PESTICIDE RESIDUES IN FOOD - 1980 Sponsored jointly by FAO and WHO EVALUATIONS 1980 Joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues Rome, 6-15 October 1980 FENTHION Explanation Fenthion was reviewed for an ADI by the Joint Meeting in 1971, 1975, 1977 and 1978 (FAO/WHO, 1972, 1976; FAO, 1978, 1979). A temporary ADI was estimated to be 0-0.0005 mg/kg bw based on an extensive series of short-term studies and human exposure data showing cholinesterase depression to be the most significant parameter of exposure and effect. Previous Meetings have expressed concern over the lack of long-term studies and on the prolonged effects of cholinesterase depression noted in animals and man. The Meetings have requested long-term toxicology data and ancillary data to evaluate the safety of food residues from agricultural use and to assure that an ADI could be estimated. Additional studies have been received that allow a complete evaluation of fenthion to be made. For this reason, the pertinent toxicological data reviewed by previous Meetings and the new data are all included in this complete monograph. DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, distribution, and excretion The first studies on mammals (rats) were reported by Brady and Arthur (1961), who use a 32P-labelled compound. Within a few hours of applying the compound, large amounts of 32P-activity was found in the tissues including the bones, evidence that fenthion was rapidly absorbed, translocated, and degraded by rats. Neither fenthion nor its oxidative metabolites were stored in tissues even when rats received daily doses of 10 mg/kg bw by the intraperitoneal route for 10 consecutive days. At 1.5 hours, following a single i.p. injection of 200 mg/kg, the following acetonitrile-soluble residues were observed: liver 29.5 mg/kg muscle 9.6 mg/kg skin 6.1 mg/kg kidney 16.9 mg/kg heart 9.6 mg/kg Most tissues from rats treated orally with 100 mg/kg (single dose) contained less than 0.01 mg/kg chloroform-soluble residues three days after treatment. Except for the liver (0.2 mg/kg), the blood, brain, and fat of these animals contained no detectable acetonitrile-solution residues. The orally treated animals eliminated 86% of the activity in the excreta within seven days after treatment. One to 4% of the activity in urine and faeces was chloroform-soluble. As a result of partial starvation, oxidative metabolism in rabbits was increased, as evidenced by greater concentrations of fenthion-oxygen analogue in blood. The peak of radioactive substances in blood of normal rabbits following oral or subcutaneous administration of 35S fenthion was observed in six to nine hours following treatment, while in starved rabbits the peak value was obtained one hour after treatment (Begum, 1968). Following intraperitoneal administration of 32P-labelled fenthion, approximately 75% of the administered dose was recovered within three days in rat urine (60%) and faeces 15%). After oral administration, 86% of the dose was excreted in urine (45%) and faeces (40%) with the majority excreted in three days (Brady and Arthur 1961). Starvation of rabbits had no effect on elimination of fenthion (or metabolites) following oral or subcutaneous acute administration (Begum, 1968). Avrahami and White (1975) treated two lactating dairy cows with 20% fenthion as a topical spot treatment used for the control of lice using 32P-labelled fenthion applied at the rate of 9 mg/kg body weight. Highest residues of total radioactivity in the blood, milk, urine and faeces appeared between the first and second day after treatment. The residues were predominantly water-soluble hydrolysis products of fenthion. The highest daily average level offenthion and its organosoluble metabolites in the milk from the two cows was approximately 0.1 mg/kg on the first day after treatment. Of the total radioactivity applied to each cow, 45-55% was recovered in the urine, 2-2.5% in the faeces and 1.5-2% in the milk over a period of 4 weeks. Johnson and Bowman (1972) administered fenthion to lactating dairy cows at the rate of 25, 50 or 100 mg/kg in the total daily ration for 28 days. Total residues consisting of fenthion, its sulphoxide and sulphone and the sulphoxide and sulphone of the oxygen analogue in the milk averaged 0.016, 0.049 and 0.099 mg/kg respectively over the period. Total residues in faeces consisted of fenthion and its sulphoxide and averaged from 0.042 to 0.308 mg/kg. Neither fenthion nor its oxygen analogue was found in urine but totals of the sulphoxide and sulphone of fenthion and its oxygen analogue averaged from 0.43 to 1.05 mg/kg. Seven days after feeding was terminated, residues could not be detected in milk, urine or faeces. Biotransformation Five metabolites were isolated from rat urine and characterized as fenthion sulphoxide and sulphone, the oxygen analogue of the parent compound, and its corresponding sulphoxide and sulphone derivatives. In rabbits, the major urinary metabolites were fenthion-sulphoxide, fenthion-O-sulphoxide, and sulphone (Begum, 1968). The metabolic scheme is shown in Figure 1. FIGURE 1;V080pr16.BMP Knowles and Arthur (1966) applied fenthion dermally to two dairy cows each weighing 360 kg at a rate of approximately 13 mg/kg per cow, and treated two other lactating cows (each weighing 41O kg) by the intramuscular route with approximately 8.5 mg of fenthion/kg per cow. In the urine, the peak concentration of radioactive materials occurred on the first day following either method of treatment. The total residue of 32P materials from intramuscular treatment decreased from 33 mg/kg at one day to 1.6 mg/kg by 21 days. More than 95% of the radioactive materials eliminated in the urine consisted of hydrolytic products. The total 32P materials eliminated in the faeces peaked two days after both types of treatment. The cumulative percentage of the administered dose was about 4%. The peak concentration of acetonitrile-soluble radioactivity occurred one day after intramuscular treatment and three days after dermal treatment. The hair of the two cows treated dermally contained about 2000 mg/kg radioactive fenthion equivalents immediately after treatment. Chloroform to water partition data indicated that fenthion underwent little change on the hair to water-soluble components. The radioactivity in the blood after