PHOSMET First draft prepared by T.C. Marrs, Medical Toxicology and Environmental Health, Department of Health, London, United Kingdom Explanation Evaluation for acceptable daily intake Biochemical aspects Absorption, distribution and excretion Biotransformation Effects on enzymes and other biochemical parameters Toxicological studies Acute toxicity Short-term toxicity Long-term toxicity and carcinogenicity Embryotoxicity and teratogenicity Genotoxicity Special studies Skin and eye irritation and skin sensitization Delayed neuropathy Observations in humans Comments Toxicological evaluation References Explanation Phosmet was reviewed by the JMPR in 1978 (Annex I, reference 30), when a temporary ADI of 0-0.005 mg/kg bw was allocated. It was reviewed again in 1979 (Annex I, reference 32), when additional data on teratogenicity were made available, and an ADI of 0-0.02 mg/kg bw was established. Further data have become available, and this monograph summarizes both the new studies and relevant summaries from the previous monograph and monograph addendum (Annex I, references 31 and 33). This compound was reviewed at the present Meeting as a result of the CCPR periodic review programme. Evaluation for acceptable daily intake 1. Biochemical aspects (a) Absorption, distribution and excretion In a study of the pharmacokinetics and biotransformation of phosmet in Long-Evans rats, 14C-phosmet was given as a single dose of 23-35.2 mg/kg bw by gavage to three male and two female rats. The material was rapidly absorbed, distributed and excreted. Label was excreted predominantly in the urine: by the time of sacrifice (72 or 120 h after treatment), 79% had been excreted in the urine and 19% in the faeces, while very little was expired as 14C-carbon dioxide. Tissue levels of radiolabel were low, especially in fat and the gonads (Ford et al., 1966). Groups of five male and five female Sprague-Dawley-derived Crl:CB(SD)BRVAF/+ rats were given single oral doses of 1 or 25 mg/kg bw of 14C-phosmet. Further groups were given 14 daily oral doses of 1 mg/kg bw phosmet followed by a single oral dose of 1 mg/kg bw labelled compound. The highest blood levels of label were observed 0.5 h after dosing in both groups; thus, the material was readily absorbed. During the next 8 h, there was a rapid decline in plasma levels of label, followed by a slower decline. Label was rapidly excreted in all treated groups (> 70% in 24 h), mainly in the urine. After 96 h, 88% of the label was recovered in the urine of the animals given 1 mg/kg bw as a single dose and 81% in the group given 25 mg/kg bw phosmet. Faecal excretion was minor (6-13% of the dose). Very little label (1.2-2.1%) was detected in the carcass 96 h after treatment. The main effect of repeated exposure before administration of labelled compound was to reduce excretion of the label, so that about 75% of the label was excreted within 96 h in the urine. The lowest concentrations of label were found in bone and fat and the highest in the skin and, to a lesser extent, the kidneys. The concentrations of label were higher in packed erythrocytes than in plasma (Fisher, 1989). Phosmet administered orally to pregnant albino rats (strain unspecified) in the final stages of pregnancy or injected into the intra-amniotic sac was absorbed rapidly and crossed the placenta. The half-life of phosmet in externalized fetuses and newborns was 50-70 min (Ackermann et al., 1976). (b) Biotransformation In the study of Ford et al. (1966), described above, < 1% of the label in the urine was found to be in the form of phosmet or phosmet oxon. Less than 0.04% of the radiolabel was recovered in expired air. Long-Evans rats (sex unspecified) administered [carbonyl-14C]-phosmet at 27 mg/kg bw excreted 41% of the label in the urine as phthalamic acid and 21% as phthalic acid; less than 0.04% was present as phosmet or its oxon. Phosmet was readily converted to phosmet oxon in the rat liver microsome NADPH2 enzyme system (McBain et al., 1968). The biotransformation of phosmet in male and female Sprague-Dawley-derived Crl:CD(SD)BRVAF/+) rats was investigated using samples from the study of Fisher (1989). Two major urinary metabolites were observed: N-(methylsulfinylmethyl)phthalamic acid (52-66%) and N-(methylsulfonylmethyl)phthalamic acid (8-26%); numerous other metabolites that occurred at low concentrations could not be identified. The other product of hydrolysis