No significant changes were observed in body weight, food and water intake, organ weights, or histopathology. The ChE activity in the brain, liver, and erythrocytes was reduced at 5 and 25 mg/kg diet during the first month but then recovered (Kanoh et al., 1982). A nose-only inhalation toxicity study of fenitrothion was conducted on Sprague-Dawley rats (Breckenridge et al., 1982). Groups of 10 male and 10 female rats (20/sex for the controls) were exposed to fenitrothion 11% emulsifier mixture at chamber concentrations of 0, 6.7, 20, or 60 mg/m3, for 2 h/day, for 30 consecutive days. ChE activity in the plasma, erythrocytes, and brain was inhibited in the 60 mg/m3 males and in all the treated females, except those in the 6.7 and 20 mg/m3 groups, in which the erythrocyte ChE activity was not affected. Hepatic and renal carboxyesterases were inhibited in the 60 mg/m3 male group and the 20 and 60 mg/m3 female groups. These enzyme activities had returned to normal values 30 days after treatment. Suppression of the brain ChE activity in the 60 mg/m3 female group persisted. Haematological, urinary, blood biochemical, and histopathological studies did not reveal any deleterious effects of fenitrothion. Durham et al. (1982) reported a short-term study of fenitrothion (11% emulsifiable concentrate) in the absence or presence of Atlox 3409F (emulsifier) and Dowanol TPM (cosolvent). Forty-five male, Sprague-Dawley rats were assigned to each of the treated and control groups. No changes in the haematological, serum biochemical parameters or in tissue morphology were observed in rats treated with fenitrothion at doses of 1, 5, 10, or 20 mg a.i./kg. The emulsifier and co-solvent did not substantially enhance or reduce the toxicity of fenitrothion. 7.3.2 Dog Groups of dogs (1 male and 1 female) were given daily oral doses (by capsule) of 0, 2, 9, or 40 mg fenitrothion/kg body weight for 98 days. Body weights, blood biochemistry, ChE levels, and haematology were checked at intervals. At the 2 mg/kg level, fenitrothion did not produce any effects on the parameters examined. At 9 mg/kg, a slight depression after 60 days and, at 40 mg/kg, a moderate depression after 29 days occurred in whole blood, plasma, and erythrocyte ChE activity. At 40 mg/kg, there were also marked toxic signs typical of cholinergic stimulation, and the dogs in this group were sacrificed before the end of 98-day period (Cooper, 1966). Groups of dogs (6 males and 6 females) were fed fenitrothion at levels of 0, 30, 100, or 200 mg/kg diet for two years. Body weights, blood biochemistry, and plasma, erythrocyte, and brain ChE activities were monitored, together with histopathological examination. The only adverse effect was a reduction in the ChE activities. Depression of plasma ChE activity was apparent in all groups, while erythrocyte enzyme activity was unaffected in the 30 mg/kg group, when the treated and control animals were compared. The brain ChE activity was decreased only after ingestion of 200 mg/kg (Mastalski et al., 1973). Groups of Beagle dogs (6 males and 6 females) were fed fenitrothion at dose levels of 0, 5, 10, or 50 mg/kg diet for one year. The only treatment-associated change was a depression of ChE activity. At 50 mg/kg diet, plasma ChE was depressed in both sexes, and erythrocyte ChE was slightly depressed in the males only. However, brain ChE was not depressed at any levels. The no-observed-effect level was 10 mg/kg or 50 mg/kg diet, based on the effects on erythrocyte or brain ChE, respectively (Griggs et al., 1984). A group of 3 male Beagle dogs was given fenitrothion in capsules at 5 mg/kg body weight per day, for 6 days a week, over 10 months. A marked depression of plasma and erythrocyte ChE activities was observed compared with the control group (2 animals). However, no appreciable accumulation of the compound was noted in the blood, fat tissue, or liver (Tomita et al., 1974). Groups of Beagle dogs (2 females) were treated orally with fenitrothion at dose levels of 0 or 2 mg/kg body weight per day (by capsule) for one year. A marked depression of plasma and erythrocyte ChE activities was observed 2 weeks after initiation of treatment. No changes attributable to treatment with fenitrothion were found in haematology, blood biochemistry, or ophthalmology (Ogata, 1972). 7.3.3 Rabbit When groups of male Japanese albino rabbits (15 animals per group) were administered fenitrothion at 0, 3, or 10 mg/kg body weight per day in the diet for 6 months, a significant depression of the plasma and erythrocyte ChE activities was observed in both treated groups. At the higher dosage, depression of the brain ChE was also found. However, no noteworthy changes, either biochemical or histochemical, were observed in musculi rectus medialis ChE, and the fine structure of the neuromuscular junctions of the tissue was essentially normal when examined using an electron microscope. No other adverse effects were observed in behaviour, mortality, haematology, clinical biochemistry, organ weights, or histopathology of major organs and tissues (Miyamoto et al., 1976a). 7.3.4 Guinea-pig Treatment of male guinea-pigs with 5 or 10 mg fenitrothion/kg ip for 30 days resulted in a dose-dependent increase in acetylcholine levels in the heart, decreased heart rate, and hypocalcaemia (Anand et al., 1989). Active sensitization toxicity by inhalation of fenitrothion (technical) or fenitrothion 22% emulsifiable concentrate (EC) was examined in 10-15 male and female Hartley guinea-pigs using bacterial alpha amylase as a positive control material. Fenitrothion (technical) suspended in 10% Tween 80 aqueous solution and the undiluted EC formulation were sprayed daily for 120 min for 7 days. The air concentrations of fenitrothion were 226 and 628 mg a.i./m3 in the chamber where the technical sample was sprayed, and 360 and 1048 mg a.i./m3 in the chamber where the EC formulation was sprayed. Animals inhaling the material at the higher air concentration of the EC formulation showed salivation from the third day. The cholinesterase activities in the brain, packed red cells, and plasma were severely inhibited in treated animals at the completion of the sensitization period. The animals were challenged 7 days after the last sensitizing inhalation, but signs of allergic asthma were not observed in any animals treated with fenitrothion. In contrast, animals treated with bacterial alpha amylase showed severe allergic signs of asthma. It was concluded that fenitrothion did not cause allergic asthma (Okuno et al., 1977). 7.4 Long-term and carcinogenicity studies Groups of Wistar rats (15 males and 15 females) were fed diets containing fenitrothion at levels of 0, 2.5, 5, or 10 mg/kg for 92 weeks, to investigate the effects of fenitrothion on ChE activities. The ChE activity in the blood was measured after 2, 4, 6, 8, 12, 16, 20, 24, 42, 68, and 92 weeks. In the 5 mg/kg group (equivalent to 0.27 mg/kg body weight per day), a 20-25% decrease in plasma ChE activity in the males during the first 16 weeks and a 20-35% decrease in the females during 12 weeks were recorded. The activity, however, recovered during the remaining test period. In the 10 mg/kg group, the plasma activity decreased during the first 8 weeks by 30-40% in males and 40-50% in females. The activity, however, gradually returned to normal during the next 8 weeks. The activity of erythrocyte ChE was decreased by 20-30% in both sexes during the first 6 weeks at 10 mg/kg and then recovered fully. The brain ChE activity, determined at the end of the test period, was not affected by fenitrothion at any dose level. The no-observed-effect level in this study was 5 mg/kg diet (0.27 mg/kg body weight per day in males or 0.28 mg/kg body weight per day in females) (Kadota et al., 1975a). Three groups of Charles-River albino rats (50 males and 50 females) were administered fenitrothion at levels of 10, 30, or 100 mg/kg diet (corresponding to 0.5, 1.5, and 5 mg/kg body weight) for a period of 104 weeks, with 60 females and 60 males as controls. These animals were derived from the F1a generation of a reproduction study (see section 7.5.1). Ten rats of each sex and group were sacrificed after one year and all the surviving animals at 104 weeks. The body weights of males and females at 100 mg/kg were lower than those of the controls from the start of the test and remained so in males until 52 weeks, but at the end of the test no significant differences were seen. Food consumption at 52 weeks was lower for the middle- and high-level males, but normal for low-level males and all the females. The mortality rate in the treated females was comparable with that in the control females, while, in males, the mortality rate was significantly higher than the controls only in the lowest-dose group. Blood and urine analyses were normal while ChE activity showed a dose-dependent decrease among the test rats. Significant depressions in ChE activities in the plasma were recorded at all 3 dosage levels (F1a being affected from the beginning), but erythrocyte ChE depression and brain ChE depression occurred only at the 30 and 100 mg/kg levels in both sexes. Statistical analysis of the probabilities of tumour incidence did not reveal any differences between the controls and the animals treated with 10 or 100 mg/kg. There was a decrease in the probability of benign tumours in males treated with 30 mg/kg and an increase in pituitary adenoma incidence in the 30 mg/kg females; however, since this was not observed at the 100 mg/kg level, it was not considered related to treatment. Absolute and relative organ weights and gross and histopathology did not reveal any dose-dependent changes (Rutter & Nelson, 1974). In a study by Rutter & Banas (1975), groups of ICR Swiss mice (200 animals/sex) were fed a diet containing 0, 30, 100, or 200 mg fenitrothion/kg for 78 weeks (18 months). No observable effects attributable to the compound were detected on body weight gain, food intake, mortality, or ophthalmological and gross/histopathological findings. It was concluded that fenitrothion is not carcinogenic in mice fed up to 200 mg/kg diet for 18 months. Groups of B6C3F1 mice (100 males and 100 females) were administered fenitrothion at levels of 0, 3, 10, 100, or 1000 mg/kg diet. Each group of mice was divided into 2 subgroups (main and satellite groups) comprising 50 mice of each sex. The main groups were maintained on the control or test diets until death, or for a maximum of 104 weeks. The satellite groups were used for interim sacrifices. Throughout the administration period, no treatment-related abnormal symptoms were observed, nor were there any significant differences in the survival rates between control and treated groups. Decreases in body weight gain, food consumption, and water intake were observed at the 1000 mg/kg level in both sexes. Urinalysis, ophthalmology, and haematology did not reveal any treatment-related effects. Significant depression of ChE activity occurred in plasma at the 3 highest levels, while, in erythrocytes and brain, the depression occurred at 100 and 1000 mg/kg levels in both sexes. The blood biochemical examination revealed an elevation of total cholesterol values in both sexes in the 100 and 1000 mg/kg groups and a decrease in glucose levels in both sexes in the 1000 mg/kg group. Some other biochemical changes were observed transiently in the 1000 mg/kg group. The incidence of alopoecia was decreased at the final sacrifice of 1000 mg/kg females. Brain weights were increased in both sexes in the 1000 mg/kg group. Histopathological examination revealed that calcification of brain parenchyma in both sexes in the 1000 mg/kg group, and hair follicular atrophy in 1000 mg/kg females were less frequent than in the controls. No treatment-related increase was observed in the incidence of any neoplastic changes. The level causing no toxicological effect was concluded to be 10 mg/kg diet, based on the depression of brain ChE (Tamano et al., 1990). 7.5 Reproductive effects, embryotoxicity, and teratogenicity 7.5.1 Reproductive effects A 2-litter, 3-generation, reproduction study on Charles River albino rats was carried out with 15 males and 30 females per test group (20 males and 40 females for control) administered dietary levels of 0, 10, 30, and 150 mg fenitrothion/kg. After the first filial generation (F1a), the highest dose level was reduced to 100 mg/kg. Fertility, gestation, lactation, and live birth indices were compared. Administration of 150 or 100 mg fenitrothion/kg in the diet caused weight reduction in the parental animals in the P0 and P1 generations and suppressed lactation indices through all generations. The highest dose group also showed a higher incidence of cannibalism and smallness at weaning, whereas all litters seemed normal at birth. No dose-dependent malformations or histopathological changes were seen (Rutter & Voelker, 1974). Crl: CD(R)(SD)BR male and female rats (30 animals/group) were exposed to technical fenitrothion (94.6% pure) in the feed for 2 generations (2 litters in the first generation and 1 litter in the second generation) at dietary levels of 0, 10, 40, or 120 mg/kg. A dose-dependent, statistically significant decrease in body weight gain and absolute and relative feed consumption occurred in males and females given 120 mg/kg diet. Body weights and body weight gains were significantly affected at 40 mg/kg diet in the P1 generation female rats during lactation, and in the F1a generation male rats during post-cohabitation. Absolute feed consumption values were significantly affected at 40 mg/kg diet in the F1a generation female rats. There was no compound-related effect on reproductive performance in either the P1 or F1a generations at levels of up to 120 mg/kg diet. The body weights of pups were significantly reduced in litters of both generations at 120 mg/kg diet and mortality was significantly increased in the P1 generation, F1a and F1b litters, and the F1a generation and F2 litters, at 120 mg/kg diet. There were no treatment-related histomorphological changes in the male and female F0 and F1 generation rats at up to 120 mg/kg diet (Hoberman, 1990). Groups of 10 male and 20 female rats were fed a diet containing 0, 10, 40, or 80 mg technical fenitrothion/kg in a 4-generation, 2-litter, reproduction study. The following parameters were monitored: body weight and food consumption of parent animals and indices of fertility, gestation, live birth, 24-h survival, 5-day survival, and lactation; gross pathology of all pups, organ weights, and histopathological examination of F4b weanlings; cholinesterase activity in whole blood in males of F2a (aged 15 weeks) and in all weanlings of F4b (aged 4 weeks). Fertility, gestation, and live birth indices were normal in all groups, whereas the 24-h and 5-day survival indices were reduced in one or both litters of the 80 mg/kg group in almost all generations. The lactation index was reduced in all generations in the 40 and 80 mg/kg groups. The mean litter size was smaller in all but 5 test litters, but this was without any clear dose-dependence. However, the lowest number of pups was found in 6 out of 8 litters in the 80 mg/kg group. The mean weight of the pups at birth and at 21 days of age was normal, whereas the growth of the parent animals was slightly decreased in the 80 mg/kg group. Plasma and erythrocyte cholinesterase activity was decreased in relation to the dose and length of exposure; in the 10 mg/kg group, the decrease was not significant. Organ weights and gross pathological examination did not reveal any abnormalities (Benes et al., 1974). Fenitrothion fed to 10 female rats and male rats at 200 mg/kg diet before mating, and during the gestation period, in a one-generation reproduction study did not affect the reproductive indices, such as fertility, gestation, and live birth indices. Moreover, it was revealed that fenitrothion did not have any estrogenic activity, according to the mouse uterine weight assay (Gowda & Sastry, 1979). 