both types of treatment reached a peak during the first 24 hours. Between 10% and 38% of the 32P materials partitioned into chloroform, but no detectable chloroform-soluble 32P materials were present in the blood at seven days after either treatment. Fenthion constituted more than 50% of the non-ionic residues in the milk for three days after dermal and seven days after i.m. treatment. In the urine, fenthion accounted for only a small percentage of the chloroform-soluble radioactivity. More than 50% of the acetonitrile-soluble radioactive materials in the faeces consisted of the parent compound. The remainder was accounted for by the other metabolites, just as in urine. The composition of the hydrolytic products was also very similar to that found in urine. In the tissues of the animals slaughtered 14 days after dermal treatment and 21 days after i.m. treatment, more than 50% of the radioactive acetonitrile-soluble materials was chromatographed as fenthion, but oxidation products were also present. The biotransformation of fenthion in plants is basically similar to that in animals. Effects on enzymes and other biochemical parameters Fenthion and its metabolites are typical organophosphorous anticholinesterase agents. Typical of this class of agents, the oxygen analogue is the most potent enzyme inhibitor of all the metabolites, containing a phosphorous triester configuration (Francis and Barnes, 1963). The molar I50 fenthion for rat brain cholinesterase is 1.3 × 10-4M (Dubois and Kinoshita, 1964). Clinically and biochemically, a prolonged cholinergic effect follows a single dose (recovery of blood and brain enzyme is very slow) (Brady and Arthur, 1961). This effect may be as a result of inhibition of cholinesterase by metabolites that are released at different rates from storage in the body (Francis and Barnes, 1963), or a possible potentiation of its own antiesterase effects by selectively inhibiting enzymes responsible for hydrolysis of the phosphate ester (Brady and Arthur, 1961). Cholinesterase inhibition cannot be reactivated by 2-PAM, TMB-4 or P-2-S in vivo, indicating that fenthion may inhibit cholinesterase in a manner different from other organophosphate esters (Dubois, 1960; Dubois and Kinoshita, 1964; Francis and Barnes, 1963). TOXICOLOGICAL STUDIES Special pharmacological studies A daily diet containing 300 mg/kg fenthion was given to 8 groups of Donrya rats: a hare's eye group, a cervial sympathectomy group, a group given antibiotic eye ointment, a group given atropine eyedrops, and groups given subcutaneous injections of pralidoxime, atropine, and GSH for about one month. All rats given fenthion showed typical symptoms of organophosphorous intoxication such as nervousness, general spasms, diarrhoea, and salivation. Also ophthalmological symptoms, such as eye-ball protrusion, keratoconus, mammiform cornea, and cornea turbity were observed. The described pretreatments did not prevent the ocular symptoms (abstract only) (Kawai et al, 1976). When fenthion was administered at doses of 0.5 mg/kg orally to rats and 1-8 mg/kg intravenously to cats, significant inhibition of heart rate and blood pressure were observed. However, an intravenous dose of 0.3 mg/kg to cats produced no significant changes in blood pressure, heart rate, or other physiological parameters (Wills et al, 1975). Special studies on reproduction Rat Except for a slight growth depression at the highest level, fenthion at levels of 0, 3 15 or 75 mg/kg in the diet for three generations (two litters per generation) produced no adverse effect on rat reproduction (Loser, 1969). Microscopic examination of the tissues of the F3b generation did not reveal any significant abnormality (Spicer, 1971). Mouse In a five-generation reproduction study (2 litters per generation), two groups of Charles River CD-1 mice consisting of 14 females, 10 males; and 22 females, 10 males received 0 or 60 mg/kg fenthion, respectively, in their drinking water. In the parameters studied (reproductivity performance, lactation, viability, and growth rate of pups) the principal effect was a significant increase in pup mortality, especially in the 2nd, 3rd, and 4th generations. The highest mortality appeared to be in the first postnatal week. No histopathological changes were noted in the liver or kidney. There was no evidence of a teratogenic potential (Budreau and Singh, 1973b). Special studies on teratogenicity Mouse Pregnant Charles River CD-1 mice were injected intraperitoneally with single doses of 40, 80 or 160 mg/kg body weight or with multiple doses of fenthion at various time periods during organogenesis. Foetuses were removed by caesarean section on days 16 and 18 and visceral and skeletal structure examined for abnormalities. The frequency of resorptions and foetal deaths was not affected. Foetal weights were reduced significantly. Although the number and type of abnormalities were increased when compared to the control group, this did not appear to be dose-related. There was no apparent teratogenic effect, however, the incidence of resorptions was increased when fenthion was injected intraperitoneally for three consecutive days (day 9, 10, 11 of gestation) at 20 mg/kg (Budreau and Singh, 1973a). Rat Fenthion was administered orally to groups of female rats for one generation (two litters) at dosage levels of 5 mg/kg body weight or 10 mg/kg body weight from both day 1 through day 7 and day 8 through day 10 of gestation. Some animals were sacrificed on day 21 and foetuses were removed by caesarean section from these and examined for internal and external abnormalities. No malformations were observed. The incidence of resorptions was increased and weight of foetuses reduced. The second progeny from the remaining females were not affected. In a further study, rats were given fenthion at a dosage level of 5 mg/kg body weight from day 1 through day 13 of gestation. There was no evidence of teratogenesis. However, the incidence of foetal resorption and abortion was increased. During the lactation period there was an increased mortality and a decrease in the body weight gain of the pups. By day 45 postpartum, surviving newborns had recovered normal weight (Fytizas-Danielidou, 1971). When preliminary studies indicated that a dose of 100 mg/kg was lethal to non-pregnant female rats in 2-4 days and that 