of phosmet would presumably be O,O-diethylphosphorothioate. Male rats excreted a greater proportion of the labelled phosmet as N-(methyl sulfonylmethyl)phthalamic acid (20-26%) than did females (8-13%). A proposed metabolic pathway is given in Figure 1. The differences between the results of the study conducted in 1968 and that conducted in 1989-90 may have been due to instability of phthalamic acid under acidic conditions if, for example, the urine was stored for a substantial length of time. The metabolic pathway would have been deamination of phthalamic acid to phthalamic anhydride and hydrolysis to phthalic acid (Fisher, 1990). In a study involving two lactating goats (strain unspecified), [carbonyl-14C]-phosmet was fed at a dietary equivalent of about 8 ppm for four days. About 60% of the dose was excreted in the urine; the levels of residues in milk were 0.014-0.017 ppm, representing about 0.2% of the administered dose. Phosmet was not detected in milk or edible tissues. The metabolites that were detected included N-(methylthiomethyl)phthalimide and N-(methylsulfonylmethyl)phthalamic acid. There were considerable differences in the relative concentrations of metabolites in different tissues; e.g. there was a high proportion of N-(methylsulfonylmethyl)phthalamic acid in the milk, kidney and muscle, whereas the most abundant metabolite in the liver was N-(methylthiomethyl)phthalimide (Tarr & Hemingway, 1993a). [carbonyl-14C]-Phosmet was fed in the diet to 15 white Leghorn laying hens at a concentration of 10.5 ppm for seven days. Of the cumulative dose, 90% was excreted within 24 h after the end of feeding. Eggs contained 0.3% of the cumulative dose. Phosmet was not detected in tissues, but 0.01% was found in egg yolks. The metabolites detected in edible tissues and egg yolks included phthalimide and phthalic acid (Tarr & Hemingway, 1993b).(c) Effects on enzymes and other biochemical parameters Erythrocyte and brain cholinesterase are more sensitive to phosmet in rats than is plasma cholinesterase. Rat aliesterases are more sensitive to inhibition by phosmet than is acetylcholinesterase. Other organophosphates (malathion, parathion, parathion-methyl, schradan, tributyl phosphorotrithioite, diazinon, EPN, ethion, demeton, mevinphos, carbophenothion, disulfoton azinphos-methyl) and a carbamate anticholinesterase (carbaryl) did not potentiate the effect of phosmet in male Sprague-Dawley rats (Lee & Miaullis, 1969). Male and female CD rats were treated orally with 0, 10 or 100 mg/kg bw phosmet (purity, 94.7%), and plasma, erythrocyte and brain cholinesterase activities were measured 4 and 24 h later. The lower dose had no effect on plasma or erythrocyte cholinesterase activities at either time or on brain cholinesterase activity at 24 h; however, 4 h after treatment with this dose, brain cholinesterase activity was inhibited by 14% in males and 21% in females. At 100 mg/kg bw, substantial inhibition was found at both times, except for plasma enzyme in females at 4 h. At that time, the activity of the erythrocyte enzyme was the most strongly inhibited (about 85%) and that of the brain enzyme somewhat less (about 65%); the activity of plasma cholinesterase was inhibited by only about 35% in males and not significantly in females. At 24 h, the activity of the brain enzyme was recovering (34% inhibition in males and 48% in females), as was that of erythrocyte cholinesterase (40 and 45% inhibition), while the activity of plasma cholinesterase was further inhibited (46 and 74% inhibition) (Hendricks & Sprague, 1983). 2. Toxicological studies (a) Acute toxicity The acute toxicity of phosmet is summarized in Table 1. (b) Short-term toxicity Mice Groups of 10 male and 10 female B6C3F1 mice received technical-grade phosmet (purity, 95%) in the diet at concentrations of 0, 5, 15, 50, 150 or 500 ppm, equivalent to 0.75, 2.25, 7.5, 22.5 or 75 mg/kg bw per day, for four weeks. Significant decreases in food consumption and body-weight gain were seen at 150 and 500 ppm in males and at 500 ppm in females; females given 150 ppm had only reduced food intake. Males at the two highest doses had a significant decrease in absolute liver and kidney weights; relative liver weights were significantly increased at 150 and 500 ppm in males and females, while relative kidney weights were significantly increased only in females at 500 ppm. Erythrocyte cholinesterase activity