7.5.2 Embryotoxicity and teratogenicity Groups of female albino rabbits were inseminated (gestation day 0) and during gestation days 6-18 were dosed with 0, 0.3, or 1 mg fenitrothion/kg per day in gelatine capsules. A positive control group given 37.5 mg thalidomide/kg per day was included. The compound did not induce any effects on the does or on the number of implantation sites, early or late resorption sites, number of dead or live young, or aborted fetuses. In the thalidomide group, approximately 10% of the fetuses showed external malformations, while none were seen in the other groups. No effects related to the administration of fenitrothion were seen on examination for internal or skeletal deformities (Ladd et al., 1971). Fenitrothion (technical grade, 96.6% purity) was dissolved in corn oil and administered orally to 14-16 pregnant rabbits (New Zealand White) during the period of organogenesis (gestation days 7-19) at dose levels of 0, 3, 10, or 30 mg/kg body weight per day. There were no treatment-related effects on pregnancy rate, fetal viability, fetal sex ratio, or mean fetal body weight values. Implantation efficiency was slightly lower at 30 mg/kg body weight per day compared with the controls. There were no dose-related increases in the incidences of external, visceral, or skeletal malformations at any dose level (Morseth et al., 1986). Groups of 25 or 27 pregnant mice (ICR) were administered fenitrothion orally at dose levels of 0, 20, 70, or 200 mg/kg per day during gestation days 7-12. Groups of 23-26 pregnant SD rats were also dosed orally with fenitrothion at levels of 0, 2, 7, or 20 mg/kg per day during gestation days 9-14. No embryotoxic or teratogenic effects were observed in mice or rats at any of these dose levels (Miyamoto et al., 1975). Fenitrothion (technical grade, 96.9% purity) was dissolved in corn oil and administered orally to 20-24 pregnant Sprague-Dawley rats during the period of organogenesis (gestation days 6-15) at dose levels of 0, 3, 8, or 25 mg/kg body weight per day. There were no adverse effects on pregnancy rates, mean implantation efficiency, fetal viability, fetal sex ratio, or mean fetal body weights. The frequency and the distribution of fetal malformation findings did not indicate a teratogenic response at any dose level. Maternal toxicity, as evidenced by body weight decrease and clinical observations (tremors), was indicated at a dose of 25 mg/kg body weight per day (Morseth et al., 1987). Prenatal administration of fenitrothion (50% EC) to CFY rats at 5, 10, or 15 mg/kg body weight by oral gavage from days 7 to 15 of gestation resulted in dose-related decreases in open field activity and motor coordination in the offspring of animals treated at the two highest dose levels. Long-lasting alterations in the acquisition and extinction of a conditioned escape response, as well as increased social interactions were observed in the adult offspring. The results indicated a no-observed-effect level of 5 mg/kg (Lehotzky et al., 1989). Fenitrothion (97.6% purity, 0.1% of 3-methyl-4-nitrophenol) was administered to groups of 20 pregnant Wistar rats in sunflower oil, by gavage, at single daily doses of 0, 2, 8, 16, or 24 mg/kg body weight during days 6-15 of gestation. On day 20 of gestation, the rats were sacrificed and the numbers of viable and dead fetuses, resorptions, implantations, and corpora lutea were recorded. Fetuses were subjected to external and internal (skeletal and soft tissue) examination. Fenitrothion was not found to be teratogenic in this study at any dose. At doses exceeding 8 mg/kg per day, fenitrothion was maternally toxic (Benes & Tejnorova, 1986). 7.6 Mutagenicity Fenitrothion was examined using a variety of mutagenicity tests including in vitro and in vivo gene mutation, DNA damage/repair, and chromosomal aberration assays (see Table 5). Most of the tests showed that fenitrothion was not mutagenic, but some of the tests gave weakly positive results: Ames tests with S. typhimurium TA100 (Kawachi, 1978; Moriya et al., 1983; Hara et al., 1989), sister chromatid exchange (SCE) assays (Kawachi, 1978) and chromosomal aberration tests (Kawachi, 1978). However, more recent studies showed that fenitrothion was negative in gene mutation assays with S. typhimurium TA100 NR, a nitro-reductase-deficient strain of TA100, and in mammalian cells, V79 Chinese hamster lung cells. Mutagenicity in S. typhimurium TA100 was considered attributable to the nitro-reductase inherent to bacteria (Hara et al., 1989). An SCE test in cultured mouse embryo cells showed a negative result for clastogenic potential (Suzuki & Miyamoto, 1980); in vitro and in vivo chromosomal aberration tests in the rat, mouse, and Chinese hamster test systems also gave negative results (Hara & Suzuki, 1982a,b; Hara et al., 1988). When CFLP mice were given 3-methyl-4-nitrophenol (25 mg/kg), intraperitoneally, once a week for 10 weeks, the numbers of chromosome gaps in bone marrow were significantly increased (Nehez et al., 1985). 7.7 Neurotoxicity Seven hens protected against acute anti-cholinesterase effects with atropine and 2-pyridine aldoxime methiodide (2-PAM) were given an oral dose of 250 mg fenitrothion/kg body weight and 3 other hens were given 500 mg/kg. Two of the 500 mg/kg group died within 1-2 days, while the remaining 8 hens did not show any signs of paralysis during the observation period of 6 weeks (Kimmerle, 1962b). Groups of 6 adult White Leghorn hens were given single oral doses of fenitrothion at 250, 500, or 1000 mg/kg body weight. Tri- O-cresyl phosphate (TOCP, 300 mg/kg) was used as a positive control. Toxic signs, which lasted 4-10 days, occurred in all groups. One half of the hens in the middle dosage group and all those in the highest fenitrothion group died within 24-48 h of treatment. No delayed paralysis of the legs occurred in the survivors in any dose group or at any time during the 5-week observation period, while all TOCP dosed animals developed paralysis within 3 weeks. The sciatic nerve in all the surviving hens given fenitrothion was normal (Kadota et al., 1975b). Sixteen adult White Leghorn hens received 500 mg fenitrothion/kg orally and were protected against intoxication by atropine and 2-PAM; this treatment was repeated 3 weeks later. TOCP was used as a positive control. Five hens died 2 days after the first treatment with fenitrothion and none after the second; the survivors showed toxic signs of cholinesterase inhibition. No paralysis was observed and histopathological findings in the sciatic nerves were normal (Kadota et al., 1975b). Groups of 8 adult, White Leghorn hens were given 16.7 or 33.7 mg fenitrothion/kg per day, 6 days/week, over 4 weeks and then observed for another 3 weeks. Slight toxic signs were seen in both groups during the administration period. One hen in the higher dosage group died on the 5th day of dosing. Body weights were decreased in both groups, but the decrease in the lower dosage group was transient. No delayed leg paralysis or histopathological changes in the sciatic nerve or spinal cord were recorded (Kadota et al., 1975b). Table 5. Mutagenicity tests on fenitrothion Tests Strains Dose levels Metabolic Results Reference activation Gene mutation tests Microorganism test E. coli K12 13.2, 132 µg/ml - Suzuki et al. (1974) Coli-phage lambda 13.2, 132 µg/ml - 1847 sus E-h+ S. typhimurium TA1535 10, 100, 1000, + - Suzuki & Miyamoto (1976) 10 000 µg/plate - - TA1537 + - - - TA1538 + - - - S. typhimurium TA98 500,750,1000, + - Kawachi (1978) 2500 µg/plate - - TA100 + + (weakly) - + (weakly) TA1537 + - - - S. typhimurium TA100 < 5000 µg/plate + + Moriya et al. (1983) - + TA98 + - - - Table 5 (contd). Tests Strains Dose levels Metabolic Results Reference activation TA1535 + - - - TA1537 + - - - TA1538 + - - - E. coli + - WP2 hcr - - S. typhimurium TA98 100, 200, 500, 1000, + - Hara et al. (1989) 2000, 5000 µg/plate - - TA1535 + - - - TA1537 + - - - TA100 + + (weakly) - + (weakly) TA100NR + - - - TA100 1,8-DNP6 + + (weakly) - - E. coli WP2uvrA + - - - Table 5 (contd). Tests Strains Dose levels Metabolic Results Reference activation Host-mediated assay ICR mouse S. typhimurium G46 100, 200 mg/kg body - Suzuki & Miyamoto (1976) weight; oral, im/ip (mouse) Mammalian cell test Chinese hamster 0.01, 0.03, 0.1, + - Hara et al. (1989) lung cells V79 0.3 mmol/litre - - DNA-Damage and repair tests Rec-assay B. subtilis up to 20 µlitre + - Shirasu et al. (1979) H17/M45 - - Sister chromatid Human embryonic cells 5 x 10-4 (mol/litre) 2.6 times Kawachi (1978) higher exchange (SCE) HE2144 SCE than control Chinese hamster cells 1 x 10-3 (mol/litre) Don-6 ICR mouse embryo cells 10-5, 5 x 10-5, + - Suzuki & Miyamoto (1980) 10-4 (mol/litre) - - Unscheduled DNA SD rat hepatocyte 300 mg/kg body - Kawamoto et al. (1989) synthesis (UDS) weight, oral) in vivo/in vitro Table 5 (contd). Tests Strains Dose levels Metabolic Results Reference activation Chromosomal aberration tests Chromosomal aberration Wistar rat F2b (male) 80 mg/kg diet - Benes et al. (1975) F3b (male) 80 mg/kg diet - Chinese hamster lung 0.1 mg/ml 21% Kawachi (1978) cells aberration Chinese hamster ovary 0.075, 0.15, 0.3 mg/ml + - Hara et al. (1988) cells-K1 0.003, 0.01, 0.03 mg/ml - - Long-Evans rat 400, 800, 1000 mg/kg + (weakly) Kawachi (1978) body weight, oral; 20, 40 mg/kg body + (weakly) weight, oral, x 5 days ICR mouse (male) 200, 400, 800 mg/kg - Hara & Suzuki (1982a) body weight, ip SD rat (male) 100, 200, 400 mg/kg, - Hara & Suzuki (1982b) oral, 20, 40, 80 mg/kg, - oral, x 5 days Wistar rat (male) 15, 30, 60 mg/kg body - Malhi & Grover (1987) weight, ip, x 5 days Q mouse (male) 1000 mg/kg body - Degraeve et al. (1984) weight, ip Table 5 (contd). Tests Strains Dose levels Metabolic Results Reference activation Micronucleus test ICR mouse (male) 200, 400, 800 mg/kg - Hara & Suzuki (1982c) body weight, ip ddy mouse (male) 200, 400, 800 mg/kg - Hayashi et al. (1988) body weight, ip 100, 300, 600 mg/kg body - weight, ip, x 4 days Wistar rat (male) 75, 165, 330 mg/kg - Grover & Malhi (1985) body weight, ip Dominant lethal test Wistar rat F2b 10, 40, 80 mg/kg diet - Benes et al. (1975) F4b 10, 40, 80 mg/kg diet - ICR mouse 20, 200 mg/kg body - Kohda & Kadota (1975) weight, oral, x 5 days SD rat 2, 7, 20 mg/kg body - weight, oral, x 5 days Q mouse 1000 mg/kg body - Degraeve et al. (1984) weight, ip Others S. cerevisiae 0.3% in DMSO per plate - Yadav et al. (1982) D. melanogaster 50, 150 mg/kg diet - Velazquez et al. (1987) The inhibitory activities of fenitrothion against neuropathy target esterase (neurotoxic esterase, NTE) and acetylcholinesterase (AChE) in the hen (White Leghorn) brain were examined. Oral treatment with 500 mg fenitrothion/kg resulted in significant (80%) inhibition of AChE, but not of NTE (less than 10%) (Ohkawa et al., 1980). The potential of a single, toxic dose of fenitrothion to elicit delayed neurotoxicity in adult White Leghorn hens (5 per group) was compared with the effects produced following similar treatment with the known neurotoxin, tri-O-cresyl phosphate (TOCP). Hens receiving single oral doses of either fenitrothion (500 mg/kg) or TOCP (500 mg/kg) were assessed for toxicity by measuring biochemical (brain and spinal cord AChE and NTE), physiological (motor function) and morphological parameters of the brain, spinal cord, and sciatic nerve 24 h, and 7, 14, 28, 42, and 56 days after treatment. At 24 h, fenitrothion caused a marked inhibition of neuronal AChE. No alteration in NTE activity was found in any fenitrothion-treated hens. A characteristic, central-peripheral, distal axonopathy was observed following treatment with TOCP, mild signs appeared 7-14 days after treatment and increased in severity up to 28 days after treatment, concomitant with morphological changes primarily in the sciatic nerve and spinal cord. Minimal morphological changes were elicited by fenitrothion at this dosage, but the tissues appeared morphologically similar to those seen in vehicle-treated control hens. The results demonstrated that fenitrothion was not neuropathic in the classic manner of TOCP (Durham & Ecobichon, 1986). 7.8 Effects on hepatic enzymes Groups of male and female Wistar rats (4 animals each) were kept on a diet containing fenitrothion at 150 mg/kg or 3-methyl-4-nitrophenol at 500 or 1500 mg/kg, and the effects on hepatic oxidative phosphorylation and mixed function oxidases were studied. Respiratory control ratios of mitochondria were normal, adenosine triphosphatase (ATPase) activity was normal, and no differences were found between the treated and control groups. A slight decrease in the adenosine diphosphate:oxygen ratio was observed in females fed 1500 mg nitrophenol/kg. However, the difference was not regarded as statistically significant. Thus, rat hepatic mitochondrial respiration systems do not seem to be affected by administration of fenitrothion or 3-methyl-4-nitrophenol. Similarly, these chemicals did not affect hepatic microsomal mixed function oxygenase activities (Hosokawa & Miyamoto, 1975). Uchiyama et al. (1975) reported that intraperitoneal injection of 25 mg fenitrothion/kg to male ddY mice inhibited aminopyrine N-demethylation and aniline hydroxylation activities in the liver by about 50%. Yamamoto et al. (1982a) reported that a single oral administration of about 13 mg fenitrothion/kg (5 µmol/rat) or repeated oral administration of about 1.3 mg/kg per day (0.5 µmol/rat per day) for 10 days to 4 or 5 Wistar rats did not affect aminopyrine N-demethylase activity and cytochrome P-450 content, or inhibit the dearylation or desulfuration of fenitrothion. Groups of 5-7 weanling male Wistar rats received 50 mg fenitrothion/kg body weight per day dissolved in peanut oil, by gavage, for 5 consecutive days. Overt signs of toxicity were observed within 30 min of receiving the third dose. Severely affected animals were sacrificed for analysis of tissue esterase activities and insecticide residues and to assess the influence of the insecticide on hepatic microsomal mono-oxygenase activity. Daily treatment was terminated after 5 days and the survivors were sacrificed at intervals to assess the recovery of activity of esterases in the tissues. Fenitrothion caused a significant reduction in liver and body weights, a marked increase in pentobarbital sleeping time, and a marked reduction in hepatic microsomal mono-oxygenase ( p-nitroanisole O-demethylase, aniline hydroxylase) activities. Marked inhibition of plasma pseudocholinesterase, hepatic and renal non-specific carboxyesterase, and erythrocyte and brain acetylcholinesterase occurred. Recovery from 5 such daily doses was slow for all tissue esterases with the exception of plasma cholinesterase, which returned to 78% of control activity values within 5 days. Activities of the other tissue esterases were 20-50% of normal at 5 days, and only 70-90% of normal 16 days after the final dose (Ecobichon & Zelt, 1979). A single oral dose of 250 mg fenitrothion/kg resulted in a slight decrease in a number of biochemical indices of liver function in rats, including mitochondrial ATPase activity, cytochrome P-450 content, aniline hydroxylase activity, and aminopyrine N-demethylase activity (Mihara et al., 1981). A dose of 25 mg/kg also had a slight effect on P-450 content and xenobiotic metabolism, while 5 mg/kg did not have any significant effects. The magnitude of the effects was greater in females than in males. Intraperitoneal doses of 50 or 500 mg fenitrothion/kg, administered to mice, depleted hepatic glutathione levels and inhibited microsomal aniline hydroxylase and paranitroanisole O-demethylase activities (Ginsberg et al., 1982). 7.9 Effects on hormonal balance Osicka-Koprowska et al. (1987) reported a significant elevation in plasma corticosterone levels in rats given a single oral dose or 260 mg fenitrothion/kg. Levels returned to control values within 12 h. Adrenal ascorbic acid content was also significantly decreased between 1 and 5 h after dosing. The authors attributed the changes to hypersecretion of ACTH. After daily dosing with fenitrothion at 13 mg/kg for 14 days, there was no significant difference in circulating corticoseterone levels between the controls and treated animals. There was a significant decrease in 14C derived from injected (ip) 14C-corticosterone in the hypothalamus, adrenals, blood, liver, and muscle, but not in the pituitary gland, at the end of the dosing period and 30 min after injection of the label. 7.10 Toxicity of metabolites and the S-isomer The acute toxicity of fenitrooxon, a metabolite of fenitrothion, is greater than that of the parent compound. 3-Methyl-4-nitro-phenol, another metabolite, is less toxic (Table 6). The intraperitoneal toxicity of fenitrothion metabolites and their related compounds was tested in mice. 3-Hydroxymethyl and 3-formyl derivatives of fenitrothion and fenitrooxon were more toxic than fenitrothion and fenitrooxon, respectively. Fifteen other compounds tested, including aminofenitrothion, demethyl fenitrothion, and demethyl fenitrooxon, were much less toxic than the parent compound (Miyamoto et al., 1978). The acute oral toxicity of the S-methyl-isomer ( O-methyl S-methyl O-(3-methyl-4-nitrophenyl) phosphorothioate) in rats and mice is approximately twice that of fenitrothion (e.g., LD50 in mice: 550 and 1400 mg/kg, respectively) and the signs of poisoning are typical of the muscarinic and nicotinic actions of acetylcholine, as seen with fenitrothion (Kovacicova et al., 1973; Rosival et al., 1974). The S-isomer, when injected intraperitoneally, is 7-9 times more toxic in mice than fenitrothion (Miyamoto, 1977a). The bimolecular inhibition constant of S-methyl fenitrothion on rat brain acetylcholinesterase is about 1000 times greater than that of fenitrothion (Thompson et al., 1989). 7.11 Factors modifying toxicity The best therapy in rats against severe poisoning with a 100% lethal dose of fenitrothion was confirmed to be repeated and combined treatment with atropine and 2-PAM, resulting in a 90% survival ratio and considerable alleviation of toxic signs (Matsubara & Horikoshi, 1983). Table 6. Acute toxicity of metabolites Compound Animal Route LD50 Reference (strain) (mg/kg) Fenitrooxon Mouse oral 90 Miyamoto et al. (1963b); Miyamoto (1969) Mouse oral 120 Hollingworth et al. (1967b) (Swiss White) Rat oral 24 Miyamoto et al. (1963b); Miyamoto (1969) iv 3.3 Miyamoto et al. (1963b); Miyamoto (1969) Guinea-pig oral 221 Miyamoto et al. (1963b); Miyamoto (1969) iv 32 Miyamoto et al. (1963b); Miyamoto (1969) Dog (Beagle) oral > 68.1 Mastalski et al. (1971) Hen oral 35 Kadota et al. (1975b) (White Leghorn) 3-Methyl-4- nitrophenol Rat (Male) (Wistar) oral 2300 Sumitomo (1971) (Female) (Wistar) oral 1200 Sumitomo (1971) Dog (Beagle) oral > 680 Mastalski (1971a) The effects of adrenalectomy (Adx), SKF 525-A, phenobarbital (PB), and diethyl maleate (DEM) on the acute toxicity of fenitrothion were investigated in male Wistar rats. PB administered (ip) at 60 mg/kg per day for 3 days, did not exert any effect on the toxicity of fenitrothion (100 mg/kg) given orally 24 h after the last injection of PB. In adrenalectomized and SKF 525-A-pretreated rats, the toxicity of fenitrothion was lower than in the controls. Fenitrothion toxicity was increased by administration of DEM at (1 ml/kg), which depletes hepatic glutathione (GSH) levels. In in vitro experiments, the rates of fenitrothion decomposition and fenitrooxon formation by microsomes were markedly affected by PB, SKF 525-A, and Adx. The decomposition of fenitrooxon by the microsomal fraction and GSH-dependent decomposition of fenitrooxon by the soluble fraction were not affected by PB, SKF 525-A, and Adx pretreatment. The GSH-dependent decomposition of fenitrothion and fenitrooxon was increased by the addition of GSH to the incubation mixture. It was considered that the GSH-dependent metabolic pathway plays an important role in the detoxification of fenitrothion (Yamamoto et al., 1983a). 