30 mg/kg induced toxic signs of poisoning, four groups of 20 pregnant rats were dosed orally at 0, 1, 3, or 10 mg/kg/day on days 6-15 of pregnancy. (Day 0 was the day semen was detected). At sacrifice (day 20 of gestation), implantation rate, numbers of live, dead, and resorbed foetuses, litter weight, and placental weights were recorded. After gross examinations were made for skeletal and soft tissue malformations, no treatment-related teratogenic effects were noted (Machemer, 1978a). Special studies on mutagenicity In vivo - mouse In a dominant lethal assay, 2 groups of 50 male mice (NMRI-strain) were given a single oral dose of 0 or 25 mg/kg bw. Additionally, a third group of mice was treated with 10 mg fenthion/kg bw, because 25 mg/kg induced toxic effects in the males (drowsiness, ruffled coat, and dilated intestines). The compound was given as a 2% aqueous emulsion. After injection, each male was caged with an untreated virgin female for a period of 4 days. This procedure was repeated for a total of 12 matings. On day 12-16 of gestation, the females were sacrificed and the number of implantations, the live and deal implants (sum of deciduomata, the resorptions, and the dead embryos) were counted. Except for an increased pre-implantation loss at the dose level of 25 mg/kg bw in the first two mating periods, no other treatment-related effects on fertility, pre- and post-implantation loss were observed (Machemer, 1978b). In vitro - Microorganisms Fenthion was examined for its mutagenic potential using 3 standard strains of Salmonella typhimurium (TA-1537, TA-98 and TA-100). Fenthion was tested in the presence and absence of an S-9 metabolising enzyme fraction obtained from Aroclor 1254-induced rat liver at concentrations ranging from 3.15 to 3150 g/plate. Under all conditions, there was no increase in the level of revertant colonies above that noted with controls. Both positive and negative acting chemicals (MMN and benzo [a]pyrene) were used to assure quality control in the test system. Under this standardised bioassay, fenthion was not mutagenic (Oesoh, 1977). Special studies on carcinogenicity Rat Groups of rats (50 male and 50 female, F344 strain rats/group, 25 of each sex were used as controls) were fed fenthion at dietary dosage levels of 0, 10 or 20 mg/kg for 103 weeks in a carcinogenicity bioassay. The animals were maintained for 1-2 weeks after the dietary administration stopped and were then sacrificed for gross and microscopic examinations. There was no mortality in the study and growth and behaviourial data were similar to control values. Histopathological studies described a variety of neoplastic and non-neoplastic lesions common to this strain of rat. Based on the histopathology and statistical evaluation of the incidence of tumours, fenthion was not considered to be carcinogenic to the rat (NCI, 1979). Mice Groups of mice (50 male and 50 female, B6C3F1 strain mice/group, 25 of each sex were used as controls) were fed fenthion in the diet at dosage levels of 0, 10 or 20 mg/kg for 103 weeks. The animals were maintained on control diets for up to 1 week after dietary administration stopped. They were then sacrificed and subjected to gross and microscopic examinations. During the first 4 months, no effects were noted on behaviour or appearance. Clinical signs of poisoning were noted thereafter (it was not indicated at what dosage levels there were clinical signs of poisoning). There were no differences in growth over the entire dosage range for the 103 weeks of study. Survival was not affected by fenthion. A variety of neoplasms were reported, the majority of which were not related to dietary administration of fenthion. It was reported that sarcomas in male mice (but not females) occurred with a greater frequency than in controls. The integument was considered to be the primary site for all primary sarcomas, MOS and fibrosarcomas. In an incidence of rhabdomyo-sarcoma, the skeletal muscle within subcutaneous tissue was defined as the site of origin. Histologically, differentiation was minimal to moderate among the various fibrosarcomas. The total incidence of skin and subcutaneous neoplasms (sarcomas) was dose related (controls 0/25; 10 mg/kg - 7/49; 20 mg/kg - 8/48) although the response was slight with respect to any individual lesion. Spontaneous rhabdosarcomas are rare in mice and the total incidence is an unusual occurrence. The histopathologic and statistical evaluation of the data suggested an increased incidence of sarcoma in male mice that may be related to the dietary presence of fenthion (MCI, 1979). The data were reviewed by the Data Evaluation/Risk Assessment Sub Group of the National Cancer Institute Clearinghouse on Environmental Carcinogens, who concluded that fenthion was not carcinogenic to rats or mice under the conditions of the test. Although, because of the increased incidence of sarcoma of the skin in male mice, fenthion was suggested to be sarcomagenic in this sex and strain. Special studies on potentiation Fenthion potentiates the acute intraperitoneal toxicity of malathion, dioxathion, and coumaphos in rats. Intraperitoneal administration of 13 other organophosphate or carbamate insecticides did not result in a greater than additive effect when administered with fenthion (Dubois and Kinoshita, 1964). Dietary combination of fenthion with coumaphos, neither of which alone affected cholinesterase when fed to dogs for six weeks, was found to potentiate the anticholinesterase activity of serum and red blood cells. Less evident potentiation was observed when fenthion and malathion were fed and when fenthion was fed in combination with dioxathion, no potentiation was noted (Doull et al, 1962). Fenthion (2 mg/kg) and malthion (100 mg/kg) resulted in moderate erythrocyte and serum cholinesterase activity inhibition (30-40%). When fenthion (2 mg/kg) and dioxathion (3 mg/kg) were fed, cholinesterase activity was not depressed. When fenthion (2 mg/kg) and coumaphos (2 mg/kg) were fed to dogs, significant inhibition (75%) of serum cholinesterase and moderate inhibition (30%) of erythrocyte cholinesterase was evident. Oral administration to rats of a 75:25 mixture of fenthion and dichlorvos did not result in a greater than theoretically additive toxicity (Kimmerle, 1967b). In rats, no synergistic effects on the acute