was depressed at 50 ppm and above, and brain cholinesterase activity was statistically significantly depressed by 16% in females receiving the highest dose. No treatment-related changes were seen histologically. The NOAEL was 50 ppm, equivalent to 7.5 mg/kg bw per day, on the basis of reduced food consumption and body-weight gain and decreased absolute liver and kidney weights at 150 ppm (Jones et al., 1981). Rats Groups of 15 male and 15 female albino rats (strain unspecified) were given phosmet (purity, 98%) in the diet at 0, 20, 100 or 500 ppm, equivalent to 1, 5 or 25 mg/kg bw per day, for 14 weeks. A second study was started four weeks later, involving four groups of the same size treated with the same doses. Decreased weight gain was found in the group receiving the highest dose. Erythrocyte cholinesterase activity was inhibited by > 20% at the middle and high doses, while plasma cholinesterase was inhibited by > 20% at the high dose only; brain cholinesterase activity was inhibited by > 20% at terminal sacrifice in the high and middle dose groups. Changes described as 'necrobiotic foci' were observed in the liver at 500 ppm, which were considered not to be related to treatment. The NOAEL was 20 ppm, equivalent to 1.0 mg/kg bw per day, on the basis of inhibition of brain cholinesterase activity at 100 ppm (Johnston, 1962). Table 1. Acute toxicity of phosmet Species Strain Sex Route LD50 (mg/kg bw) Purity Reference or LC50 (mg/m3) (%) (95% CI or range) Mouse Swiss-Webster albino M Oral 50.1 (34.4-73.0) NR Meyding, 1965 Mouse Swiss-Webster albino M Oral 20-43 a Bullock, 1971 Mouse NR M Oral 36.9 (21.7-62.8) 95 Bullock, 1972 Mouse Albino M&F Oral 38 b Johnston, 1966 Mouse Albino M&F Oral 49 c Johnston, 1966 Mouse Albino M&F Oral 43 d Johnston, 1966 Mouse Albino NR Oral 26-60 NR Danilenko, 1969 Mouse Swiss-Webster M Intraperitoneal 40-50 NR Meyding, 1965 Mouse Swiss-Webster M Subcutaneous 300 NR Meyding, 1965 Rat Albino M Oral 310 (267-360) NR Ray, 1964 Rat Sprague-Dawley M Oral 245 (161-367) NR Meyding, 1965 Rat Sprague-Dawley albino M Oral 140 (76-255) 98 Nuclear Science Corp., 1962 Rat Albino NR Oral 92.5-164 NR Danilenko, 1969 Rat Sprague-Dawley albino M Oral 135-147a a Bullock, 1971 Rat Sprague-Dawley albino M Oral 121.3 (90.6-162.5) 92.5 Castles, 1977 Rat Sprague-Dawley albino F Oral 121.3 (96.7-152.1) 92.5 Castles, 1977 Rat Sprague-Dawley M Intraperitoneal approx. 100 NR Meyding, 1965 Rat Sprague-Dawley M Subcutaneous > 1200 NR Meyding, 1965 Rat Sprague-Dawley albino F Inhalation > 0.15e 92.5 Castles, 1977 Guinea-pig NR NR Oral 200 NR Danilenko, 1969 Rabbit New Zealand white NR Percutaneous > 4600 a Bullock, 1971 Rabbit New Zealand white NR Percutaneous > 5000 92.5 Castles, 1977 Cat NR NR Inhalation 65f NR Cited by Izmerov, 1983 Chicken White Leghorn F Oral 2020 94.7 Sprague, 1982 Table 1 (continued) NR, not reported a Precise figure depended on formulation and route of synthesis of active ingredient. b Technical-grade in corn oil; purity not stated c Technical-grade in 20% PEG300; purity not stated d Imidan 50% wettable powder in aqueous suspension; concentration of active ingredient, 50%; results given for active ingredient e LC50' 1 h: mg/l f LC50' time unstated Three groups of 10 male and 10 female albino rats (strain unspecified) were treated with phosmet for 16 weeks. Animals in the 'low dose' group initially received 450 ppm, equivalent to 22.5 mg/kg bw per day, which was increased stepwise to 6000 ppm, equivalent to 300 mg/kg bw per day, by the 12th week. The 'high dose' group was started on 800 ppm, equivalent to 40 mg/kg bw per day, which was increased stepwise to 1120 ppm, equivalent to 56 mg/kg bw per day. Clinical signs (nervousness, tremors, diarrhoea) were observed in all treated animals. Body-weight gain was decreased in the high dose group in comparison with controls, and marked hepatic degenerative changes (eosinophilia, vacuolation and swelling, with little change in nuclear morphology) were also seen in the high-dose group. Erythrocyte cholinesterase activity was inhibited by about 100% in both groups, and plasma cholinesterase activity was inhibited by > 50% in all groups. Brain cholinesterase was inhibited by 75 and 80% in males at the low and high doses and by 84 and 82% in females at the low and high doses, respectively. There was no NOAEL, as brain cholinesterase activity was inhibited in both treated groups and