7.12 Mechanism of toxicity - mode of action 7.12.1 Mode of action Fenitrothion is not a strong inhibitor of AChE in vitro, but is much more so in vivo. The compound is converted in the animal body to the active esterase inhibitor, fenitrooxon [ O,O-dimethyl O-(3-methyl-4-nitrophenyl)phosphate], by the action of microsomal mixed function monooxygenase in liver and other tissues (Miyamoto et al., 1963b; Miyamoto, 1964a). Plasma ChE is the enzyme most susceptible to acute and short-term administration of fenitrothion in rats, guinea-pigs, dogs, rabbits, and humans (Miyamoto et al., 1963b; FAO/WHO, 1975b). Brain AChE in rabbits is less inhibited by fenitrothion (Miyamoto et al., 1976a). 7.12.2 Selective toxicity Hollingworth et al. (1967a,b) and Hollingworth (1969) concluded that dealkylation was an important factor among the many that contribute to the lower mammalian toxicity of fenitrothion compared with that of methylparathion. For example, the cholinesterase inhibition of fenitrooxon is less, the activation by conversion of P=S to P=O, slower, the translocation of fenitrothion more rapid, and the detoxification rate of fenitrothion, higher. Comparison of metabolites, at equitoxic doses in white mice (i.e., 17 mg methylparathion/kg and 850 mg fenitrothion/kg) showed that demethylation is the major detoxification path for fenitrothion at high doses (200-850 mg/kg), but not for methylparathion. However, inherently, demethylation of both compounds proceeds in a similar way (Miyamoto et al., 1968) and both fenitrothion and methylparathion are metabolized at a similar rate in vivo (Miyamoto, 1964a, 1969). On the basis of these findings, Miyamoto (1969) concluded that the relatively poorer penetration of fenitrooxon into the brain (Miyamoto, 1964b) explained the selectively lower toxicity of fenitrothion rather than the dealkylation detoxification mechanism. Similar conclusions were reached by Kuroiwa & Yamamoto (1977). The mechanisms for the lower toxicity of fenitrothion compared with methylparathion were investigated in male Wistar rats. The difference in acute toxicity between fenitrothion and methylparathion could be because of the more rapid decomposition of fenitrothion and fenitrooxon in rat liver compared with that of methylparathion and methylparaoxon. In particular, the decomposition of fenitrothion by hepatic microsomes was accelerated by increasing the insecticide concentration. The oxygen analogues of both insecticides, fenitrooxon and methylparaxon, were not detected in the brain after administration of the parent compounds. It was considered that the lower toxicity of fenitrothion compared with that of methylparathion could be due to the greater rate of decomposition of fenitrothion to its less toxic metabolites rather than to the different rates of penetration of the oxygen analogues into the brain (Yamamoto et al., 1983b). 7.12.3 Potentiation of toxicity of other chemicals Female rats were administered ip a combination of fenitrothion and parathion, malathion, diazinon, or carbaryl. No potentiation was demonstrated. However, a marked potentiation (increased mortality) was observed when male and female Sprague-Dawley rats were given single oral doses of fenitrothion and phosphamidon. In female rats, potentiation occurred only with mixtures containing relatively low concentrations of fenitrothion (Dubois & Kinoshita, 1963; Braid & Nix, 1968). The effects of a combination of fenitrothion with malathion in male rats were more than additive. The potentiation was most pronounced (half of the expected LD50) with a combination rate of 1:1. No potentiation was observed with other tested organophosphates, i.e., bromophos, amidithion, and trichlorfon (Benes & Cerna, 1970). Hladka et al. (1974) noted that a single dose of a mixture of fenitrothion and malathion caused a significant increase in fenitrooxon but not fenitrothion levels in the blood and muscles of female Wistar rats. Fenitrothion at a subtoxic oral dose (100 mg/kg body weight; 4 h pretreatment or 1000 mg/kg diet for one week) potentiated the acute oral toxicity of 2-sec-butylphenyl methylcarbamate (BPMC) in male ICR mice. Through several in vivo and in vitro studies, it was suggested that competitive inhibition of BPMC metabolism in the liver by fenitrothion played, in part, a role in the inhibition of BPMC detoxication, resulting in the potentiation of its toxicity (Takahashi et al., 1984, 1987; Tsuda et al., 1984). The same effects were investigated in female Beagle dogs. Oral co-administration of fenitrothion (100 mg/kg) doubled the duration of symptoms of BPMC (50 mg/kg) (5 h). The plasma level of BPMC in the eliminating phase was increased by the co-administration and began to decrease after 6 h, while ChE inhibition continued for 8 h. Pretreatment with fenitrothion at 5 mg/kg per day, for 7 days, caused one death in 3 dogs after the administration of BPMC (100 mg/kg), while the same dose of BPMC without pretreatment did not cause any deaths. The pretreatment with fenitrothion increased the duration of the toxic symptoms of BPMC 2.5-fold. The time course of the toxic symptoms was correlated with the plasma concentration of BPMC (Miyaoka et al., 1983). 8. EFFECTS ON MAN 8.1 General population exposure 8.1.1 Acute toxicity Fenitrothion was given to a total of 24 human volunteers in single oral doses of 0.042-0.33 mg/kg body weight or 2.5-20 mg per person. The excretion of a metabolite, 3-methyl-4-nitrophenol, in the urine was almost complete within 24 h, and ranged from about 70% of the dose (0.042 mg/kg) to about 50% (0.33 mg/kg). Neither plasma nor erythrocyte cholinesterase (ChE) activities were depressed below normal, except in one person given 0.33 mg/kg, whose plasma ChE activity was about 65% of the pretest level after 6 and 24 h. When repeated doses of 0.04-0.08 mg/kg were given to 5 individuals, 4 times at 24-h intervals, most of the metabolites appeared in the urine within 12 h of administration. After receiving the third and fourth doses, there was a trend towards a rise in erythrocyte ChE activity (Nosal & Hladka, 1968; Hladka et al., 1977). 8.1.2 Poisoning incidents Several cases of acute fenitrothion poisoning, a few of them lethal, have been described in the literature. These were either accidental, intentional (suicide), or due to gross neglect of safety precautions. A review of these cases is given by Hayes & Lawes (1991). In all cases, the onset of poisoning was rapid, early signs and symptoms being exhaustion, headache, weakness, confusion, vomiting, abdominal pain, excessive sweating, and salivation. The pupils were small. Difficulty in breathing may be experienced, due to either congestion of the lungs or weakness of the respiratory muscles. In severe cases of poisoning, muscle spasms, unconsciousness, and convulsions may develop and death may result from respiratory failure. In atypical cases, symptoms of poisoning may be observed for a more prolonged period and up to 8 months after exposure. It has been suggested that fenitrothion can be stored in human fat tissue and then released under stress conditions (Ecobichon et al., 1977). An attempted suicide using a large quantity of fenitrothion was treated successfully by 2-PAM, atropine, and glutathione with artificial respiration. The case was characterized by delay in the onset of severe signs of intoxication (the 3rd day after hospitalization) and relatively prolonged poisoning (the 70th day after hospitalization), as evidenced by electroencephalogram and inhibition of ChE. It was reported that the patient (56-year-old female) had been suffering from diabetes, which presumably caused delayed biotransformation of fenitrothion to fenitrooxon or delayed absorption of the compound from the intestines, resulting in the delay in the onset of symptoms and prolonged poisoning. However, no evidence leading to this presumption was seen in the study (Tsukimoto et al., 1981). A case of delayed neurotoxicity of late onset has been reported in a 70-year-old female who ingested 40 ml of 50% Fenitrothion EC. At first, no toxic symptoms were apparent. However, 48 h after ingestion, certain signs became apparent. An impediment in consciousness was observed. Fasciculation and muscular weakness were noted, while plasma and urinary levels of 3-methyl-4-nitro-phenol reached a maximum. Neither atropine sulfate nor 2-PAM was effective. For 3 weeks, the patient required ventilatory support, and consequently her muscle strength and neurological status gradually recovered with falling of the phenol level (Sakamoto et al., 1984). The late symptoms reported by Sakamoto et al. (1984) are not those of the organophosphorus ester-induced delayed neurotoxicity (OPIDN) reported for some other organo-phosphorus compounds (Martinez Chuecos & Sole Violan, 1985). A 56-year-old male attempted suicide by the ingestion of about 60 ml of 50% fenitrothion emulsion. Five hours later, combined haemoperfusion and haemodialysis (HP-HD) treatment was performed for 60 min and, subsequently, the symptoms gradually improved. Four days after ingestion, cholinergic symptoms recurred. Immediate HP-HD treatment was of no use and the patient died 6 days after ingestion of fenitrothion. Analysis of the organ and tissue distribution of fenitrothion revealed that the highest concentration of fenitrothion was found in fat (59.0 mg/kg wet weight, more than 10 times the concentrations in other organs). It was suggested that a slow release of the pesticide from adipose tissue can give rise to a protracted clinical course or late symptoms of intoxication (Yoshida et al., 1987). 8.1.3 Contact dermatitis An analysis of 202 patients with contact dermatitis caused by organophosphorus insecticides was undertaken. The organophosphorus insecticides presumably attributing to the dermatitis were dichlorvos, salithion, fenitrothion, leptophos, cyanophos, amidothion, diazinon, and malathion. The dermatitis was located on the fingers, face, forearms, neck and nape. About one quarter (25.2%) of the cases with dermatitis had complications with symptoms of acute poisoning by these compounds. The prognosis of the dermatitis was relatively good; 44.1% of the cases healed but 23.8% of the patients were incompletely cured (Matsushita et al., 1985). 8.1.4 Possible links with Reye's syndrome Concerns have been raised about the possible association between the aerial spraying of forests with fenitrothion formulations and the incidence of Reye's Syndrome, an encephalopathy complicated by hepatic damage, occurring primarily in children up to 18 years of age and linked to viral infections (Reye et al., 1963; Ruben et al., 1976; Corey et al., 1976). Crocker et al. (1976a) reported that patients from a fenitrothion-sprayed area had reduced plasma ChE and erythrocyte AChE activities compared with those in children living in an unsprayed region. However, Pollack et al. (1977) confirmed that, while the serum ChE of Reye's patients was lower, the difference was not significant. No correlation between aerial spraying and the incidence of Reye's Syndrome was established in epidemio-logical studies conducted in New Brunswick, Canada, and Maine, USA (Schneider, 1976; Spitzer, 1982; Wood & Bogdan, 1986). Attention was focused on the potential of various emulsifiers and co-solvents used in oil- and water-based formulations of fenitrothion to enhance virus-induced lethality in neonatal mice or to promote viral growth in cell cultures (Crocker et al., 1974, 1976b). However, in a neonatal animal model, the infection of neonatal mice by influenza virus was not potentiated by any emulsifiers in fenitrothion formulations (Menna, 1985). Similarly, in an in vitro cell culture system, the growth of the virus was not enhanced by co-incubation with various concentrations of fenitrothion, in the presence or absence of a wide range of emulsifiers, co-solvents and diluents, commonly used in aerial spraying formulations (Brookman et al., 1984). 8.2 Occupational exposure In a WHO (1973) programme, 3 different water-dispersible powder formulations of fenitrothion were applied indoors as a residual spray with the aim of depositing 2 g active ingredient/m2 on the wall. The first three rounds of spraying lasted for approximately six, 5-day, working weeks and the fourth round lasted for 8 weeks. A slight to moderate depression of cholinesterase (ChE) activity was observed in most of the spraymen towards the end of the spraying rounds. Except for one case of headache, no other complaints attributable to insecticide exposure were recorded during a total of 2000 man-days of spraying. No complaints were received from the 20 000 inhabitants whose houses had been sprayed repeatedly. However, no ChE activity determinations were performed. During 30-days indoor spraying of fenitrothion (2 g/m2) for malaria control in Southern Iran in August 1971, a group of 28 pest control operators and 925 inhabitants were monitored with respect to their health and ChE activity. Clinical investigations and ChE tests on 840 workers showed 42 cases of clinical symptoms, most of which were very slight and subsided after the workers had showered and rested (2-3 h). Out of 20 spraymen, 8 showed decreased ChE levels, and one individual preparing the spray mixture showed a significant depression of the enzyme activity, which was reactivated after an appropriate treatment. Among 925 inhabitants, only 15 cases of very mild complaints, namely dizziness and nausea, were reported. While fenitrothion was characterized as a pesticide that is safe for the inhabitants in a subtropical region during dry and hot seasons, further investigations were recommended on the toxic effects on operators under tropical conditions (Motabar et al., 1972). In a field spraying operation in a village in southern Nigeria using a 5% spray of fenitrothion, 18 villagers examined one week later did not show any clinical symptoms of toxicity or plasma ChE depression. The ChE levels in the 3 spraymen examined on the first, second, and sixth days after spraying were also not depressed compared with pre-spraying levels (Vandekar, 1965). In another field spraying operation in northern Nigeria, 10 000 huts, in which about 16 500 people lived, were sprayed. Field test ChE determinations on whole blood did not show any appreciable differences in the ChE levels of 535 villagers tested before spraying and 299 villagers tested 5-30 days after spraying. After one week of intensive spraying, 5 out of 20 spraymen developed a 50% depression of ChE, which returned to a stable level after a period of rest. One sprayman developed symptoms of intoxication that lasted only a few hours and disappeared without treatment (Wilford et al., 1965). The health was monitored of workers employed in forest spraying operations using fenitrothion, in New Brunswick, and plasma and erythrocyte ChE activities, measured. There were no instances of ChE activity fluctuating beyond the accepted range or of suspected poisoning resulting from occupational exposure to this insecticide (Braid & McCarthy, 1977). Moderate poisoning of 25 workers was reported in Czechoslovakia (Kalas, 1978; Hayes, 1982), where a formulation containing 50% fenitrothion was applied by aircraft during a strong wind. Onset of poisoning developed 2.5-6 h after inhalation and the symptoms were typical. Whole blood ChE activity was decreased by 48%. Recovery required 3 days of treatment with atropine. In the Haitian malaria control programme, depressed whole blood cholinesterase activity (< 50% of normal) was detected rapidly prior to the development of serious symptoms. Evidence of fenitrothion over-exposure appeared in spraymen early in the first spray cycle, and was associated with faulty protective clothing and failure to follow strictly the recommended safety measures at work. After these deficiencies were corrected, insecticide application continued without serious incidents or interruption of the programme. It was recommended that training and monitoring programmes should be instituted whenever organophosphate pesticides are used as residual sprays for malaria control (Warren et al., 1985a). Similar observations were made in another study undertaken in Pakistan and Haiti (Miller & Shah, 1982). Cholinesterase activity was significantly reduced at the end of the working week in 3 out of 28 fenitrothion workers in Haiti. Urinary levels of 3-methyl-4-nitrophenol in the spraymen ranged from 2.2 to 25.2 mg/litre. In fenitrothion workers who had no direct contact with spraying (weighers and supervisors), the cholinesterase activity