oral toxicity was noted of fenthion with edifenphos and the active ingredient of Bassa (2-sec-butylphenyl N-methylcarbamate) (Thyssen, 1977). Special studies on neurotoxicity No evidence for delayed neurological disruption in hens was evident when fenthion was administered orally at a single dose of 25 mg/kg (Kimmerle, 1965a). When chickens were fed up to 100 mg/kg in the diet for 30 days, clinical examination of the animals and histological examination of nerve tissues indicated no demyelinating effect from fenthion (Kimmerle, 1965b; Dieckmann, 1971). Acute toxicity LD50 Animal Sex Route (mg/kg bw) Reference Mouse M Oral 150 Francis & Barnes, 1963 227 Dubois, 1968 F 190 Francis & Barnes, 1963 225 Dubois, 1968 F i.p. 150 Dubois & Kinoshita, 1964 M 125 Dubois & Kinoshita, 1964 Rat F Oral 245-310 Dubois & Kinoshita, 1964; Gaines, 1960 615 Francis & Barnes, 1963 M 175-470 Dubois & Kinoshita, 1964; Klimmer, 1963; Gaines, 1969; Francis & Barnes, 1963 M&F Inhalation 1197 mg/m3 (1 hour) Thyssen, 1978 M i.p. 325 Dubois & Kinoshita, 1964 F 260 Dubois & Kinoshita, 1964 M 152 Klimmer, 1963 M Dermal 330-650 Gaines, 1969; Klimmer, 1963; Francis & Barnes, 1963 1680 Mihail, 1978 F 2830 Mihail, 1978 F 330-500 Dubois & Kinoshita, 1964; Gaines, 1969; Francis & Barnes, 1963 Mouse F i.p. 200-240 Budreau & Singh, 1973a Guinea Pig M Oral 1000 Francis & Barnes, 1963 260 Dubois & Kinoshita, 1964 310 Dubois & Kinoshita, 1964 Rabbit M Oral 150-175 Francis & Barnes, 1963 Dermal 150 Klimmer, 1963 Duck Oral 15 Dubois & Doull, 1960 1-2 Keith & Mulla, 1966 Chicken 30 Dubois & Doull, 1960 28 Sherman & Ross, 1961 30-40 Francis & Barnes, 1963 Calf Approx. 40 McGrath, 1961 The signs of poisoning are typical of the central and peripheral cholinergic effects of organophosphorus esters with a gradual onset of the symptoms. The symptoms in humans and other animals include tremors, lacrimation, salivation, vomiting, diarrhoea, and other signs of cholinergic stimulation. The rate of absorption through the skin of rabbits is slow. When fenthion was applied to a cotton plug and placed in a rabbit ear for 4 hours, swelling occurred. When it was left for 24 hours, mortality resulted (Kimmerle, 1960). Various solvents used to dissolve fenthion in combination with water or ethanol had no significant effect on the acute oral LD50 (Kimmerle, 1967a). Fenthion is an organophosphorus insecticide of intermediate toxicity to mammals, although it displays considerable differences in its toxicity to various species, e.g., avian species are very sensitive (Keith and Mulla, 1966). Acute Toxicity of the Metabolites LD50 Compound Oral1 i.p.2 I50(M)3 Fenthion 220 325 >5 × 10-4 Fenthion sulphoxide 125 250 4.5 × 10-5 Fenthion sulphone 125 250 4.7 × 10-4 Fenthion Oxygen analogue 125 26 2.66 × 10-6 Fenthion O-Sulphoxide 50 22 4.8 × 10-5 Fenthion O-Sulphone 30 9 3.2 × 10-5 4-(methylthio)m-cresol 65004 4-methyl(thiosulphoxide) m-cresol 35004 4-methyl(thiosulphone) 70004 1 Male rats - according to Francis and Barnes, 1963 2 Female rats - according to Dubois and Kinoshita, 1964 3 I50 = Molar concentration resulting in 50% inhibition of human RBC cholinesterase (Francis and Barnes, 1963) 4 Female rats according to Nelson, 1967 Antidotes A number of antidotes that are commonly used for organophosphorus poisoning have been shown to be relatively inactive when used following fenthion intoxication. Studies with atropine, 2-PAM, Toxogonin, P-2-S, and TMB-4 (Dubois and Kinoshita, 1964; Francis and Barnes, 1963; Dubois, 1960 and Lorke and Kimmerle, 1969) administered alone and in combination showed that these materials did not successfully alleviate the parasympathomimetic signs of organophosphate poisoning. When BH-6 (Merck; Darmstadt, Germany) was administered three to four times in combination with atropine, the LD50 value increased from 250 to 440 mg/kg (Kimmerle, 1963). Toxogonin was not effective as a cholinesterase reactivator following oral intoxication of dogs by fenthion (Hahn and Henschler, 1969). Short-term studies Inhalation Female rats tolerated a daily one-hour inhalation challenge of 0.163 mg/l air for 30 days with cholinesterase depression but no mortality. At 0.415 mg/l air, all animals were dead within 10 days (Dilley and Doull, 1961a). Following a standard 4-hour exposure, the LC50 for fenthion for male and female rats was approximately 1200 and 800 mg/m3. Five consecutive 4-hour exposures resulted in an LC50 for males of approximately 212 mg/m3 and for females the LC50 was between 55 and 212 mg/m3 (Thyssen, 1978). Exposure by inhalation daily for nine days, six hours per day at 210 mg/m3 (initial concentration in a static inhalation chamber), resulted in signs of poisoning, but no mortality in cats, guinea pigs, rabbits, and rats. Cholinesterase, which was severely depressed, recovered in three weeks (Klimmer, 1963). Fenthion exhibits a relatively low degree of acute mammalian toxicity. In only one instance was a sex difference in susceptibility noted, and this is in contrast to the generally noted resistance of males to other phosphorothioates (Dubois and Kinoshita, 1964). Duck Mallard ducks fed 25 mg/kg of fenthion in the diet for six weeks became emaciated and could not fly or walk; after two days on normal food, recovery was evident. A dietary level of 5 mg/kg produced no adverse clinical reaction (Keith and Mulla, 1966). Rat Dermal administration of fenthion at 14.5 and 25 mg/kg for 60 days to rats resulted in 40% mortality in the higher-dosed group and no mortality in the lower-dosed group. However, blood cholinesterase levels were depressed to about 20% of normal at the lower treatment level (Dubois, 1961). Cholinesterase was depressed and mortality was absent when fenthion was applied to rats dermally for 12 days at 2.9 mg/kg (Dubois and Puchala, 1960). Rats tolerated daily intraperitoneal administration of 10 mg/kg fenthion for 60 days with no mortality. At 20 mg/kg, 80% of the treated animals died within 20 days (Dubois and Kinoshita, 1964). Mortality (12 dead of 30 rate tested) occurred following daily oral administration of approximately 25 mg/kg (1/10 LD50) for 75 days (6 days per week). Signs of poisoning were transient, disappearing shortly after dosing (Klimmer, 1963). In a preliminary study, male rats were orally administered fenthion five days a week for 13 weeks at a dose of 30 mg/kg/day. Mortality occurred in approximately 30% of the rats over the course of the experiment and cholinesterase activity was depressed between 80-90% of normal. At the conclusion of the experiment, cholinesterase recovery was very slow, up to 40 days (Kimmerle, 1961). Rats (22 male and 22 female per group) were fed dietary levels of fenthion at 0.25, 0.50, 2.5 or 5.0 mg/kg/day for three months. Cholinesterase activity depression was evident at 0.5 mg/kg/ day in red blood cells, serum, liver, and heart at all testing intervals. At the lowest feeding level (0.25 mg/kg), the inhibition (approximately 10-20%) did not progressively increase with time, indicating lack of cumulative effects. Mortality in females was evident at 5.0 mg/kg. The animals died manifesting muscarinic and nicotinic effects. Body-weight gain was reduced in males at 0.25 mg/kg and above, while in females it was evident only at 2.5 mg/kg. Behaviourial effects were noted (piloerection) at 0.5 mg/kg and above (especially in females). This effect decreased with time and disappeared by week 7. Organ weights were all distinctly lower than the controls, but as the body weight was also reduced, the organ-to-body-weight ratio did not appear to be affected. Histological examination showed the testes to have reduced spermatogenesis and atrophic prostate glands were noted at the highest feeding levels (2.5 and 5.0 mg/kg). The ovary was not affected (Shimamoto and Hattori, 1969). Rats (six groups of 12 male and 12 female) were fed for 16 weeks on diets containing 0, 2, 3, 5, 25, or 100 mg/kg. Cholinesterase depression was evident at 25 mg/kg and absent at 5 mg/kg. No adverse effects were noted in food consumption, weight gain, or gross and microscopic examination of tissues (Doull et al, 1961). Rats (six groups of 25 male and 25 female) were fed for one year on diets containing 0, 2, 3, 5, 25 or 100 mg/kg of fenthion. There was no evidence of significant changes in growth rate, food consumption, general appearance, and gross or microscopic examination of tissues. Survival of male rats at 25 mg/kg was slightly depressed. Cholinesterase examinations indicated depression at the 5 mg/kg level and above, with 3 mg/kg showing no adverse enzyme effects. A mild extramedullary haematopoiesis was observed in controls and all dosage levels, and haemosideresis was evident in the spleen of the rats at 100 mg/kg levels (Doull et al, 1963a). Dog Groups of dogs (4 male and 4 female beagle dogs/group) were fed fenthion in the diet for two years at dosage levels of 0, 3, or 10 mg/kg. A high dose group received 30 mg/kg for 64 weeks, 50 mg/kg for 2 weeks (weeks 65 to 67) and 60 mg/kg for the remainder of the study (weeks 68 to 104). There was no mortality in the study and all dogs appeared healthy over the course of the study. When the high-dose level was increased from 30 to 60 mg/kg, faecal changes were noted, although diarrhoea was not observed. Food consumption was normal except for those animals at the 60 mg/kg level, where at some time intervals, all the food was not consumed at each meal. There were no ophthalmological changes, and most clinical blood chemistry, haematology, and urinalyses parameters were unaffected by fenthion. Cholinesterase depression in both plasma, erythrocyte, and brain was observed. Plasma cholinesterase was the most sensitive parameter, being depressed at dietary concentrations of 10 mg/kg and above. Erythrocyte cholinesterase was depressed in males at 10 mg/kg and in females in the high dose group only. Brain cholinesterase of both males and females was depressed, only at the highest concentration tested. There were no remarkable observations associated with gross or microscopic examinations of tissues and organs. A no-effect level in this study was 3 mg/kg, equal to a dietary intake of 0.09 mg/kg body weight for fenthion (Hoffmann and Weischer, 1975). Dog Dogs (four groups of two males and two females per group) were fed fenthion at 0, 2, 5 or 50 mg/kg for 12 weeks. Growth was not affected at any dietary level. Erythrocyte cholinesterase activity was depressed at 50 mg/kg while serum cholinesterase was depressed at 5 mg/kg and above. Little, if any, depression of the serum cholinesterase was evident before five weeks, after which it progressively decreased to about 40% inhibition (Doull et al, 1961). Dogs (four groups of two males and two females) were fed fenthion at 0, 2, 5, or 50 mg/kg in the diet for one year. There was no effect of fenthion on food consumption or growth over the test interval. Erythrocyte and serum cholinesterase were significantly depressed at 50 mg/kg with the serum also depressed at 5 mg/kg. An increase in the weight of the spleen, which was not dose dependant, was evident in all of the treated animals. Microscopic examinations of the tissues showed splenic congestion and some decrease in the cellularity of the red pulp was evident at all dose levels fed. Extramedullary haematopoiesis and haemosideresis was also observed in the spleen. Microscopic examination of other tissues did not reveal any significant changes (Doull et al, 1963b). Monkey Four groups of 5 male and 5 female rhesus monkeys received 0, 0.02, 0.07, or 0.2 mg fenthion/kg body weight, as a freshly prepared solution in corn oil, daily by stomach tube for one year. Animals were observed daily for general appearance and body weight and ophthalmological examinations were reported monthly. Clinical chemistry, haematology, and urinalyses were performed at 0, 1, 3, 6 and 12 months. Plasma and erythrocyte cholinesterase activity was measured at 0, 1, 2, 3, and 4 weeks and thereafter monthly. One monkey/sex from the 0 and 0.2 mg/kg groups was sacrificed at 7 months, 3 weeks. Brain cholinesterase, absolute and relative organ weights, and gross and histopathology analyses were reported. The plasma cholinesterase was depressed in both sexes at 0.2 mg/kg. Plasma cholinesterase depression occurred at 0.07 mg/kg, but was inconsistent and minimal. No adverse effects were noted on any other parameter (Coulston et al, 1978). Long-term studies Rat In a 2-year toxicity experiment, 50 male and 50 female rats per group were fed a diet containing 0, 3, 15, or 75 mg/kg fenthion. In the control group, 100 males and 100 females were used. The rats were weighed weekly during the first 26 weeks and thereafter