remained > 75% of the normal control value, and the urinary 3-methyl-4-nitrophenol levels were relatively low. The cholinesterase levels improved and the urinary excretion of metabolites decreased after 2 days of rest from the spraying operations. In the residents of the sprayed houses, low concentrations of 3-methyl-4-nitrophenol were detected in the urine, 1 day after spraying, and measurable, but reduced, levels were still present after 7 days. In all these cases, the cholinesterase activity remained > 75% of the normal control value (Warren et al., 1985b). In an epidemiological study on the effects of fenitrothion on occupationally exposed male workers in the production department and female workers in the packing room during a 5-year period, the results of clinical examinations pointed to parasympathetic stimulation and disposition to hypotonia. Neurological and psychiatric findings revealed a low-grade pseudoneurasthenic syndrome in 33% of females and in 15% of males. The results of psychodiagnostic tests after exposure to fenitrothion and its intermediate products showed partial deterioration of retention, impairment of visuomotor coordination of movements in tapping, impaired orientation readiness, prolonged average time in decision-making, and prolonged average reaction time for complex sensorimotor responses. The following effects on biochemical parameters after exposure to fenitrothion should be mentioned: inhibition of cholinesterase in the blood, increase of glutamate pyruvate transaminase, increase of isoenzyme lactate dehydro-genase (LDH-5), and changes in protein fractions, all of which were statistically significant (P < 0.001). The values of 3-methyl-4-nitrophenol excreted in the urine of males after the exposure to fenitrothion averaged 5.61 mg/litre, compared with an average value of 1.54 mg 3-methyl-4-nitrophenol/litre before exposure. The average values of 3-methyl-4-nitrophenol excreted in the urine of females involved in bottling fenitrothion were 4.0 mg 3-methyl-4-nitrophenol before exposure and 6.58 mg 3-methyl-4-nitrophenol/litre of urine after exposure. The concentrations of fenitrothion in the air of the workplace ranged from 0.028 to 0.118 mg/m3. From the values of the 3-methyl-4-nitrophenol excreted in the urine of the exposed workers and of volunteers, to whom fenitrothion was administered in doses of 2.5-20 mg, it could be judged that the exposed male workers received approxi-mately 15 mg of fenitrothion per capita a day and the exposed female workers received 20 mg or more per capita a day (Liska et al., 1982). The introduction of the ultra-low-volume application of the organophosphate pesticide fenitrothion in grain terminals presented a risk to workers of skin contact with a high concentration. Blood testing, by the Ellman method, of a group of 5 grain terminal workers engaged in grain treatment showed a lowering of mean erythrocyte cholinesterase activity to 23 units/g Hb (normal value 28-40) with a range of 16-29. The probable cause was identified as percutaneous absorption of fenitrothion through ungloved hands exposed to clean blocked drip feed nozzles. Modification of work practices was followed by a rise of mean erythrocyte ChE activity to 33.6 units/g Hb (range 32-36) during the following grain treatment season. Erythrocyte ChE activity measured during the intervening winter season, i.e., during a non-exposure period, showed a mean of 33.3 units/g Hb (range 23-40) (Gun et al., 1988). 9. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 9.1 Microorganisms and algae Salonius (1972) reported that a 12-month incubation of forest soils with massive doses of fenitrothion emulsion at the rate of 48 mg/pot, equivalent to approximately 112 kg/ha, based on surface area of the soil, did not alter the population or respiration of the soil microflora. No effects of fenitrothion were observed on the growth of 6 species of fungi responsible for the decomposition of organic detritus in streams and swamp water containing 15, 150, or 1500 µg fenitrothion/litre for up to 3 months (Eidt, 1978). In Maine (USA), viable populations of bacteria, yeasts, fungi, and actinomycetes were monitored in forest leaf litter treated with fenitrothion at 1 mg/kg (Spillner et al., 1979a); fenitrothion treatment did not appear to affect microbial populations or respiration in the forest litter. Furthermore, fenitrothion (1 or 5 mg/kg) did not have any effects on cellulose-degrading organisms (Spillner et al., 1979b). Total numbers of bacteria and the nitrification activity in the soil were not affected by a 5-year application of fenitrothion 50% EC diluted 1000 times at 125 ml/m2 (Nishio & Kusano, 1978). No effects on urease and glucanase were observed when fenitrothion was incorporated into silt loam soil at field rates (0.70-2.11 kg a.i./ha) (Burns & Lethbridge, 1981). Mandoul et al. (1968) reported that a concentration of 5 mg fenitrothion/litre did not affect microplankton in a freshwater environment. They stated that 2 applications of fenitrothion at 140 g/ha would not approach 5 mg/litre, even assuming that all of the material reached the lakes or streams. Growth inhibition tests were carried out using 3 species of algae, and EC50 values were determined to be 4-9 mg/litre for diatom and blue-green algae, and more than 100 mg/litre for green algae (Kikuchi et al., 1984) (Table 7). 9.2 Aquatic organisms 9.2.1 Fish Toxicity data of fenitrothion on aquatic non-target organisms are summarized in Table 7. Fenitrothion is moderately toxic for fish species with LC50 values of more than 1 mg/litre. Table 7. Toxicity of fenitrothion for aquatic non-target organismsa Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) Microorganisms Activated sewage sludge 4-h growth EC50 450 22 ± 2 Kwasniewska et al. (1980) sediment soil Algae (Chlorella vulgaris) F growth EC50 100 T 23 ± 2 Kikuchi et al. (1984) (Nitzschia closterium) F growth EC50 3.9 T 23 ± 2 Kikuchi et al. (1984) (Anabaena flos-aquae) F growth EC50 8.6 T 23 ± 2 Kikuchi et al. (1984) Mollusca (Pila globosa) F 30 ± 2 g 72-h LC50 1.2 T 29 ± 2 Madhu et al. (1982) (Phya acuta) F 48-h LC50 15 EC Hashimoto & Nishiuchi (1981) Red snail F 48-h LC50 8.5 EC Hashimoto & Nishiuchi (1981) (Indoplanorbis exustus) Marsh snail F 48-h LC50 6.0 EC Hashimoto & Nishiuchi (1981) (Semisulcospira libertina) Eastern oyster M juvenile 96-h EC50 0.450 T 27 Mayer (1987) (Crassostrea virginica) growth Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) Crustacean Lobster M larva 96-h approx. T 15 Mcleese (1974) 0.001 (Homarus americanus) adult 96-h LC50 approx. T 15 Mcleese (1974) 0.001 Prawn M nauplius 24-h LC50 1.9 T 23-25 Hirayama & Tamanoi (1980) (Penaeus japonicus) postlarva 24-h LC50 0.0005- T 23-25 0.0009 Crab M zoea 24-h LC50 0.005-0.008 T 23-26 Hirayama & Tamanoi (1980) (Portunus trituberculatus) megalopa 24-h LC50 0.0002- T 23-26 0.0005 young 24-h LC50 0.003 T 23-26 Blue crab M 8.5- 96-h LC50 0.0086 T 22 Johnston & Corbett (1985) (Callinectes sapidus) 11.0 cm Brown shrimp M juvenile 96-h LC50 0.0015 T 29 Mayer (1987) (Panaeus aztecus) Water fleas (Daphnia pulex) F adult 3-h LC50 0.050 T 24-26 Hashimoto & Nishiuchi (1981) (Daphnia magna) adult 48-h LC50 0.0086 T 20 ± 2 Forbis (1987) adult/young 21-day MATC 0.00014 T 20 ± 2 Burgess (1988) (Moina macrocopa) F adult 3-h LC50 0.050 T 24-26 Hashimoto & Nishiuchi (1981) Mite (Hydrachna trilobata viets) F 48-h LC50 0.074 T 28 ± 3 Nair (1981) Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) Arthropod Insects Caddisfly larva F 96-h LC50 11 T 5 Symons & Metcalf (1978) (Brachycentrus numberosus) Scud M 96-h LC50 0.01 T 18 Swain & Ivanikiw (1976) (Gammarus pseudolimnaeus) 96-h LC50 0.0043- T 12 Woodward & Mauck (1980) 0.0088 Stonefly naiad (Peleronarcys californica) F 96-h LC50 0.004 T 16 Swain & Ivanikiw (1976) (Pteronarcella badia) 96-h LC50 0.0051- T 12 Woodward & Mauck (1980) 0.0072 Mayfly larva F 9.3 mm, 48-h LC50 0.0032 EC 25 Nishiuchi (1981) (Cloeon dipterum) 5.6 mg Dragon fly larva F 2.3 cm, 48-h LC50 0.055 EC 25 Nishiuchi (1981) (Orthetrum albistylum 0.62 g speciosum) (Sigara substriata) F 5.9 mm, 48-h LC50 0.023 EC 25 Nishiuchi (1981) 6.1 mg (Micronecta sedula) F 3.2 mm, 48-h LC50 0.058 EC 25 Nishiuchi (1981) 1.8 mg (Sympetrum frequens) F 2.1 mm, 48-h LC50 0.050 EC 25 Nishiuchi (1981) (larva) 0.56 g Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) (Eretes sticticus) 1.5 cm, 48-h LC50 0.062 EC 25 Nishiuchi (1981) 0.20 g Amphibian Clawed toad embryo 24-h LC50 10 T 18 Elliott-Feeley & (Xenopus laevis) 24-h EC50 4.2 T 18 Armstrong (1982) 24-h LC50 10 T 25 24-h EC50 0.37 T 25 24-h LC50 0.33 T 30 24-h EC50 0.17 T 30 (Bufo b. japonics) tadpole 48-h LC50 9.0 EC Hashimoto & Nishiuchi (1981) (Microhyla ornatas) embryo 96-h LC50 3.21 T Pawar & Katdare (1984) tadpole 96-h LC50 1.14 T Freshwater fish Carp 5.1 cm 48-h LC50 8.2 T 25 ± 1 Hashimoto & Nishiuchi (1981) (Cyprinus carpio) 7-9 cm 72-h LC50 2.3 50% EC 28- 32 Toor & Kaur (1974) eyed egg 24-h LC50 3.5 EC 25 ± 2 Hashimoto et al. (1982) sac fry 24-h LC50 1.5 EC 25 ± 2 Hashimoto et al. (1982) floating fry 24-h LC50 1.7-4.0 EC 25 ± 2 Hashimoto et al. (1982) 6.0 cm, oral LD50 10 mg/kg T 20 ± 22 Hashimoto & Fukami (1969) 2.5 g Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) Killifish 48-h LC50 7.0 T 25 ± 1 Hashimoto & Nishiuchi (1981) (Oryzias latipes) embryo 96-h LC50 10 T 25 ± 1 Takimoto et al. (1984b) yolk sac 96-h LC50 6.94 T 25 ± 1 Takimoto et al. (1984b) fray postlarva 96-h LC50 2.36 T 25 ± 1 Takimoto et al. (1984b) juvenile 96-h LC50 3.54-4.66 T 25 ± 1 Takimoto et al. (1984b) adult 96-h LC50 3.70 T 25 ± 1 Takimoto et al. (1984b) Rainbow trout fingerling 96-h LC50 2.0 T 15 Klaverkamp et al. (1977) (Salmo gairdneri) 9.2 ± 0.1 cm, 10.35 ± 0.78 g egg/fry 60-days post- 0.12 T 10 ± 1 Cohle (1988) hatch MATC Brook trout 96-h LC50 1.7 T 12 Swain & Ivanikiw (1976) (Salvelinus fontinalis) 96-h LC50 2.1 40% EC 7 Swain & Ivanikiw (1976) 96-h LC50 2.2 40% EC 12 Swain & Ivanikiw (1976) 96-h LC50 1.8 40% EC 17 Swain & Ivanikiw (1976) 15-21 cm No effect on 10 mg/kg T 15 ± 2 Wildish & Lister (1977) (42-120 g) growth food 8.3-12.6 cm Effect on 0.50 T 15 Peterson (1974) critical swimming velocity Cutthroat 118 mm, 20 g 96-h LC50 2.57-2.88 T 12 Woodward & Mauck (1980) (Salmo clarki) 96-h LC50 2.88 87% EC 12 96-h LC50 2.70 87% EC 7 Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) Gold fish 2-3 g, 4-5 24-h LC50 4.5 pure 25 ± 2 Gras (1966) (Carassius auratus) product Goldfish 9-11 cm 48-h LC50 3.4 T 25 Hashimoto & Nishiuchi (1981) (Carassius auratus) threshhold for approx. 0.01 T 15 Scherer (1975) avoidance Eel (Anguilla anguilla) 2 g, 10 cm 24-h LC50 3.2 pure 25 ± Gras (1966) product Gambusia 0.25-0.60 g 24-h LC50 2.6 pure 25 ± Gras (1966) (Gambusia affinis) product Fathead minnow embryo-larva 31 days 0.13-0.30 T 23.8 ± 1 Kleiner et al. (1984) (Pimephales promelas) MATC Pond loach 48-h LC50 4.8 T 25 ± 1 Hashimoto & Nishiuchi (1981) (Misqurnus anquilicaudatus) (Acheilognathus moriokae 5.5-6.0 cm, 72-h LC50 5.0 T 25 Nishiuchi (1977) 1.2-1.4 g (Channa gachua) 116 mm, 18 g 96-h LC50 12.2 50% EC 24 ± 2 Verma et al. (1978a) (Saccobranchus fossilis) 135 mm, 25 g 96-h LC50 12.5 50% EC Verma et al. (1978b) 50-75 mm, 96-h LC50 12.6 50% EC 18 ± 2 Verma et al. (1982) 5-10 g (Mystus cavasius) 6-8 cm 96-h LC50 3.3 T 28 ± 2 Murty et al. (1983) Table 7 (contd). Species Size Parameters Toxicity Formulation Temperature Reference (mg/litre) (°C) (Labeo rohita) 118 mm, 20 g 96-h LC50 4.63 50% EC Verma et al. (1977) 3-4.4 cm 96-h LC50 2.8 T 28 ± 2 Murty et al. (1983) 4.5-5.9 cm 96-h LC50 4.1 T 28 ± 2 Murty et al. (1983) 6-8 cm 96-h LC50 4.6 T 28 ± 2 Murty et al. (1983) (Aplocheilus latipes) 24-h LC50 4.5 T 25 Shim & Self (1973) (Zacco platypus) 24-h LC50 7.4 T 25 Shim & Self (1973) (Puntius ticto) 50-68 mm, 96-h LC50 5.8 50% EC 11-29 Bhatia (1971) 1.6-5.1 g Seawater fish Japanese striped knifejaw egg-prelarva 24-h LC50 2.4-4.2 50% EC 22 ± 0.1 Seikai (1982) (Oplegnathus fasciatus) postlarva 24-h LC50 0.145 50% EC 22 ± 0.1 Seikai (1982) postlarva- 24-h LC50 1.25-2.35 50% EC 22 ± 0.1 Seikai (1982) juvenile Agohaze (Chasmichthus 0.02-0.06 g 96-h LC50 1.1 50% EC 15 Hirose et al. (1979) dolichognathus d.) 96-h LC50 1.7 50% EC 20 Hirose et al. (1979) Sheepshead minnow juvenile 48-h LC50 > 1.0 T 9 Mayer (1987) (Cyprinodon variegatus) 24-h EC50 0.17 T 30 a EC = Emulsifiable concentrate; F = Freshwater; M = Marine; MATC = Maximum Acceptable Toxicant Concentration; NEC = No effect concentration; T = Technical ingredient. In studies on the relative toxicity of fenitrothion in different developmental stages of fish, postlarvae of killifish (Takimoto et al., 1984b), and Japanese striped knifejaw (Seikai, 1982) and the sac fry of carp (Hashimoto et al., 1982) were most susceptible with LC50 values of 2.36, 0.145, and 1.5 mg/litre, respectively. Oral administration of fenitrothion to carp showed a high LD50 value (more than 10 mg/kg) (Hashimoto & Fukami, 1969), whereas the 4-week, no-effect, dietary concentration was 1 mg/kg food (Wildish & Lister, 1973). Ingestion of contaminated, aquatic or terrestrial insects by salmonids is extremely unlikely to cause lethal or sublethal effects in the fish. Behavioural changes did not occur in laboratory studies until brook trout ingested 3000 times more fenitrothion than the 3.19 mg/kg found in poisoned insects in treatment areas (Wildish & Lister, 1973). Exposure of young Atlantic salmon to 0.1 or 1 mg fenitrothion per litre for 15-16 h caused a 20 or 50% reduction in numbers of fish holding territories, respectively. Recovery of the parr from the above effects appeared to be complete in 3 weeks. Feeding and swimming behaviours returned to normal within 24-48 h (Symons, 1973). After exposure to 1.0 mg fenitrothion/litre for 24 h, Atlantic salmon parr were more vulnerable than unexposed fish to predation by large brook trout; fenitrothion at 0.1 mg/litre did not have any noticeable effects on vulnerability (Hatfield & Anderson, 1972). Juvenile Atlantic salmon exposed to 6.7 µg fenitrothion/litre for 7 days showed a decrease in the reaction distance to prey, but no significant decrease in the efficiency of the salmon's attack sequence (Morgan & Kiceniuk, 1990). The movement of goldfish was dependent on the fenitrothion concentration in water, the threshold level being about 0.01 mg/litre (Scherer, 1975). Long-term studies revealed that the no-observed-effect level or maximum acceptable toxicant concentration (MATC) was at 0.1 mg/litre and above 0.1 mg/litre, respectively, in fathead minnows in a 31-day early life stage test (Kleiner et al., 1984) and in guppies in a 2-month reproduction test (Yasuno et al., 1980). Exposure of freshwater murrel ( Channa punctatus) to a subtoxic concentration of 1.5 mg fenitrothion 50% EC/litre resulted in a reduction in protein-bound iodine levels after 60, but not 30, days exposure (Saxena & Mani, 1985a). On day 120 of exposure, effects on male and female reproductive function were observed, such as reductions in testicular and ovarian weight, growth rates of spermatocytes and oocytes, and the numbers of sperm and ova (Mani & Saxena, 1985; Saxena & Mani, 1985b, 1987). However, it is not clear whether such effects were derived from fenitrothion or other EC components. Pregnant female guppies were exposed to 10 mg fenitrothion/litre for 4 h, 5, 10, or 15 days before the next parturition. Half of the females gave premature birth when exposed 5 or 10 days before parturition, and only 32 or 63%, respectively, of the eggs were delivered alive. The females exposed to the fenitrothion 15 days before parturition had normal births and only 9.4% of the offspring were stillborn. The body lengths of the young produced by the females after exposure were significantly shorter than those produced before exposure in all the studies (Yasuno et al., 1980). In a study by Miyashita (1984), exposure of pregnant guppies ( Poecilia reticulata) to 10 mg/litre for 4 h at various stages of gestation resulted in a reduction in the body lengths of the offspring at birth. Rainbow trout ( Salmo gairdneri) were exposed to fenitrothion in a flow-through, early life stage, toxicity study at concentrations of 0, 0.025, 0.046, 0.088, 0.17, or 0.35 mg/litre, for 60-days after hatching at 10 ± 1 °C. Survival and growth of fry showed that the maximum acceptable toxicant concentration (MATC) limits were 0.088-0.17 mg/litre and that the point estimate MATC value was 0.12 mg fenitrothion/litre (Cohle, 1988). There were no direct lethal effects on wild and caged salmonid fish after forest spraying with fenitrothion at dosages varying from double sprays of 140 g/ha to single sprays of up to 280 g/ha in Newfoundland, Canada (Hatfield & Riche, 1970). Studies of the effects on wild salmon of fenitrothion sprays in New Brunswick, Canada, from 1966 to 1969 revealed no mortality in streams at spray levels of up to 560 g/ha (MacDonald & Penney, 1969). Studies in Manitoba, Canada, on stream-caged rainbow trout exposed to a spray of 280 g fenitrothion/ha did not show any significant biochemical changes, including changes in brain and serum ChE activities. In the 24-h period after spraying, fenitrothion residues in whole fish averaged 0.5 mg/kg wet weight. Peak residue values in the fish were as high as 1.84 mg/kg wet weight but declined to less than 0.02 mg/kg wet weight in 4 days. Lockhart et al. (1973) concluded that no long-term toxic effects would be expected among the caged fish. In the 1979 aerial spraying programme in Canada, concentrations of fenitrothion of up to 0.64 µg/litre were detected in stream water in the spray block within 40 h; no insecticide-related deaths of caged fish or abnormal fish behaviour occurred (Gillis, 1980). In 1979, fenitrothion was sprayed on a Scottish forest at a rate of 300 g/ha. The maximum concentration in a river was 18.8 µg per litre, 1-2 h after application. There was no evidence that the resident fish population was disturbed, and no short-term effects were noticeable in caged fish (Morrison & Wells, 1981). Gillis (1978) demonstrated, in a 1977 study, that, in an area with a long history of perennial treatment with fenitrothion (8 years since 1969), there were consistently higher numbers of salmon per 100 m of stream, but that the density of trout was similar to that in the control area. It was concluded that the long history of fenitrothion usage in Canadian forests was unlikely to have resulted in depletion of the population or biomass of salmon parr trout. 