at 14-day intervals. Food consumption was recorded weekly. Clinical chemistry was performed on 5 male and 5 female rats per group at intervals of 1, 3, 6 and 12 months, and on 10 males and females at the end of the experiment. The clinical chemistry included: haematology, liver and kidney function tests, urinalysis, blood sugar, and serum cholesterol determinations. Plasma and erythrocyte cholinesterase activities were determined after 1, 2, 4, 8, 13, 26, 52, 78 and 105 weeks. Brain cholinesterase activity was not measured. At the end of the experiment, the rats were examined macroscopically, the organs weighed and studied microscopically. Fenthion at 3 and 15 mg/kg did not affect the physical appearance, behaviour, growth, and survival rate. The male rats of the 75 mg/kg group had a significantly lower body weight. A tendency toward increased mortality was observed in the 75 mg/kg group in both sexes. Haematology, blood chemistry, urinalysis, and gross and microscopic pathology revealed no compound-related effects. Dietary concentrations of 15 and 75 mg/kg fenthion caused dose-dependant depression of plasma and erythrocyte cholinesterase activity. At 3 mg/kg, cholinesterase activity was only slightly depressed in the plasma of the females. A no-effect level for fenthion in this study is 3 mg/kg (Bomhard and Loser, 1977). OBSERVATIONS IN MAN Fenthion has been widely used in many parts of the world for control of household pests, mosquitoes, etc. Cholinesterase studies conducted on individuals in areas treated by the World Health Organization for malaria eradication have shown that very slight plasma cholinesterase depression occurs when exaggerated spray schedules were followed. The plasma cholinesterase levels were depressed for up to six weeks after spraying (Elliot and Barnes 1963). It was also evident that the children in the population (less than seven years old) were more susceptible to the anticholinesterase effects (Taylor, 1963). A man who ingested two ounces of a fenthion formulation (Entex(R)) recovered from severe organophosphorous poisoning after being in critical condition for the first six days after poisoning. Recovery was slow, lasting up to 30 days. 22 days after poisoning, the cholinesterase activity was still depressed (Pickering, 1966). In humans, the signs of poisoning appear rapidly, beginning with blurred vision, unsteady gait, and slurred speech. After 72 hours of emergency treatment following an unknown quantity of fenthion, a man suffered extreme respiratory difficulty necessitating artificial ventilation and endotracheal intubation. The patient began to recover only after 11 days of treatment, which included atropine, PAM, and toxogonin (Dean et al, 1967). In another case, 45 minutes after ingestion of 30 ml of a fenthion formulation a man was in a comatose state with pale skin, cyanotic mucous membranes, slow regular heart beat, no peripheral blood pressure, and no reactions to pain or light stimulation on the pupils. Recovery took six days (von Clarmann and Geldmacher-von-Mallinkrodt, 1966). The potential dermal and respiratory exposure to fenthion during field application by hand gun power spray equipment, back-pack hand pressure sprayer, and hand granular dispersal for mosquito control was studied over two work seasons (Fytizas-Danielidou, 1971). Human workers exposed to 3.6-12.3 mg/h (dermal) or <0.02-0.09 mg/h (inhalation), equivalent to 0.5-1.5 mg/kg/day (dermal) and 0.01-0.05 mg/kg/day (inhalation), showed a decrease in plasma, but not erythrocyte cholinesterase activity (Wolfe et al, 1974). A study was carried out on 150 cases of anticholinesterase insecticide poisoning to observe the influence of the type of insecticide used on the clinical picture and prognosis. Of the 150 cases, 32 had consumed fenthion, 48 fenitrothion, and 50 malathion. Twenty did not know exactly what agent was consumed. Paralytic signs were significantly more frequent with fenthion than with malthion or fenitrothion (being 81.2%, 30% and 23% respectively). These signs occurred later with fenthion and lasted longer. Death occurred significantly more often with fenthion (the mortality rate being with fenthion 35.5%, with malathion 4%, and with fenitrothion 2.1%). Pulmonary oedema was most common with malathion and not encountered with fenthion. The cholinesterase activity was most marked with fenthion reaching 0 in 18 of the 27 cases studied (Wadia, et al, 1977). A group of male volunteers were administered fenthion orally for periods of time up to 4 weeks at dosage levels of 0, 0.04 or 0.07 mg/kg body weight. There were no effects reported on physical signs or symptoms, haematology, or urinalysis parameters. With the exception of a slight plasma cholinesterase depression noted at the high dosage level, no effects were noted on the various clinical chemistry parameters (Griffin et al, 1979). EVALUATION COMMENTS The meeting reviewed new data requested by previous meetings and considered all of the available information on fenthion. Fenthion, an organophosphorus insecticide, is rapidly absorbed, metabolised and excreted. Fenthion does not accumulate in the body. In most instances, those metabolites that remain fully esterified are more toxic than the parent compound. Fenthion and its biologically active metabolites are anticholinesterase agents and the signs and symptoms of poisoning are typical of the cholinergic response. The signs of intoxication from a single oral dose develop slowly and persist for a considerable time. Although there is no explanation for the long-lasting cholinesterase depression, slow appearance and disappearance of cholinergic signs and lack of appropriate antidote, these are of minimal concern in establishing an ADI. It would however be of interest to have such information, which could be of high value in cases of acute poisoning. The cholinergic signs of poisoning are not readily alleviated by atropine or by the common oxime reactivators. Fenthion is not mutagenic in mammalian or microbial test systems. It is not carcinogenic, or teratogenic and does not affect reproduction in rodents. Fenthion does not induce delayed neurotoxicity in hens nor is it potentiated by other cholinergic chemicals. In extended short-term studies with rats, dogs and monkeys, and in a long-term rat study, there were no indications of adverse effects other than cholinesterase depression. Studies of humans exposed occupationally or through malaria-control programmes, as well as of volunteers ingesting a standardised dose, do not indicate any short- or long-term adverse effects except plasma depression and acute cholinergic response. From the available data no-effect levels in rat, dog and a monkey were noted. Observations in humans provide additional assurance of the safety of the residue level in food. Maximum level causing no toxicological effect Rat: 3 mg/kg in the diet equivalent to 0.15 mg/kg bw/day. Dog: 3 mg/kg in the diet equivalent to 0.09 mg/kg bw/day. Monkey: 0.07 mg/kg bw/day Man: 0.02 mg/kg bw/day Estimate of acceptable daily intake for man 0-0.001 mg/kg bw FURTHER WORK AND INFORMATION Desirable Studies to elucidate the mechanism of the long-lasting cholinesterase inhibition noted in human studies as well as in animal bioassays. REFERENCES Avrahami, M. and White, D.A. Residues in milk of cows after spot-treatment with 32P-fenthion. New Zealand Expte. Agric. 3: 309-11. Begum, A. Effect of diet on metabolism of fenthion in animals. Ph. D. thesis, Auburn University, Auburn, Alabama. Dissert. Abstr., Sect. B, 28: 4165. Bomhard, E. and Loser E. Chronic toxicity study on rats. (1977) Unpublished report (No. 6769) from the Institut für Toxikologie, submitted to the World Health Organization by Bayer AG. Brady U.E., Jr. and Arthur, B.W. Metabolism of O,O-dimethyl O-[4-(methylthio)-m-tolyl] phosphorothioate by white rats. J. Econ. Entomol. 54: 1232-1236. Budreau, C.H. and Singh, R.P. Teratogenicity and embryotoxicity of demeton and fenthion in CF 1 mouse embryos. Tox. Appl. Pharm. 24: 325-322. Budreau, C.H. and Singh, R.P. Effect of fenthion and dimethoate on reproduction in the mouse. Tox. Appl. Pharm. 26: 29-38. Bull, D.L. and Stokes, R.A. Metabolism of dimethyl p-(methylthio)phenyl phosphate in animals and plants. J. Agr. Food Chem. 18: 1134-1138. Coulston, F., Rosenblum, I. and Ford, W. A safety evaluation of fenthion in rhesus monkeys (Macaca mulatta). (1978) Unpublished twelve-month interim report from Albany Medical College of Union University, Albany, New York, submitted to the World Health Organization by Bayer AG. Dean, G., Cozon, J. and Brereton, D. Poisoning by an organophosphorus compound. A case report. So. African Med. J., 1017-19. Dieckmann, W. Neurotoxizitatsunter-suchungen an Huhnern-Histopathologie. (1971) Unpublished report of Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Dilley, J. and Doull, J. Chronic inhalation toxicity of Bayer 29493 to rats and mice. (1961a) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organisation by Bayer AG. Dilley J. and Doull, J. Acute inhalation toxicity of Bayer 29493 to rate and mice. (1961b) Unpublished report from Department of Pharmacology University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. The absence of antidote activity by 2-PAM and TMB-4 against acute poisoning by Bayer 29493. (1960) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. Effects of repeated dermal application of Bayer 29493 on rats. (1961) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. Acute oral toxicity of a sample of Bayer 29493 to female rats. (1962) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. Comparison of the acute oral toxicity of Bayer 29493 and Sumithion to mice. (1968) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois. K.P. and Doull, J. The acute toxicity of Bayer 29493 to chickens and ducks. (1960) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. and Puchala, E. Influence of Bayer 29493 on the cholinesterase activity of the blood of rats. (1960) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Dubois, K.P. and Kinoshita, F. Acute toxicity and anticholinesterase action of O,O-dimethyl O-4-(methylthio-m-tolyl phosphorotioate) (DMTP;Baytex) and related compounds. Tox. Appl. Pharmacol. 6: 86-95. Doull J., Root M. and Cowan, J. Determination of the safe dietary level for Bayer 29493 for dogs. (1961) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Doull J., Root, M. and Cowan, J. Effect of adding Bayer 29493 in combination with other cholinergic insecticides to the diet of male and female dogs. (1962) Unpublished report from Department of Pharmacology, University of Chicago, submitted to the World Health Organization by Bayer AG. Doull, J., Root, M., Cowan, N.J., Vesselinovitch, D., Fitch, F.M. and Meskauskas, J. Chronic oral toxicity of Bayer 29493 to male and female rats. (1963a) Unpublished report from Department of Pharmacology, University of Chicago, submitted to WHO by Bayer AG. Doull, J., Root, M., Cowan, J. and Vesselinovitch, D. Chronic oral toxicity of Bayer 29493 to male and female dogs. (1963b) Unpublished report from Department of Pharmacology, University of Chicago, submitted to WHO by Bayer AG. Doull, J., Vesselinovitch, D., Fitch, F., Cowan, J., Root, M. and Meskauskas, J. The effects of feeding diets containing Bayer 29493 to rats for a period of 16 weeks. (1961) Unpublished report from Department of Pharmacology, University of Chicago, submitted to WHO by Bayer AG. Elliot, R. and Barnes, J.M. Organophosphorous insecticides for the control of mosquitoes in Nigeria. Bull. Wld. Hlth. Org. 18: 35-54. Francis, J.I. and Barnes, J.M. Studies on the mammalian toxicity of fenthion. Bull. Wld. Hlth. Org. 29: 205-12. Fytizas-Danielidou, R. Effects des pesticides sur la reproduction des rats blancs. I. Lebaycide. Fakulteit van de Landbouwweten-schappen. 23. International Symposium over Fytofarmacie, 4 Mei, 1971. Gaines, T.B., Acute toxicity of pesticides, Toxicol. Appl. Pharmacol. 14: 515-34. Griffin, T., Rosenblum, I. and Coulston, F. Safety evaluation of fenthion in human volunteers. Final report. (1979) Unpublished report from the Institute of Comparative and Human Toxicology and the International Center of Environmental Safety, submitted to WHO by Bayer AG. Hahn, H.L. and Henschler, D. The ability of phosphorylated cholinesterase to be reactivated by obidoxime chloride (Toxogonin) in vivo. Arch. Toxikol. 