9.2.2 Invertebrates The acute toxicity of fenitrothion for Daphnia magna was assessed using the 48-h static method at 20 ± 2 °C. The 48-h LC50 value was 8.6 µg/litre (6.8-11 µg/litre) and the no-observed-effect level was estimated to be < 2.0 µg/litre after 48 h (Forbis, 1987). Daphnia magna was exposed to fenitrothion in a dynamic 21-day, life cycle, toxicity study at concentrations of 0, 0.029, 0.042, 0.087, 0.23, or 0.44 µg/litre, at 20 ± 2 °C. Statistical analyses of survival, adult mean length, and length in days to first brood, showed that the maximum acceptable toxicant concentration (MATC) limits were estimated to be 0.087 and 0.23 µg/litre and the point estimate MATC value was 0.14 µg/litre (Burgess, 1988). Fenitrothion is highly toxic for arthropods, including insect larvae, shrimps, crabs, and daphnids. LC50 values for these invertebrates are generally at µg/litre levels, except that for caddis fly larvae with a value of 11 mg/litre (Table 7). Exposure of the freshwater rice-field crab ( Oziotelphusa senex senex) to sublethal concentrations of fenitrothion showed a number of effects: limb regeneration was completely inhibited at 0.1 mg/litre and partially inhibited at 0.01-0.05 mg/litre, during continuous 60-days exposure (Reddy et al., 1983a); exposure to 0.04 mg/litre for 30 days reduced glycolysis and increased gluco-neogenesis in the hepatopancreas and muscle (Reddy et al., 1982a, 1983b); exposure to 0.1 mg/litre induced inhibition of molting and ovarian growth, perhaps by triggering the release of molt-inhibiting hormone and gonad-inhibiting hormone (Reddy et al., 1982b, 1983c); exposure for 1 day to 0.1 mg/litre produced an increase in muscle protease activity and a decrease in the protein content, while exposure for 20 days resulted in increases in both parameters (Bhagyalakshmi et al., 1983a); continuous exposure for 20-30 days to higher fenitrothion concentrations of 0.5, 1, or 2 mg/litre resulted in a decrease in oxygen consumption, an increase in haemolymph glucose, and a reduction in carbohydrate metabolism rate in the hepatopancreas, with the maximal effect occurring after 3-7 days of exposure. During the exposure, levels of haemolymph glucose and oxygen consumption returned to the control levels, accompanied by an increase in carbohydrate metabolism (Bhagyalakshmi et al., 1983b, 1984a). Exposure to 1, 2, or 4 mg/litre for 48 h resulted in a dose-dependent inhibition of acetylcholinesterase activity of the thoracic ganglionic mass, where mean activity levels in the treated groups ranged from 30 to 60% of the control values. On cessation of exposure, activity levels returned to normal within 10-15 days (Bhagyalakshmi et al., 1984b). Fenitrothion was experimentally added to a stream at a concentration of 10 mg/litre, when the predominant and prevalent species in the drift samples were shrimps ( Anisogammarus sp.), mayfly ( Epeorus ikanonis, and Baetis sp.), stonefly ( Nemovra sp.), and blackfly ( Simulium sp.) larvae. In the course of the study, Simulium sp. increased in density, but Anisogammarus sp. did not recover after 4 months (Yasuno et al., 1981). When fenitrothion was applied at 1 mg/litre to a stream, drifting aquatic invertebrates including shrimp ( Anisogammarus annandalei), Baetis sp., Nemouridae, Epeorus sp., Perla quadrata, and Simulium sp., but not caddis fly larvae (Arctopsyche sp.) or crab ( Geothelephusa dehaanii), were affected by the insecticide (Hasegawa et al., 1982). After treatment of a small lake with 140 g fenitrothion/ha, surface populations of zooplankton and phantom midge larvae (Chaoborus sp.) were depressed for a short period. No substantial impact was found on benthic invertebrates, emerging insects, and amphibians in the lake (Kingsbury, 1978). 9.2.3 Amphibians and arthropods Acute toxicity tests revealed that fenitrothion at 0.1 mg/litre did not induce any significant effects in amphibian embryos ( Xenopus laevis) (Elliott-Feeley & Armstrong, 1982). When the frog embryo (Microhyla ornata), at the yolk-plug stage, was exposed to 1 mg fenitrothion/litre for 96 h, no effects were observed on development. Exposure at 3 mg/litre resulted in blistering of the body surface and exposure at 5 mg/litre or more resulted in abnormal behaviour, curvature of the spine, diminished pigmentation, and retarded growth (Pawar & Katdare, 1983, 1984). The LC50 value for fenitrothion in tadpoles of Bufo buto japonicus was 9.0 mg/litre (Hashimoto & Nishiuchi, 1981). The toxicity of fenitrothion in mollusca was low with LC50 values of 1.2-15 mg/litre in freshwater molluscs and 0.45 mg/litre in eastern oyster (Table 7). Fenitrothion residues in frogs, collected near stagnant water 1 day after spraying (280 g/ha), ranged from 0.03-0.17 mg/kg wet weight (Lockhart et al., 1977). No effects were observed on amphibians and small mammals in Northern Maine, USA, where the forest had been treated twice with fenitrothion at the rate of 140 g/ha (USDA, 1976). Large numbers of hatching salamander eggs were present throughout the treatment period in the silty bottomed pond located in a treatment plot. No deaths were observed up to a week after the second spray. When the pond was examined approximately 2 months after treatment, it still contained many larval salamanders and aquatic invertebrates. A stream was treated with fenitrothion at a calculated concentration of 73 µg/litre for 2.5 h. The standing crop of benthic arthropods decreased, most of the kill consisting of stonefly larvae (Leucta sp.). Benthos, including the stonefly larvae, completely recovered 50 days after the treatment (Eidt, 1981). MacDonald & Penney (1969) studying the effects on aquatic insects of fenitrothion, applied twice at a rate of 140 g/ha, found that the aquatic insect population remained stable. The results of other studies suggested that populations of aquatic insects may be reduced following operational spraying with fenitrothion at 140-280 g/ha (National Research Council of Canada, 1975). Stonefly nymphs, in particular, and mayfly nymphs, to a lesser extent, appeared to be susceptible to fenitrothion, along with caddis fly larvae. Flannagan (1973) reported that within 24 h of spraying at 280 g/ha in Canada, the drift of chironomid larvae increased by 700-800% (total numbers/net). In some instances, Eidt (1975) and Peterson & Zitko (1974) observed that the drift returned to normal shortly after the pulse of fenitrothion had cleared. Fenitrothion was sprayed on a Scottish forest at a rate of 300 g/ha. The maximum concentration in a river within the sprayed region, which was 18.8 µg/litre, fell to 0.5 µg/litre after 24 h. Invertebrate drift increased 12-16 h after spraying, but decreased to pre-spray levels within 48 h. Caged insects remained alive during the 5-day post-spray period (Morrison & Wells, 1981). Levels of fenitrothion residues in stream insects would not be sufficiently high to cause mortality in fish; 3.19 mg fenitrothion per kg was detected in a sample of mayfly nymphs one week after spraying with fenitrothion at 280 g/ha, but no residues of fenitrothion were found after this date (Kingsbury, 1976). An application of fenitrothion at 210 g/ha in Quebec, Canada, in 1978, had few or no adverse effects on aquatic invertebrates or fish, though a small increase in the drift of mayfly nymphs was observed after application (Holmes, 1979). In an area with a long history of perennial fenitrothion spraying (8 years since 1969), a light depletion of the invertebrate population was observed on both drift and benthos in streams after each spray, but the invertebrate density stabilized within 1 month and was comparable with the control (Gillis, 1978). When fenitrothion was dispersed by a helicopter in Japan at a rate of 884 g a.i./ha on a paddy field, a peak concentration of 554 µg/litre was reached immediately after spraying, and the concentration of fenitrothion in the paddy field decreased to less than 5 µg/litre, 3 days after spray. A crustacean Moina sp., which was prevalent in the field, disappeared after fenitrothion spraying, but the population recovered to pre-spray levels within 10 days (Takaku et al., 1979b). 9.3 Terrestrial organisms The acute and short-term toxicities of fenitrothion for terrestrial, non-target organisms are summarized in Table 8. 9.3.1 Terrestrial invertebrates Studies using drop cloths (Leonard, 1971; Kettela & Varty, 1972; Miller et al., 1973) indicated that large numbers of Lepidoptera, sawfly larvae, balsam twig aphids, and perching flies (nematocerous Dipterans, etc.) were killed directly after the spraying operation (140 or 210 g/ha), usually within the first 4 days. Generally, other defoliating insects were reduced in about the same proportion as the target species; the larval sawflies were affected more severely. Various preliminary measurements have been made on the effects of fenitrothion on invertebrate fauna (National Research Council of Canada, 1975). Populations of ground-inhabiting invertebrates declined after two operational applications of 140 and 210 g fenitrothion/ha (Carter & Brown, 1973). The densities of predatory invertebrates were higher in the 2 years before and the year following the application. Thus, while the invertebrate populations appeared to be depressed during the years of application, they were generally able to recover to the normal levels. On the basis of field observations on the long-term effects of fenitrothion on non-target arthropods in Canada, Varty (1977) concluded that: - The non-target arthropod community on balsam fir was not perceptibly destabilized by perennial or intermittent applications at conventional rates (140-210 g/ha) and timing. - A few fir-dwelling insects had become scarcer during the 1970s, but the cause-effect was undetermined, and natural fluctuation could account for the population decline. - The abundance of predators was related primarily to cycles of preabundance on fir and spruce, and to budworm modification of habits. - Herbivore populations tended to be depressed by budworm competition, but fungivores might be favoured. - The abundance of the two most important species parasitizing spruce budworm larvae persisted, in spite of perennial spraying. - Population densities of some species-predatory arthropods in the soil community might suffer some setback, but in short-term studies recuperation seemed adequate. - Minor-pest eruptions in the 1970s did not appear to be triggered by the local disruption of biocontrol mechanisms following spraying. Fenitrothion is highly toxic for bees (Anderson & Atkins, 1968; Okada & Hoshiba, 1970), the LD50 is approximately 0.03-0.13 µg per bee (Anderson & Atkins, 1968) (Table 8). However, studies on the effects of fenitrothion on colonies of honey-bees indicated that an application of 280 g/ha had few long-term effects (National Research Council of Canada, 1975). Initially, mortality of adult foraging bees was evident. Within 4 days of treatment, the daily adult mortality of foraging bees had apparently returned to normal. The total detected mortality in excess of controls was about 500 adult bees, which was estimated to be about 1% of the total hive population. Buckner (National Research Council of Canada, 1975) reported that hive activity was unaffected compared with controls, and that hive weight and eventual honey yield were almost identical in all experimental and control hives. The observed mortality was probably restricted to actively foraging worker bees that were actually exposed to the spray. Table 8. Toxicity of fenitrothion for terrestrial non-target organismsa Species Size Toxicity Formulation Condition Reference Birds Bobwhite quail 14 days old LC50 5000 mg/kg diet T 8-day dietary Hill et al. (1975) (Colinus virginianus) Japanese quail 14 days old LC50 5000 mg/kg T 8-day dietary Hill et al. (1975) (Coturnix c japonica) diet (no mortality) 5 weeks old (M) LD50 84.85 mg/kg 50% EC oral Hattori et al. (1974) 5 weeks old (F) LD50 73.87 mg/kg 50% EC oral Hattori et al. (1974) 3-6 weeks old (M) LD50 110 mg/kg T oral Kadota & Miyamoto (1975) 3-6 weeks old (F) LD50 140 mg/kg T oral Kadota & Miyamoto (1975) 3-6 weeks old NEL approx. 5 mg/kg diet T 4-week dietary Kadota & Miyamoto (1975) Ring-necked pheasant 10 days old LC50 5000 mg/kg T 8-day dietary Hill et al. (1975) (Phasianus colchicus) diet (no mortality) Mallard duck (Anas platyrhynchos) 10 days old LC50 5000 mg/kg T 8-day dietary Hill et al. (1975) diet (no mortality) 13-16 weeks old (M) LD50 1190 mg/kg T oral Hudson et al. (1979) 55-61 weeks old (M) LD50 504 mg/kg T percutaneous Hudson et al. (1979) Redwinged blackbird (Agelaius phoeniceus) LD50 25 mg/kg oral Schafer (1972) Table 8 (contd). Species Size Toxicity Formulation Condition Reference Pigeon 250-380 g LD50 42.24 mg/kg 50% EC oral Hattori (1974) (Columba livia) Grackle (Quiscalus quiscula) LC50 78 mg/kg diet T 5-day dietary Grue (1982) Insect Honeybee 7 days old 24-h LD50 0.13 µg/bee T topical Takeuchi et al. (1980) (Apis mellifera) 32 ± 1 °C 24-h LD50 0.03 µg/bee 50% EC topical Okada & Hoshiba (1970) 32 ± 1 °C LD90 0.25 µg/bee 60% EC oral Clinch & Ross (1970) 30 °C Silkworm II-V instar 24-h LD50 T topical Kashi (1972) (Bombyx mori) 4.88-18.7 µg/g a M = Male; F = Female; T = Technical ingredient; EC = Emulsifiable concentrate. Plowright (1977) demonstrated that fenitrothion, sprayed at a dose level of 210 g/ha, was capable of inducing direct mortality in caged bumble-bees. Aerially sprayed fenitrothion at 210 g/ha in Canada caused 100% mortality in exposed habitats and 47% under dense forest canopy, among caged bees (Bombus sp). Bumble bees foraging in sprayed areas suffered significantly higher mortality than in unsprayed areas. The abundance of bee species was 3 times less in sprayed areas compared with unsprayed areas. Population recovery appeared to be complete within a few years (Plowright et al., 1978). Plowright & Rodd (1980) further examined the effects of fenitrothion in wild bees, and found that fenitrothion sprayed at 210 g/ha caused high mortality among solitary bees and vespid wasps, similar to that in bumble bees (Plowright et al., 1978). Wood (1979) found that spraying of fenitrothion over nearby woodland resulted in very low counts of native bees; however, the population returned to normal levels within 3 years of spraying, with satisfactory pollination of blueberry. Wild Bombus sp. queen territories were identified prior to treatment and a search was made for these queens after the application of fenitrothion (280 g/ha) in Larose Forest, Canada. Queens identified prior to a morning spray were again identified 1, 2, and 3 days after treatment. In this single study, no significant effects were indicated (National Research Council of Canada, 1975). The low yield of low-bush blueberry was reported to be attributable to the mortality of native bees (Kevan, 1975) and lack of pollination following aerial fenitrothion spraying to control spruce budworm in nearby forests in New Brunswick. However, field experiments in 1980 showed that there was no evidence of any harmful effects on the blueberry as a result of fenitrothion spraying and that the concentration of fenitrothion aerosols found in blueberry fields during the 1980 budworm spray programme was estimated to be well below the toxic levels for all bee species (Wood, 1980). Bee, pollen, and wax samples were collected from forest areas that had been sprayed with fenitrothion for budworm control at an operational dosage of 140-280 g/ha, over a 3-year period from 1972. The level of fenitrothion in bees was low (maximum 2.08 mg/kg) initially, and decreased rapidly to trace levels within a week. Fenitrothion levels in pollen were very low initially, but declined less rapidly than in bees. Accumulations of the insecticide in honey and wax samples were negligibly small, but traces seemed to persist in the wax for some time (Sundaram, 1975). Fenitrothion is toxic for one of the beneficial insects, silkworm ( Bombyx mori) larvae. Silkworms were fed mulberry leaves that had been treated with fenitrothion at the rate of 100 ml of 0.0025 or 0.005% fenitrothion solution /kg leaves (equivalent to 2.5 and 5 mg/kg). The administration during the 5 instar larva stage resulted in a reduction in the number of eggs laid, fertility, and hatching (Kuribayashi, 1981). At a lower concentration (1 mg/kg), no effect was observed on mortality, egg laying, and hatching (Yamanoi, 1980). Growth after hatching was not affected by fenitrothion treatment (Yamanoi, 1981). The populations of nematodes, rotifers, and tardigrades in soil were not affected after fenitrothion was sprayed on the surface of a pasture at a rate of 2.24 kg a.i./ha (Martin & Yeates, 1975). 