24: 147-63. Hoffman, K. and Weischer, C.H. Fenthion chronic study on dogs (two-year feeding experiment). (1975) Unpublished report from Bayer AG Institut für Toxikologie (No. 5737), submitted to WHO by Bayer AG. Johnson, J.C. and Bowman, M.C. Responses from cows fed diets containing fenthion or fenitrothion, J. Dairy Sci. 55: 777-82. Katague, D.B. Determination of fenthion residues in milk by electron-capture gas chromatography. (1966) Chemagro Corporation, Research Department, Report No. 17, 887, submitted to WHO by Bayer AG. Kawai, M., Tojo, K., Miyazawa, S., Maruta, H. and Naito, M. Experimental studies on the effects of organophosphorous compounds on the eyes. Nat. Def. Med. J. 23(1): 1-10 (abstract). Keith, J.O. and Mulla, M.S. Relative toxicity of five organophosphorous mosquito larvicides to mallard ducks. J. Wildlife Management 30: 553-63. Kimmerle, G. Re: Active substance S1752. Unpublished report from Farbenfabriken Bayer AG, submitted to WHO by Bayer AG. Kimmerle, G. Subchronische oral versuche bei ratten mit S-1752-Wirkstoff. (1961) Unpublished report from Farbenfabriken Bayer AG submitted to WHO by Bayer AG. Kimmerle, G. Produc BH6 and S1752 poisoning. (1963) Unpublished report from Farbenfabriken Bayer AG, submitted to WHO by Bayer AG. Kimmerle, G. Neurotoxic studies with Bayer 29493. (1965a) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Kimmerle, G. Neurotoxische untersuch-ungen mit S-1752-Werkstoff. (1965b) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Kimmerle, G. Langdauernde Inhalationsversuche bei Hunden mit dem Baytex-Wirkstoff (S-1752). (1966) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Kimmerle, G. Abhangigkeit der aduten oralen Toxizitat bei Patten vom Lössungmittel. (1967a) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Kimmerle, G,. Potenzierung von DDVP und S-1752. (1967b) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Klimmer, R. Toxicologioal testing of Bayer 29493. (1963) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Knowles, C.O. and Arthur, B.W. Metabolism of and residues associated with dermal and intramuscular application of radio-labelled fenthion to dairy cows. J. Econ. Entomol. 59: 1346-52. Lorke D. and Kimmerle, G. The action of reactivators in phosphoric acid ester poisoning. Arch. Pharmakol. 263: 237-8. Löser E. Generations versuche an ratten. (1969) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Machemer, L. S1752 (Fenthion, Lebaycid-Wirkstoff) Untersuchungen auf embryotoxische und teratogene Wirkungen an Ratten nach oraler Varabreichung, Rep. No. 7580. (1978a) Unpublished report from Institut für Toxikologie, Bayer AG, submitted to the World Health Organization by Bayer AG. Machemer, L. S1752 (Fenthion, Lebaycid active ingredient) Dominant lethal study of male mice to teat for mutagenic effects. Report. No. 7449. (1978b) Unpublished report from Institut für Toxikologie, Bayer AG, submitted to the World Health Organization by Bayer AG. McGrath, H.B. Toxicity of Bayer 29493 in calves. (1961) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Metcalf, R.L., Fukoto, T.R. and Winton M.Y. Chemical and biological behaviour of fenthion residues. Bull. Wld. Hlth. Org. 29: 219-226. Mihail, F. S1752 Lebayoid active ingredient. Determinations of percutaneous toxicity. (1978) Unpublished report from Institut für Toxicologie, Bayer AG, submitted to the World Health Organization by Bayer AG. Möllhoff, E. Determination of trichlorfon and fenthion residues in animals of different species. Pestic. Sci. 2: 179-181. NCI. Bioassay of fenthion for possible carcinogenicity. National Cancer Institute Carcinogenesis Technical Report Series No. 103. U.S. Dept. of HEW publication No. (NIH) 79-1353. Bioassay conducted by Gulf South Research Institute, New Iberia, Louisiana, under contract to NCI and subcontract to Tracor Jitco, Inc., who prepared the final report. Nelson, D.L. The acute oral toxicity of three phenolic compounds to adult female rats. (1967) Unpublished report from Farbenfabriken Bayer AG, submitted to the World Health Organization by Bayer AG. Oesch F. Ames test for Lebycid (Fenthion). (1977) Unpublished report from Pharmakologisches Institut der Unwersitat Mainz, submitted to the World Health Organization by Bayer AG. Pickering, E.N. Organic phosphate insecticide poisoning. Can. J. Med. Tech., p. 174. Sherman, M. and Ross, E. Acute and subacute toxicity of insecticides to chicks. Toxicol. Appl. Pharmacol. 3: 512-33. Shimamoto, K. and Hattori, K. Chronic feeding of Baytex (O,O-dimethyl-o-(4-methylmercapto-3-methyl) phenyl-thiophosphate) in rats. Acta Med. Univ. Kyoto, 40: 163-71. Spicer, E.J.F. Pathology Report of Bay 29493. Generation study in rats. (1971) Unpublished report from Farbenfabriken Bayer AG submitted to the World Health Organization by Bayer AG. Taylor, A. Observations on human exposure to the organophosphorus insecticide fenthion in Nigeria. Bull. Wld. Hlth. Org. 29: 213-18. Thyssen, J. Untersuchungen zur kombinationstoxizität von Edifenphos, Fenthion und Bassa-Wirkstoff. Report No. 7176. (1977) Unpublished report from Bayer AG Institut für Toxikologie, submitted to the World Health Organization by Bayer AG. Thyssen, J. S1752. (Lebaycid-Wirkstoff). Akute inhalationstaxizitat. Unpublished report from Bayer AG Institut für Toxikologie, submitted to the World Health Organization by Bayer AG. von Clarmann, M. and Geldmacher-von Mallinckrodt, M. A successfully treated case of acute oral poisoning by fenthion and its demonstration in the gastric contents and urine. Arch. Toxik. 22: 2-11. Wadia, R.S., Bhirud, R.H., Gulavani, A.V. and Amin, R.B. Neurological manifestations of three organophosphate poisons. Indian J. Med. Res. 66(3): 446-48. Wills, J.H., Broblewski, G.E. and Coulston, F. (1975) Unpublished status report from Institute of Comparative and Human Toxicology, Albany Medical College, Albany, New York, submitted to the World Health Organization by Bayer AG. Wolfe H.R., Armstrong J.F. and Durham, W.F. Exposure of mosquito control workers to fenthion. Mosquito News 34: 263-67.
See Also: Toxicological Abbreviations Fenthion (ICSC) Fenthion (WHO Pesticide Residues Series 1) Fenthion (WHO Pesticide Residues Series 5) Fenthion (Pesticide residues in food: 1977 evaluations) Fenthion (Pesticide residues in food: 1978 evaluations) Fenthion (Pesticide residues in food: 1979 evaluations) Fenthion (Pesticide residues in food: 1983 evaluations) Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental) Fenthion (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental) Fenthion (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)