9.3.2 Birds The acute oral LD50 values of fenitrothion in birds are shown in Table 8. The values range from 25 mg/kg (Redwinged blackbird) to 1190 mg/kg (Mallard duck). Except for the grackle with a dietary LD50 of 78 mg/kg, values were generally more than 5000 mg/kg diet and, at this dose level, no mortality was observed (Hill et al., 1975). The effects of fenitrothion on the brain cholinergic system were investigated in male Japanese quail (8-14 weeks old). Cholinergic signs, such as salivation and convulsions in legs and wings, were seen 6-120 min after the administration of fenitrothion (250-350 mg/kg). Sixty minutes after an oral dose of fenitrothion (300 mg/kg), free acetylcholine increased and acetylcholinesterase (AChE) activity decreased to 20% of the control value. In vitro, fenitrothion inhibited AChE activity in brain homogenate with an I50 of 10-5 mol/litre (Kobayashi et al., 1983). Japanese quail (60 per sex; 20 per sex in the 1.5 mg/kg group) received 0, 1.5, 5, 15, or 50 mg fenitrothion/kg in the diet for 4 weeks. No animals died and no toxic signs were seen; no abnormalities in body weight or food consumption were observed. A dose-related decrease in blood ChE activity was observed in females in the 5 mg/kg group (25%), and in males and females in the 15 mg/kg (60%) and 50 mg/kg (85%) groups during the treat-ment period. When these animals were fed the control diet again, partial recovery of ChE activity occurred within 2 weeks, while the brain ChE activity was reduced in females in the 15 mg/kg group (25%) and males and females in the 50 mg/kg group (65%). Full recovery of ChE activity occurred after 4 weeks. In the 50 mg/kg group, the egg-laying rate was decreased, but returned to normal after 3 weeks (Kadota & Miyamoto, 1975). Reproduction studies on bobwhite quails and mallard ducks revealed that short-term feeding of fenitrothion at rates of up to 10 mg/kg diet (quails) or 100 mg/kg diet (ducks) did not adversely affect parental growth and reactions, egg production, egg weight, hatchability, and the growth and viability of the young (Miyamoto, 1977b). Adverse effects on bird species were observed occasionally when fenitrothion was applied at dosages higher than those commonly used for operational applications (National Research Council of Canada, 1975); above 280 g/ha, mortality was observed in adults that inhabited the crown canopy, and, at rates of 560 g/ha or more, adult mortality increased markedly. At rates of 210 or 280 g/ha, behavioural changes were observed in adults as well as some juvenile mortality. When fenitrothion was sprayed at 1.7 kg a.i./ha, twice a year, for three consecutive years in Japan, Takano & Hijikata (1981) were unable to detect impacts on bird diversity, abundance, and reproductive success, when 9 species (including the long-tailed tit, which is most sensitive to fenitrothion) out of 48 were monitored in the forests and fields (55 ha). The various effects of fenitrothion on White-throated Sparrows in New Brunswick, Canada, were investigated, with the following results (Pearce & Busby, 1980): - The parent compound fenitrothion was detected at levels as low as 0.02 to 0.41 mg/kg in the male birds from the spray zone, but none of its metabolites were found. There were no correlations between fenitrothion residue levels and brain ChE activity in sparrows. - Singing frequency, song structure, clutch size, hatching success, and fledging rates were similar in the control and experimental area. - Growth parameters, such as body weight, tarsus length, bill length and width, and wing length, of the nestling birds appeared to be lower in the exposed nestlings than in the controls after fenitrothion spraying at a rate of 210 g a.i./ha. - The reproductive success was reduced in the exposed area after repeated spraying of fenitrothion, first at 420 g/ha and several days later at 210 g/ha. The young White-throated Sparrows from 11.6% of the eggs laid fledged in the sprayed area, whereas the young from 58.3% of the eggs laid fledged in the control area. - The main causes of reduced productivity in the sprayed area were the high rate of nest desertion, the occasional death or incapacitation of incubating females, and the high rate of nestling disappearance from nests. Eight hours after being exposed to an operational spray of fenitrothion at 280 g/ha, the crops and carcasses of caged Japanese quail contained 0.045-0.459 mg fenitrothion/kg (wet tissue basis), when cages were placed in open locations, and the crops, up to 1.89 mg/kg, when the cages were placed below the tree canopy (Lockhart et al., 1977). However, fenitrothion residues in all samples declined sharply to an undetectable level (< 0.02 mg/kg) after 5 days. Although these birds suffered a drop in serum ChE activity, they were not killed and recovery of enzyme activity was observed 5 days after spraying (Lockhart et al., 1977). Experimental fenitrothion spraying at the rate of 210-280 g a.i./ha was conducted using 2 types of spray hardware (boom and nozzle and rotary atomizer) in southwest New Brunswick, Canada. The brain ChE activity of the 5 avian species monitored (Tennessee Warbler ( Vermivora peregrina), Magnolia Warbler ( Dendroica magnolia), Blackburnian Warbler ( D. fusca), Bay-breasted Warbler ( D. castanea), and White-throated Sparrow ( Zonotrichia albicollis)) was significantly inhibited compared with that in the control birds, and 16-30% of the captive birds showed more than 20% inhibition compared with the controls. However, no dead birds or abnormal avian behaviour was observed (Busby et al., 1981). Brain cholinesterase (ChE) inhibition and fenitrothion residues were determined in White-throated Sparrows ( Zonotrichia albicollis), exposed to aerial applications of fenitrothion (210 g a.i./ha applied twice with a 5-8 day interval) during the breeding seasons in 1978 and 1979, in New Brunswick (Canada). Brain ChE activity was significantly reduced in birds exposed to the sprays (50-66% inhibition) and fenitrothion and metabolite residues were detected in all exposed birds (0.08-1.4 mg/kg); however, they did not show any consistent correlation with brain ChE activity. An acute brain ChE response, manifested as sudden ChE reduction followed by gradual recovery, was noted in birds collected after spraying with 420 g a.i./ha (Busby et al., 1983). A study was conducted to assess the response of selected forest songbird species, including the Tennessee Warbler ( Vermivora peregrina), Bay-breasted Warbler ( Dendroica castanea), Magnolia Warbler ( D. magnolia), and White-throated Sparrow ( Zonotrichia albicollis), to aerial ultra ULV fenitrothion (40% content) spraying (210 g a.i./ha applied twice with a 6-day interval) through measurements of brain cholinesterase (ChE) depression. A slight reduction (6-17% less brain ChE activity than in the controls) was observed in birds collected on day 2 after the second spray; birds collected on day 1 of the first spray were least affected (0-5% less activity). As a group, the Tennessee Warbler, the upper canopy forager and singer, exhibited the highest degree of ChE inhibition (6-17% less activity) and the White-throated Sparrow, the ground-to-low crown dweller, showed the least (0-8%) inhibition (Busby et al., 1987). Brain AchE activity in songbirds exposed through experimental fenitrothion spraying was monitored in Scotland in 1979 and 1980 (Hamilton et al., 1981). The brain ChE activity of songbirds was significantly inhibited in the first 2 days after spraying of fenitrothion at dosages of 300 g/ha in 1979 and 280 g/ha in 1980. However, the enzyme activity in willow warblers ( Phylloscopus trochilus) and chaffinches ( Fringilla coelebs) returned to the normal levels, 7 and 21 days after spraying, respectively. The residues of fenitrothion found in skin and plumage samples taken from birds during the first few days after spraying were relatively high, but declined rapidly to a low level. The fenitrothion residues in viscera samples were very small initially and were not detectable a few days after spraying (Hamilton et al., 1981). Several publications concerning the possible effects of fenitrothion on avian species including: Rushmore (1971), Hill et al. (1975), National Research Council of Canada (1975), Paul & Vadlamudi (1976), USDA (1976), Buckner & McLeod (1977), Germain (1977), Pearce & Peakall (1977), Germain & Morin (1979), and Pearce et al. (1979b) are not cited in extenso, because they report findings similar to those above. 9.3.3 Mammals Bailey & Swift (1968) classified fenitrothion as moderately toxic for mammals. Buckner reported that, at operational application rates below 420 g/ha, fenitrothion spraying did not produce any measurable effects on small mammals in Maine (USA). Spraying of fenitrothion at recommended rates would not be expected to cause mortality or interrupt the breeding cycle of small mammal populations in forests (Buckner & Sarrazin, 1975; Varty, 1976; Buckner et al., 1977) though, at very high rates, some ill effects have been observed on shrew and rodent populations (USDA, 1976). In addition, the discriminatory behaviour of mature animals suggested that fenitrothion-contaminated food material was rejected and that it was a learned process (Buckner et al., 1977). When fenitrothion was sprayed twice a year, at the rate of 1200 g/ha, by helicopter, there was no decrease in either plasma or erythrocyte ChE activity in the Japanese wood mouse ( Apodemus speciosus) inhabiting the sprayed area (Tabata & Kitahara, 1980). The metabolism of fenitrothion in red-backed voles, which inhabit the coniferous forests of Canada, did not differ substantially from that demonstrated for laboratory strains of mice, rats and guinea-pigs. When fenitrothion was administered ip at doses of 48.4-2040 mg/kg, it was rapidly metabolized and excreted. No accumulation of fenitrothion residues in the body was indicated. The metabolic detoxification mechanism in red-backed voles involves the cleavage of both the P-O-aryl and P-O-alkyl bonds, the latter being more prominent at high dose levels (above 1250 mg/kg) (Tschaplinski & Gardner, 1981). Thus, the standard programme of forest spraying with the insecticide does not appear to have serious ecological consequences (Symons, 1977). 10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES Fenitrothion was evaluated by the Joint FAO/WHO Expert Committee on Pesticide Residues (JMPR) in 1969, 1974, 1976, 1977, 1979, 1982, 1983, 1984, 1986, 1987, 1988, and 1989, (FAO/WHO, 1970, 1975a,b, 1977, 1978a,b, 1980a,b, 1983a,b, 1984a,b, 1985a,b, 1986a,b, 1987a,b, 1988a,b, 1989a,b,c). In 1988 the JMPR established an Acceptable Daily Intake (ADI) for man of 0-0.005 mg/kg body weight. This was based on the following levels causing no toxicological effects: - Rat: 10 mg/kg in the diet, equivalent to 0.5 mg/kg body weight per day (based on brain acetylcholinesterase inhibition and reproduction). - Dog: 50 mg/kg in the diet, equivalent to 1.25 mg/kg body weight per day. - Man: 0.08 mg/kg body weight per day (highest dose tested). The FAO/WHO Codex Committee advised maximum residue limits (MRLs) in specified food commodities (FAO/WHO, 1986c; 1990) as follows: Milks 0.002 mg/kg Cucumbers, meat, onions, potatoes 0.05 mg/kg Cauliflower, cocoa beans, egg plants, peppers, soybeans (dry) 0.1 mg/kg Bread (white), leeks, radishes 0.2 mg/kg Apples, cabbage, cabbage red, cherries, grapes, lettuce, pear, peas, strawberries tea (dried, green), tomatoes 0.5 mg/kg Peach, rice (polished) 1 mg/kg Citrus fruits, wheat flour (white) processed wheat bran 2 mg/kg Wheat flour (whole meal) 5 mg/kg Cereal grains 10 mg/kg Raw wheat bran, rice bran unprocessed 20 mg/kg WHO (1990) classified technical fenitrothion as "moderately hazardous" (Class II). WHO issued a data sheet on Fenitrothion (No. 30) (WHO, 1977). REFERENCES ABDEL-KADER, M.H.K. & WEBSTER, G.R.B. (1980) Low temperature degradation and translocation of malathion and fenitrothion in stored wheat. Can. Plant. Proc., 9: 143-153. ABDEL-KADER, M.H.K. & WEBSTER, G.R.B. 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YAMAMOTO, T., EGASHIRA, T., YOSHIDA, T., & KUROIWA, Y. (1982a) Comparison of the effect of an equimolar and low dose of fenitrothion and methylparathion on their own metabolism in rat liver. J. toxicol. Sci., 7: 35-41. YAMAMOTO, T., EGASHIRA, T., YOSHIDA, T., & KUROIWA, Y. (1982b) Increase of adrenal weight in rats by the repeated administration of fenitrothion. Toxicol. Lett., 11: 187-191. YAMAMOTO, T., EGASHIRA, T., YOSHIDA, T., & KUROIWA, Y. (1983a) Effect of adrenalectomy, pretreatment with SKF 525-A, phenobarbital and diethyl-maleate on the acute toxicity of fenitrothion in male rats. Arch. Toxicol., 52: 233-242. YAMAMOTO, T., EGASHIRA, T., YOSHIDA, T., & KUROIWA, Y. (1983b) Comparative metabolism of fenitrothion and methylparathion in male rats. Acta pharmacol. toxicol., 53: 96-102. YAMANOI, F. (1980) [Effect of insecticides on the progeny in the silkworm, Bombyx mori. I. Effect of organophosphorus insecticides on egg laying and their hatching.] J. Sericult. Sci. Jpn, 49: 434-439 (in Japanese). YAMANOI, F. (1981) [Effect of insecticides on the progeny in the silkworm, Bombyx mori. II. Effect of organophosphorus insecticides on the next generation.] J. Sericult. Sci. Jpn, 50: 83-87 (in Japanese). YASUNO, M., HATAKEYAMA, S., & MIYASHITA, M. (1980) Effect on reproduction in Guppy (Poecilia reticulata) under chronic exposure to temephos and fenitrothion. Bull. environ. Contam. Toxicol., 25: 29-33. YASUNO, M., OKITA, J., SAITO, K., NAKAMURA, Y., HATAKEYAMA, S., & KASUGA, S. (1981) Effect of fenitrothion on benethic fauna in small stream of Mt. Tsukuba, Japan. Jpn. J. Ecol., 31: 237-245. YOSHIDA, M., SHIMADA, E., YAMANAKA, H., AOYAMA, Y., YAMAMURA, Y., & OWADA, S. (1987) A case of acute poisoning with fenitrothion (Sumithion). Hum. Toxicol., 6: 403-406. YULE, W.N. (1974) The persistence and fate of fenitrothion insecticide in a forest environment II. Accumulation of residues in balsam fir foliage. Bull. environ. Contam. Toxicol., 12: 249-252. YULE, W.N. & DUFFY, J.R. (1972) The persistence and fate of fenitrothion insecticide in a forest environment. Bull. environ. Contam. Toxicol., 8: 10-18. ANNEX I TREATMENT OF ORGANOPHOSPHATE INSECTICIDE POISONING IN MAN (From EHC 63: Organophosphorus Insecticides - A General Introduction) All cases of organophosphorus poisoning should be dealt with as an emergency and the patient sent to hospital as quickly as possible. Although symptoms may develop rapidly, delay in onset or a steady increase in severity may be seen up to 48 h after ingestion of some formulated organophosphorus insecticides. Extensive descriptions of treatment of poisoning by organophosphorus insecticides are given in several major references (Kagan, 1977; Taylor, 1980; UK DHSS, 1983; Plestina, 1984) and will also be included in the IPCS Health and Safety Guides to be prepared for selected organophosphorus insecticides. The treatment is based on: (a) minimizing the absorption; (b) general supportive treatment; and (c) specific pharmacological treatment. 1.1 Minimizing the absorption When dermal exposure occurs, decontamination procedures include removal of contaminated clothes and washing of the skin with alkaline soap or with a sodium bicarbonate solution. Particular care should be taken in cleaning the skin area where venepuncture is performed. Blood might be contaminated with direct-acting organophosphorus esters and, therefore, inaccurate measures of ChE inhibition might result. Extensive eye irrigation with water or saline should also be performed. In the case of ingestion, vomiting might be induced, if the patient is conscious, by the administration of ipecacuanha syrup (10-30 ml) followed by 200 ml water. This treatment is, however, contraindicated in the case of pesticides dissolved in hydrocarbon solvents. Gastric lavage (with addition of bicarbonate solution or activated charcoal) can also be performed, particularly in unconscious patients, taking care to prevent aspiration of fluids into the lungs (i.e., only after a tracheal tube has been put into place). The volume of fluid introduced into the stomach should be recorded and samples of gastric lavage frozen and stored for subsequent chemical analysis. If the formulation of the pesticide involved is available, it should also be stored for further analysis (i.e., detection of toxicologically relevant impurities). A purgative can be administered to remove the ingested compound. 1.2 General supportive treatment Artificial respiration (via a tracheal tube) should be started at the first sign of respiratory failure and maintained for as long as necessary. Cautious administration of fluids is advised, as well as general supportive and symptomatic pharmacological treatment and absolute rest. 1.3 Specific pharmacological treatment 1.3.1 Atropine Atropine should be given, beginning with 2 mg iv and given at 15-30-min intervals. The dose and the frequency of atropine treatment varies from case to case, but should maintain the patient fully atropinized (dilated pupils, dry mouth, skin flushing, etc.). Continuous infusion of atropine may be necessary in extreme cases and total daily doses up to several hundred mg may be necessary during the first few days of treatment. 1.3.2 Oxime reactivators Cholinesterase reactivators (e.g., pralidoxime, obidoxime) specifically restore AChE activity inhibited by organophosphates. This is not the case with enzymes inhibited by carbamates. The treatment should begin as soon as possible, because oximes are not effective on "aged" phosphorylated ChEs. However, if absorption, distribution, and metabolism are thought to be delayed for any reasons, oximes can be administered for several days after intoxication. Effective treatment with oximes reduces the required dose of atropine. Pralidoxime is the most widely available oxime. A dose of 1 g pralidoxime can be given either im or iv and repeated 2-3 times per day or, in extreme cases, more often. If possible, blood samples should be taken for AChE determinations before and during treatment. Skin should be carefully cleansed before sampling. Results of the assays should influence the decision whether to continue oxime therapy after the first 2 days. There are indications that oxime therapy may possibly have beneficial effects on CNS-derived symptoms. 1.3.3 Diazepam Diazepam should be included in the therapy of all but the mildest cases. Besides relieving anxiety, it appears to counteract some aspects of CNS-derived symptoms that are not affected by atropine. Doses of 10 mg sc or iv are appropriate and may be repeated as required (Vale & Scott, 1974). Other centrally acting drugs and drugs that may depress respiration are not recommended in the absence of artificial respiration procedures. 1.3.4 Notes on the recommended treatment 220.127.116.11 Effects of atropine and oxime The combined effect far exceeds the benefit of either drug singly. 18.104.22.168 Response to atropine The response of the eye pupil may be unreliable in cases of organophosphorus poisoning. A flushed skin and drying of secretions are the best guide to the effectiveness of atropinization. Although repeated dosing may well be necessary, excessive doses at any one time may cause toxic side-effects. Pulse-rate should not exceed 120/min. 22.214.171.124 Persistence of treatment Some organophosphorus pesticides are very lipophilic and may be taken into, and then released from, fat depots over a period of many days. It is therefore quite incorrect to abandon oxime treatment after 1-2 days on the supposition that all inhibited enzyme will be aged. Ecobichon et al. (1977) noted prompt improvement in both condition and blood-ChEs in response to pralidoxime given on the 11th-15th days after major symptoms of poisoning appeared due to extended exposure to fenitrothion (a dimethyl phosphate with a short half-life for aging of inhibited AChE). 126.96.36.199 Dosage of atropine and oxime The recommended doses above pertain to exposures, usual for an occupational setting, but, in the case of very severe exposure or massive ingestion (accidental or deliberate), the therapeutic doses may be extended considerably. Warriner et al. (1977) reported the case of a patient who drank a large quantity of dicrotophos, in error, while drunk. Therapeutic dosages were progressively increased up to 6 mg atropine iv every 15 min together with continuous iv infusion of pralidoxime chloride at 0.5 g/h for 72 h, from days 3 to 6 after intoxication. After considerable improvement, the patient relapsed and further aggressive therapy was given at a declining rate from days 10 to 16 (atropine) and to day 23 (oxime), respectively. In total, 92 g of pralidoxime chloride and 3912 mg of atropine were given and the patient was discharged on the thirty-third day with no apparent sequelae. REFERENCES TO ANNEX I ECOBICHON, D.J., OZERE, R.L., REID, E., & CROCKER, J.F.S (1977) Acute fenitrothion poisoning. Can. Med. Assoc. J., 116: 377-379. KAGAN, JU.S. (1977) [Toxicology of organophosphorus pesticides], Moscow, Meditsina, pp. 111-121, 219-233, 260-269 (in Russian). PLESTINA, R. (1984) Prevention, diagnosis, and treatment of insecticide poisoning, Geneva, World Health Organization (Unpublished document VBC/84.889). TAYLOR, P. (1980) Anticholinesterase agents. In: Goodman, L.S. & Gilman, A., ed. The pharmacological basis of therapeutics, 6th ed., New York, Macmillan Publishing Company, pp. 100-119. UK DHSS (1983) Pesticide poisoning: notes for the guidance of medical practitioners, London, United Kingdom Department of Health and Social Security, pp. 41-47. VALE, J.A. & SCOTT, G.W. (1974) Organophosphorus poisoning. Guy's Hosp. Rep., 123: 13-25. WARRINER, R.A., III, NIES, A.S., & HAYES, W.J., Jr (1977) Severe organophosphate poisoning complicated by alcohol and terpentine ingestion. Arch. environ. Health, 32: 203-205. ANNEX II. No-observed-effect levels in plasma, red blood cells, and brain ChE, in animals treated with fenitrothion ANNEX II. No-observed-effect levels in plasma, red blood cells, and brain ChE, in animals treated with fenitrothion Study/Dosage No-observed-effect levels in mg/kg body weight per day and in (mg/kg diet)a Sex Plasma Red blood cells Brain Reference I F I F I F Rat 30 days male 2.5 2.5 2.5 2.5 < 2.5 < 2.5 Trottier et al. (1980) Gavage 0, 2.5, 5.0, 10.0, female 2.5 2.5 2.5 2.5 < 2.5 < 2.5 20.0 (mg/kg body weight) Rat 5 weeksb male - - - 0.25 - 0.5 Carshalton (1964) 0, 5, 10, 20 mg/kg diet (5) (10) Rat 90 daysb male 3.2 3.2 < 1.6 3.2 3.2 12.5 Misu et al. (1966) 0, 32, 63, 125, 250, 500 (63) (63) (< 32) (63) (63) (250) mg/kg diet Rat 90 days male - < 1.7 - < 1.7 - - Cooper (1966) 0, 20, 92.8, 430.7, 2000 (< 20) (< 20) mg/kg diet female < 1.9 < 1.9 - - (< 20) - (< 20) Rat 90 days male - < 1.2 - 1.2 - - Cooper (1966) 0, 10, 46.4, 215, 1000 (< 10) (< 10) (mg/litre water) female - < 1.3 - 1.3 - - (< 10) (< 10) Rat 6 months male - 1.8 - 1.8 - 1.8 Sumitomo Chem. Co. 0, 10, 30, 150 mg/kg diet (30) (30) (30) (1972) female - < 0.64 - 0.64 - 0.64 (< 10) (< 10) (10) Annex II (contd). Study/Dosage No-observed-effect levels in mg/kg body weight per day and in (mg/kg diet)a Sex Plasma Red blood cells Brain Reference I F I F I F Rat 34 weeksb male 0.25 0.25 < 0.25 < 0.25 - 6.3 Benes & Cerna (1970) 0, 10, 50, 150 (5) (5) (< 5) (< 5) (125) 0, 5, 25, 125 mg/kg diet female < 0.25 < 0.25 < 0.25 < 0.25 - 6.3 (< 5) (< 5) (< 5) (< 5) (125) Rat 63 weeksb male - < 1.25 - 1.25 - 1.25 Ueda & Nishimura (1966) 0, 25, 100, 400 mg/kg diet (< 25) (25) (25) Rat 1 year male 1.0 1.0 1.0 1.0 1.0 1.0 Ecobichon et al. (1980) Gavage 0, 0.5, 1, 5, 10 (mg/kg body weight) Rat 1 yearb male > 1.25 > 1.25 0.25 > 1.25 0.05 > 1.25 Kanoh et al. (1982) 0, 1, 5, 25 mg/kg diet (> 25) (> 25) (5) (> 25) (1) (> 25) female > 1.25 > 1.25 0.25 > 1.25 0.25 > 1.25 (> 25) (> 25) (5) (> 25) (5) (> 25) Rat 30 days male - 20 - 20 - 20 Breckenridge et al. (1982) by inhalation 0, 6.7, female - < 6.7 - 20 - < 6.7 20, 60 (mg/m3) Rat 92 weeksb male 0.13 > 0.5 0.25 > 0.5 - > 0.5 Kadota et al. (1975a) 0, 2.5, 5, 10 mg/kg diet (2.5) (> 10) (5) (> 10) (> 10) female 0.13 > 0.5 0.25 > 0.5 - > 0.5 (2.5) (> 10) (5) (> 10) (> 10) Annex II (contd). Study/Dosage No-observed-effect levels in mg/kg body weight per day and in (mg/kg diet)a Sex Plasma Red blood cells Brain Reference I F I F I F Rat 2 yearsb male < 0.5 < 0.5 0.5 0.5 0.5 1.5 Rutter & Nelson (1974) 0, 10, 30, 100 mg/kg diet (< 10) (< 10) (10) (10) (10) (30) female < 0.5 < 0.5 0.5 0.5 0.5 1.5 (< 10) (< 10) (10) (10) (10) (30) Mouse 2 yearsb male 0.43 0.43 1.43 1.43 1.43 1.43 Tamano et al. (1990) 0, 3, 10, 100, 1000 (3) (3) (10) (10) (10) (10) mg/kg diet female 0.43 0.43 1.43 1.43 1.43 1.43 (3) (3) (10) (10) (10) (10) Dog 98 days oral by male/ 2 - 2 - - - Cooper (1966) capsule 0, 2, 9, 40 (mg/kg body weight) Dog 1 yearb male 0.25 0.25 0.25 0.25 > 1.25 > 1.25 Griggs et al. (1984) 0.5, 10, 50 mg/kg diet (10) (10) (10) (10) (> 50) (> 50) female 0.25 0.25 > 1.25 > 1.25 > 1.25 > 1.25 (10) (10) (> 50) (> 50) (> 50) (> 50) Dog 10 months male - < 5 - < 5 - - Tomita et al. (1974) oral by capsule 0, 5 (mg/kg body weight) Dog 1 year female - < 2 - < 2 - - Ogata (1972) oral by capsule 0, 2 (mg/kg body weight) Annex II (contd). Study/Dosage No-observed-effect levels in mg/kg body weight per day and in (mg/kg diet)a Sex Plasma Red blood cells Brain Reference I F I F I F Dog 2 yearb male < 0.75 < 0.75 0.75 0.75 - 2.5 Mastalski et al. (1973) 0, 30, 100, 200 mg/kg diet (< 30) (< 30) (30) (30) (100) female < 0.75 < 0.75 0.75 0.75 - 2.5 (< 30) (< 30) (30) (30) (100) Rabbit 6 months male - <3 - < 3 - 3 Miyamoto et al. (1976a) in diet, 0, 3, 10 (mg/kg body weight) a I = Interim sacrifice; F = Final sacrifice. b Calculated by dietary concentration providing that 1 mg/kg body weight per day equals 20, 7, and 40 mg/kg in rats, mice, and dogs, respectively. RESUME ET EVALUATION, CONCLUSIONS ET RECOMMANDATIONS 1. Résumé et évaluation 1.1 Exposition Le fénitrothion est un insecticide organophosphoré utilisé depuis 1959. On l'emploie en agriculture pour détruire les insectes qui s'attaquent au riz, aux céréales, aux fruits, aux légumes, aux céréales ensilées et au coton. On l'emploie également pour la désinsectisation des forêts ainsi que pour la destruction des mouches, des moustiques et des blattes dans le cadre des programmes de santé publique. Il se présente sous la forme de concentrés émulsionnables, de concentrés à très bas volume, de poudres, de granulés, de poudres pour poudrage, de bouillies huileuses ainsi qu'en association avec d'autres pesticides. La production de fénitrothion oscille entre 15 000 et 20 000 tonnes par an. Le fénitrothion pénètre dans l'air par volatilisation à partir des surfaces contaminées et peut être entraîné pendant l'épandage au-delà de la zone à traiter. Dans la plupart des terrains, il n'est éliminé que très lentement par lessivage, néanmoins une certaine quantité peut être entraînée par les eaux de ruissellement. Le fénitrothion est décomposé par photolyse et hydrolyse. En présence de rayonnement UV ou de lumière solaire, la demi-vie du fénitrothion dans l'eau est inférieure à 24 heures. La présence d'une microflore peut également accélérer la décomposition. En l'absence de lumière solaire ou de contamination microbienne, le fénitrothion est stable dans l'eau. Dans le sol, il est essentiellement dégradé par voie biologique, encore que la photolyse puisse jouer un certain rôle. La concentration du fénitrothion dans l'air peut atteindre 5 µg/m3 immédiatement après l'épandage mais elle est susceptible de diminuer fortement au cours du temps et en fonction de la distance au lieu d'épandage. Dans l'eau, la concentration peut atteindre 20 µg/litre mais elle diminue rapidement. En cas d'exposition continue, on observe des facteurs de bioconcentration qui se situent entre 20 à 450 chez un certain nombre d'espèces aquatiques. Les résidus de fénitrothion dans les fruits, les légumes et les céréales peuvent aller de 0,001 à 9,5 mg/kg immédiatement après le traitement mais ils diminuent rapidement, leur demi-vie étant de 1 à 2 jours. 1.2 Fixation, métabolisme et excrétion Le fénitrothion est rapidement résorbé dans les voies digestives et se répartit ensuite dans les divers tissus. La demi-vie du fénitrothion après absorption percutanée chez le singe a été estimée à 15-17 heures. Sa métabolisation s'effectue selon les grandes voies d' O-déméthylation ainsi que par clivage de la liaison P-O-aryle. Le groupement NO2 est réduit par la microflore intestinale, mais seulement chez les ruminants. La principale voie d'élimination est la voie urinaire, la plupart des métabolites étant excrétés en l'espace de 2 à 4 jours chez le rat, le cobaye, la souris et le chien. Les principaux métabolites observés sont le déméthyl- fénitrothion, le déméthyl-fénitrooxon, l'acide diméthylphosphoro-thioïque et l'acide diméthylphosphorique ainsi que le 3-méthyl-4-nitrophénol et ses conjugués. Les différences qui ont été observées dans la composition en métabolites entre la plupart des animaux de laboratoire et entre les sexes, chez une même espèce, semblent être essentiellement d'ordre quantitatif. Seul le lapin semble excréter du fénitrooxon et de l'aminofénitrooxon en quantités faibles mais néanmoins mesurables, par la voie urinaire. Des études portant sur des lapins et des chiens montrent que le fénitrothion se dépose préférentiellement dans les tissus adipeux. Des résidus qui avaient été décelés dans le lait de vache après exposition à du fénitrothion ont disparu dans les deux jours. Même s'il est rapidement résorbé après administration orale, le fénitrothion est métabolisé et excrété sans délai et il est peu probable qu'il demeure dans l'organisme pendant une longue période. 1.3 Effets sur les êtres vivants dans leur milieu naturel A la concentration où on le rencontre vraisemblablement dans l'environnement, le fénitrothion n'a aucun effet sur les microorganismes présents dans le sol ou dans les eaux. Il est extrêmement toxique pour les invertébrés aquatiques d'eau douce ou d'eau de mer, la CL50 étant de l'ordre de quelques µg/litre pour la plupart des espèces étudiées. La dose sans effet observable pour la daphnie, lors d'épreuves à 48 heures, s'est révélée < 2 µg/litre; lors de tests portant sur la totalité du cycle évolutif, on a fixé à 0,14 µg/litre la concentration maximum acceptable de produit toxique. Les observations et études effectuées sur le terrain dans des étangs expérimentaux ont révélé l'existence d'effets sur les populations d'invertébrés. Toutefois, la plupart d'entre eux étaient passagers, même à des concentrations beaucoup plus élevées que celles auxquelles donne vraisemblablement lieu l'emploi de fénitrothion conformément aux recommandations. Les poissons sont moins sensibles au fénitrothion que les invertébrés, les valeurs de la CL50 à 96 heures dans leur cas allant de 1,7 à 10 mg/litre. Ce sont les jeunes larves qui constituent le stade le plus sensible. Des études à long terme ont fixé à 0,1 mg/litre ou plus la concentration maximale admissible de produit toxique pour deux espèces de poissons d'eau douce. Une étude écologique effectuée après l'épandage de fénitrothion sur des forêts a montré qu'il n'en résultait aucun effet sur les populations sauvages de poissons ou sur la survie des poissons d'expérience placés dans des nasses, les concentrations de fénitrothion dans l'eau allant jusqu'à 0,019 mg/litre. Des épandages répétés de fénitrothion sur des forêts n'ont eu aucun effet sur les poissons. Lors d'essais en laboratoire, on a constaté que la CL50 pour les mollusques dulçaquicoles allait de 1,2 à 15 mg/litre. Aucun effet écologique n'a été constaté après épandage sur des forêts à la dose de 140 g/hectare. Le fénitrothion est extrêmement toxique pour les abeilles (DL50 topique comprise entre 0,03 et 0,04 µg/abeille). Des effets écologiques ont été observés qui consistaient essentiellement en une mortalité localement élevée chez les abeilles et d'autres espèces. Toutefois cette mortalité ne représentait qu'un faible pourcentage de la population totale des ruches. Pour les oiseaux, les valeurs de la DL50 aiguë par voie orale vont de 25 à 1190 mg/kg de poids corporel et, dans la plupart des cas, la CL50 alimentaire à huit jours dépasse 5000 mg/kg de nourriture. Les valeurs de la dose sans effet observable sur la reproduction sont de 10 mg/kg de poids corporel pour la caille et de 100 mg/kg pour le malard. Après épandage de fénitrothion à la dose de 280 g/hectare, on a observé une mortalité parmi les oiseaux chanteurs, mortalité qui augmentait sensiblement chez les espèces peuplant la canopée lorsque la dose était portée à 500 g/hectare. Après épandage à des doses de 420 g/hectare puis de 210 g/hectare quelques jours plus tard, le nombre de nichées de pinsons à gorge blanche (Zonotrichia albicollis) a diminué. Dans de nombreuses études, on a constaté, chez les oiseaux chanteurs, une inhibition de la cholinestérase peu après l'épandage de fénitrothion dans les forêts. L'observation sur le terrain n'a pas révélé d'effets sur les populations de petits mammifères sauvages. 1.4 Effets sur les animaux d'expérience et les systèmes d'épreuve in vitro Le fénitrothion est un organophosphoré qui réduit l'activité de la cholinestérase plasmatique, érythrocytaire, cérébrale et hépatique. Il est métabolisé en fénitrooxon, composé dont la toxicité aiguë est encore plus élevée. La toxicité du fénitrothion peut être potentialisée par un certain nombre d'organophosphorés. Le fénitrothion est un insecticide modérément toxique dont la DL50 par voie orale chez le rat et la souris va de 330 à 1416 mg/kg de poids corporel. Sa toxicité aiguë par voie dermique chez les rongeurs varie de 890 mg/kg de poids corporel à plus de 2500 mg/kg. Le fénitrothion n'est que très peu irritant pour les yeux et n'irrite pas la peau. Deux études portant sur des cobayes ont fait ressortir une certaine tendance à la sensibilisation cutanée. Le fénitrothion a fait l'objet d'études à court terme sur des rats, des chiens, des cobayes, des lapins ainsi que d'études de cancérogénicité à long terme chez des rats et des souris. Les études à court terme sur les rats et les chiens ont permis de fixer respectivement à 10 mg/kg de nourriture et 50 mg/kg de nourriture la dose sans effet nocif observable, d'après l'activité de la cholinestérase cérébrale. Les études à long terme sur le rat et la souris ont donné une dose sans effet nocif observable, basée sur l'activité de la cholinestérase cérébrale, de 10 mg/kg de nourriture. Aucune des études à long terme signalées n'a mis en évidence d'effets cancérogènes. Le fénitrothion ne s'est pas révélé mutagène dans les études in vitro et in vivo. A des doses allant jusqu'à 30 mg/kg de poids corporel chez le lapin et jusqu'à 25 mg/kg de poids corporel chez le rat, le fénitrothion n'a pas produit d'effets tératogènes. Lorsque la dose dépassait 8 mg/kg de poids corporel, le fénitrothion était toxique pour la mère. Après exposition in utero, on a observé des déficits comportementaux après la naissance chez des ratons en cours de développement. La dose sans effet observable sur le comportement a été fixée à 5 mg/kg de poids corporel et par jour. Des études de reproduction portant sur plusieurs générations de rats n'ont pas fait ressortir d'effets morphologiques. Ces études ont permis de fixer à 120 mg/kg de nourriture, d'après les paramètres génésiques, la dose sans effet nocif observable. On a fait état d'une neurotoxicité retardée après exposition au fénitrothion. 1.5 Effets sur l'homme Administré à des volontaires humains en dose orale unique de 0,042 à 0,33 mg/kg de poids corporel puis en doses répétées de 0,04 à 0,08 mg/kg, le fénitrothion n'a pas entraîné d'inhibition de la cholinestérase plasmatique ou érythrocytaire. Un des métabolites, le 3-méthyl-4-nitrophénol, a été totalement excrété par voie urinaire dans les 24 heures. Plusieurs cas d'intoxication se sont produits. La symptomatologie de l'intoxication par le fénitrothion est celle d'une stimulation du parasympathique. Il est arrivé que les manifestations toxiques n'apparaissent pas immédiatement mais récidivent pendant quelques mois. On a avancé que l'allongement de la durée de l'évolution clinique de l'intoxication et l'apparition de symptômes tardifs pouvaient s'expliquer par une libération lente de l'insecticide à partir du tissu adipeux. Certaines dermatites de contact ont été attribuées à une exposition à l'insecticide. Rien n'indique qu'une exposition au fénitrothion puisse entraîner une neurotoxicité retardée ou l'apparition d'un syndrome de Reye. Dans le cadre des programmes de l'OMS, on utilise du fénitrothion dans quelques pays pour la lutte antipaludique en pulvérisation à effet rémanent à l'intérieur des habitations (dose d'emploi: 2,0 gr de matière active par m2). Des observations portant sur plusieurs milliers de résidents n'ont fait ressortir aucun signe de toxicité à l'exception d'une enquête au cours de laquelle 2% des personnes enquêtées se sont plaintes de légers symptômes. Toutefois, chez environ 25% des ouvriers pulvériseurs, on a observé une inhibition à 50% de l'activité de la cholinestérase du sang total. Après épandage par voie aérienne d'un concentré émulsionnable à 50%, on a constaté chez un certain nombre de travailleurs des symptômes d'intoxication accompagnés d'une réduction de l'activité cholinestérasique du sang total en l'espace de 48 heures. Des ouvriers et des ouvrières exposés de par leur profession pendant cinq ans à du fénitrothion respectivement dans un atelier de production et dans une unité de conditionnement ont présenté, pour 15% d'entre eux et 33% d'entre elles, des symptômes cliniques d'intoxication. La concentration de fénitrothion dans l'air des lieux de travail variait entre 0,028 et 0,118 mg/m3. 2. Conclusions * Le fénitrothion est un insecticide organophosphoré modéré- ment toxique. Toutefois, en cas d'exposition excessive résultant de manipulations au cours de la production ou de l'épandage ou encore par suite d'une ingestion accidentelle ou intentionnelle, il peut s'ensuivre une grave intoxication. * L'exposition de la population générale, qui résulte principalement de l'emploi du fénitrothion en agriculture, en foresterie et dans les programmes de santé publique, ne devrait pas présenter de danger pour la santé. * Moyennant de bonnes pratiques de fabrication et le respect des mesures d'hygiène et de sécurité, le fénitrothion ne devrait pas présenter de danger pour les personnes qui y sont exposées de par leur profession. * Malgré sa forte toxicité pour les arthropodes non visés, le fénitrothion est utilisé très largement comme pesticide avec des effets indésirables minimaux sur les populations animales présentes dans l'environnement. 3. Recommandations * Afin de préserver la santé et le bien-être des travailleurs et de la population générale, il importe de ne confier la manipulation et l'épandage du fénitrothion qu'à des personnes expérimentées qui prendront les mesures de sécurité nécessaires et procéderont à l'épandage en respectant les règles de bonne pratique. * Les opérations de production, de formulation, d'épandage et d'élimination du fénitrothion doivent être effectuées avec tout le soin nécessaire pour réduire au minimum la contamination de l'environnement, et notamment des eaux de surface. * Les travailleurs habituellement exposés doivent subir un examen médical périodique. * La dose d'emploi du fénitrothion doit être limitée afin d'éviter tout effet sur les arthropodes non visés. L'insecticide ne doit jamais être épandu sur des étendues ou cours d'eau. RESUMEN Y EVALUACION, CONCLUSIONES Y RECOMENDACIONES 1. Resumen y evaluación 1.1 Exposición El fenitrotión es un insecticida organofosforado que se viene utilizando desde 1959. Se emplea en la agricultura para combatir los insectos del arroz, los cereales, las frutas, las hortalizas, el grano almacenado y el algodón. Se usa también para luchar contra insectos en los bosques, y en programas de salud pública para combatir moscas, mosquitos y cucarachas. Se ha formulado como concentrado emulsionable, concentrados de volumen muy bajo, microgránulos, gránulos, polvo, pulverizadores oleosos y en combinación con otros plaguicidas. Cada año se fabrican entre 15 000 y 20 000 toneladas. El fenitrotión se incorpora al aire por volatilización a partir de superficies contaminadas y puede ser arrastrado fuera de la zona de tratamiento durante el rociamiento. Su lixiviación es muy lenta en la mayoría de los suelos, pero es previsible que se produzca algún arrastre en el agua. Se degrada por fotólisis e hidrólisis. En presencia de la radiación ultravioleta o de la luz solar, la semivida del fenitrotión en el agua es inferior a 24 horas. La presencia de microflora también puede acelerar la degradación. En ausencia de luz solar o de contaminación microbiana, es estable en el agua. En el suelo, la vía principal de eliminación es la biodegradación, aunque la fotólisis también puede influir. Las concentraciones de fenitrotión en el aire pueden ser de hasta 5 µg/m3 inmediatamente después del rociamiento, pero decrecen de manera considerable con el tiempo y la distancia del lugar de aplicación. Los niveles en el agua pueden alcanzar valores de hasta 20 µg/litro, pero disminuyen con rapidez. Los factores de bioconcentración calculados en varias especies acuáticas sometidas a una exposición constante al fenitrotión varían entre 20 y 450. Sus niveles residuales en frutas, hortalizas y grano de cereales oscilan entre 0,001 y 9,5 mg/kg inmediatamente después del tratamiento, pero decrecen rápidamente, con una semivida de 1 a 2 días. 1.2 Ingestión, metabolismo y excreción El fenitrotión se absorbe con rapidez del tracto intestinal de los animales de experimentación y se distribuye a diversos tejidos corporales. La semivida en el caso de la absorción cutánea en el mono fue de 15 a 17 horas. Se ha demostrado que su metabolismo se realiza a través de las principales vías de demetilación oxidativa y por rotura del enlace P-O-arilo. Los microorganismos intestinales reducen, sólo en los rumiantes, el grupo nitrogenado del fenitrotión. La principal vía de excreción es la orina; la mayor parte de los metabolitos se eliminan en un periodo de 2 a 4 días en el caso de la rata, el cobayo, el ratón y el perro. Los principales metabolitos detectados son el demetilfenitrotión, el demetilfenitrooxón, el ácido dimetilfosforotioico, el ácido dimetilfosfórico y el 3-metil-4-nitrofenol y sus conjugados. Las diferencias en la composición de los metabolitos que se detectan en la mayor parte de los animales de laboratorio y entre los dos sexos de la misma especie parecen ser principalmente de carácter cuantitativo. Sólo los conejos parecen excretar fenitrooxón y aminofenitrooxón en cantidades pequeñas, pero cuantificables, con la orina. En estudios realizados en conejos y perros se ha puesto de manifiesto que el fenitrotión se deposita preferentemente en el tejido adiposo. Los residuos encontrados en la leche de vaca tras la exposición no se detectaban dos días más tarde. Aunque el fenitrotión se absorbe rápidamente por vía oral, se metaboliza y excreta con rapidez y no es probable que permanezca en el organismo durante un tiempo prolongado. 1.3 Efectos en los seres vivos del medio ambiente La concentraciones normales de fenitrotión en el medio ambiente no tienen efecto alguno en los microorganismos del suelo o del agua. El fenitrotión es muy tóxico para los invertebrados acuáticos de agua dulce y salada; los valores de la CL50 son de pocos µg/litro en la mayoría de las especies analizadas. El nivel sin efectos observados (NOEL) determinado en Daphnia en pruebas de 48 horas fue < 2 µg/litro; en pruebas del ciclo biológico se estableció una concentración tóxica aceptable máxima (MATC) de 0,14 µg/litro. Las observaciones y los estudios sobre el terreno en estanques experimentales han puesto de manifiesto ciertos efectos en las poblaciones de invertebrados, si bien la mayor parte de los cambios observados fueron transitorios, incluso con concentraciones muy superiores a las que cabe esperar tras el uso recomendado. Los peces son menos sensibles al fenitrotión que los invertebrados y muestran valores de la CL50 a las 96 horas que oscilan entre 1,7 y 10 mg/litro. La fase más sensible del ciclo biológico es la larva joven. En estudios prolongados se ha establecido una MATC igual o superior a 0,1 mg/litro para dos especies de peces de agua dulce. Los estudios sobre el terreno tras la aplicación de fenitrotión a bosques no demostraron efecto alguno en las poblaciones silvestres de peces ni en la supervivencia de peces de experimentación en vivero, con concentraciones medidas en el agua de 0,019 mg/litro. La aplicación repetida en bosques no tuvo efectos en las poblaciones de peces. En pruebas de laboratorio, los valores de la CL50 para moluscos de agua dulce oscilaban entre 1,2 y 15 mg/litro. No se observaron efectos sobre el terreno tras rociar bosques con 140 g/ha. El fenitrotión es muy tóxico para las abejas (DL50 tópica, 0,03-0,04 µg/abeja). Se han comunicado efectos sobre el terreno, con un elevado número de abejas de la miel y de otras especies muertas en la zona de aplicación. Sin embargo, el número total de individuos muertos representaba solamente un pequeño porcentaje de la población de las colmenas. Los valores de la DL50 en la toxicidad aguda por vía oral en las aves oscilan entre 25 y 1190 mg/kg de peso corporal, y en la mayor parte de las dietas de ocho días las CL50 excedieron de 5000 mg/kg de la dieta. Los valores del NOEL para la reproducción fueron de 10 mg/kg de peso corporal en la codorniz y de 100 mg/kg de peso corporal en el pato silvestre. Poco después de aplicar fenitrotión en una concentración de 280 g/ha, se observaron muertes de pájaros cantores y la mortalidad aumentó considerablemente con 560 g/ha para las especies que vivían en las copas de los árboles del bosque. Después de rociar con una concentración de 420 g/ha y unos días más tarde con 210 g/ha, se redujo la reproducción de la especie zonotrichia albicollis. En muchos estudios, los pájaros cantores mostraron inhibición de la colinesterasa inmediatamente después de rociar los bosques con fenitrotión. Las observaciones sobre el terreno no han puesto de manifiesto efecto alguno del fenitrotión en las poblaciones de pequeños mamíferos silvestres. 1.4 Efectos en los animales de experimentación y en sistemas de prueba in vitro El fenitrotión es un organofosfato y reduce la actividad de la colinesterasa en el plasma, los eritrocitos y los tejidos cerebral y hepático. Se metaboliza a fenitrooxón, con mayor toxicidad aguda. Otros compuestos organofosfatados pueden potenciar aún más la toxicidad del fenitrotión. El fenitrotión es un insecticida de toxicidad moderada, con valores de la DL50 por vía oral que oscilan entre 330 y 1416 mg/kg de peso corporal en ratas y ratones. La toxicidad aguda cutánea en roedores varió desde 890 mg/kg hasta más de 2500 mg/kg de peso corporal. El fenitrotión apenas irrita los ojos y no irrita la piel. En uno de los dos estudios realizados en cobayos, el producto mostró cierto potencial de sensibilización dérmica. Se ha ensayado el fenitrotión en estudios de corta duración en ratas, perros, cobayos y conejos y en estudios prolongados de carcinogenicidad en ratas y ratones. En los estudios de corta duración realizados en ratas y perros los niveles sin efectos adversos observados (NOAEL), basados en la actividad de la colinesterasa cerebral, fueron, respectivamente, de 10 mg/kg y 50 mg/kg de la dieta. Los estudios de larga duración en ratas y ratones pusieron de manifiesto un NOAEL (basado en la actividad de la colinesterasa cerebral) de 10 mg/kg de la dieta. No se han encontrado efectos carcinogénicos en ninguno de los estudios de larga duración que se han publicado. En los estudios in vitro e in vivo, el fenitrotión no mostró efectos mutagénicos. No se han detectado efectos teratogénicos con dosis de fenitrotión de hasta 30 mg/kg de peso corporal en conejos y de hasta 25 mg/kg de peso corporal en ratas. Las dosis superiores a 8 mg/kg de peso corporal produjeron toxicidad materna. Las ratas jóvenes en fase de crecimiento presentaron problemas de comportamiento postnatal tras la exposición in utero. Para este efecto se estableció un NOEL de 5 mg/kg de peso corporal al día. En estudios multigeneracionales de reproducción en ratas no se detectó ningún efecto morfológico. En estos estudios se puso de manifiesto un NOAEL de 120 mg/kg de la dieta, basado en parámetros de la reproducción. No se ha informado de neurotoxicidad retardada como consecuencia de la exposición al fenitrotión. 1.5 Efectos en el ser humano La administración de fenitrotión en una dosis oral única de 0,042 a 0,33 mg/kg de peso corporal y en dosis repetidas de 0,04 a 0,08 mg/kg de peso corporal en voluntarios humanos no causó la inhibición de la colinesterasa del plasma y los eritrocitos. La excreción urinaria del metabolito 3-metil-4-nitrofenol fue completa en 24 horas. Se han registrado varios casos de intoxicación, con los signos y síntomas característicos de la estimulación parasimpática. En algunos casos, las manifestaciones tóxicas tardaron en aparecer y se repitieron durante unos meses. Se ha sugerido que la liberación lenta del insecticida a partir del tejido adiposo puede dar lugar a un curso clínico prolongado o a síntomas tardíos de intoxicación. En algunos casos, la dermatitis de contacto se ha atribuido a la exposición al insecticida. No hay pruebas de neurotoxicidad tardía ni de relación con el síndrome de Reye. El fenitrotión se ha utilizado en algunos países en programas de la OMS para el rociamiento residual de interiores en la lucha contra el paludismo (dosis de aplicación: 2,0 g de principio activo/m2). No se apreciaron indicios de toxicidad en los miles de habitantes observados, a excepción de un estudio en el que se presentaron trastornos leves en menos del 2% de los habitantes. Sin embargo, alrededor del 25% de los encargados del rociamiento mostraron una inhibición de hasta el 50% de la actividad de la colinesterasa en sangre total. En las 48 horas posteriores a la aplicación aérea de una fórmula de concentrado emulsionable al 50%, algunos trabajadores mostraron síntomas de intoxicación y una disminución de la actividad de la colinesterasa en sangre total. En una fábrica de producción, la exposición profesional durante más de 5 años de los trabajadores varones y de las mujeres del departamento de envasado produjo signos clínicos y síntomas de intoxicación en el 15% de los hombres y en el 33% de las mujeres. La concentración de fenitrotión medida en el aire del lugar de trabajo oscilaba entre 0,028 y 0,118 mg/m3. 2. Conclusiones * El insecticida fenitrotión es un éster organofosforado moderadamente tóxico. Sin embargo, la exposición excesiva durante su fabricación o uso y la ingestión accidental o intencional pueden ocasionar una intoxicación grave. * La exposición de la población general, debida fundamentalmente a las prácticas agrícolas y forestales y a los programas de salud pública, no representa en principio amenaza alguna para la salud. * Con buenas prácticas de trabajo, medidas higiénicas y precauciones de seguridad no es probable que el fenitrotión represente un riesgo para las personas sujetas a exposición profesional. * A pesar de su elevada toxicidad para los artrópodos no destinatarios, el fenitrotión se ha utilizado ampliamente en la lucha contra las plagas, con pocos efectos adversos o ninguno en las poblaciones presentes en el medio ambiente. 3. Recomendaciones * Para salvaguardar la salud y el bienestar de los trabajadores y de la población general, el manejo y la aplicación del fenitrotión sólo se deben encomendar bajo una atenta supervisión a personas bien capacitadas que se ajusten a las medidas de seguridad adecuadas y utilicen el fenitrotión correctamente. * Se cuidarán especialmente la fabricación, la formulación, el uso y la eliminación del compuesto, a fin de reducir al mínimo la contaminación del medio ambiente, en particular de las aguas superficiales. * Los trabajadores regularmente expuestos deben someterse a revisiones médicas periódicas. * Se ha de limitar el número de aplicaciones de fenitrotión, para evitar los efectos en artrópodos no destinatarios. No se deben rociar jamás con este insecticida masas o corrientes de agua.
See Also: Fenitrothion (PDS) Fenitrothion (PIM 659)