because of the variable dosing (Johnston, 1963a). Cats Veterinary use of phosmet as a dip for treating flea infestation caused toxic epidermal necrolysis in a female Himalayan cat. This observation has not been repeated (Frank et al., 1992). Dogs Groups of four male and four female beagle dogs were treated with dietary concentrations of 0, 10, 75 or 563 ppm, equivalent to 0.25, 1.9 or 14 mg/kg bw per day, for 14 weeks. All of the animals gained weight, except for one given the middle and one given the low dose. Haematological and clinical chemical parameters were unaffected by the treatment, except that marked depression of erythrocyte cholinesterase activity and somewhat less marked depression of plasma cholinesterase activity were found at the high dose. Brain cholinesterase activity at terminal sacrifice was also depressed at the high dose. The levels of plasma, erythrocyte and brain cholinesterase were normal in the other three groups. At autopsy, no pathological changes attributable to treatment were observed. The NOAEL was 75 ppm, equivalent to 1.9 mg/kg bw per day (Johnston, 1962). Groups of three male and three female beagle dogs received phosmet (purity unspecified) in the diet at concentrations of 0, 20, 40 or 400 ppm, equivalent to 0.5, 1 or 10 mg/kg bw per day, for two years. One male at the highest dose was killed in extremis; survival was otherwise unaffected. Erythrocyte cholinesterase activity was depressed at 400 ppm throughout most of the study. At termination, brain cholinesterase activity was considerably depressed in the animals at the high dose, to 58% of control activity in males and 32% in females. Interpretation of the study was hampered by the small group size. The NOAEL was 40 ppm, equivalent to 1 mg/kg bw per day (Lobdell & Johnston, 1966). (c) Long-term toxicity and carcinogenicity Mice Groups of 60 male and 60 female B6C3F1 mice were fed phosmet (purity, 94.7%) at dietary concentrations of 0, 5, 25 or 100 ppm, equal to 0.75, 4 or 15 mg/kg bw per day for two years. Up to 10 mice of each sex in each group were killed at 12 months, and cholinesterase activity and haematological parameters were measured in these animals and in 10 animals of each sex from each group at terminal sacrifice. Plasma and brain cholinesterase activities were measured at the time of the interim kill, and plasma, brain and erythrocyte cholinesterase at termination. Phosmet did not affect survival. Body weight was slightly but significantly increased for most of the study in animals receiving the highest dose, and food consumption was occasionally reduced. In males at the highest dose there was an increased frequency of convulsions, usually associated with handling of the animals. Plasma cholinesterase activity was inhibited by about 50% in males and females at the highest dose and by about 13% in females at the middle dose at the time of interim sacrifice. Brain cholinesterase activity was inhibited by > 20% in all treated groups at interim sacrifice. Plasma cholinesterase activity was inhibited at termination in the groups receiving the highest dose, but the activity in erythrocytes was comparable in all groups. Some inhibition of brain cholinesterase activity was found in females at the middle and highest doses at termination, but, while statistically significant, the depression was < 20% in the middle dose group and 22% in the highest dose group. Brain cholinesterase activity was not depressed in males at the terminal kill. No treatment-related effects were seen on haematological parameters at interim or final sacrifice, and no treatment-related changes in organ weights or macroscopic or microscopic appearance were seen, except in the liver. Relative liver weights were increased at 12 months in males receiving 100 ppm, and at termination there was an increase in the prevalence of mild vacuolation. There was also an increase in the incidence of liver adenomas (25/50, with 13/49 in controls) in males at the highest dose. When animals killed at 12 months were included, liver adenomas were found in 13/60 controls, 10/60 at 5 ppm, 14/60 at 25 ppm and 27/60 at 100 ppm. In an addendum to the report, the prevalence of liver adenomas in the group given the highest dose was reported to be comparable to that in historical controls. No increase in the incidence of liver tumours was seen in females. The NOAEL was 25 ppm, equal to 4 mg/kg bw per day, on the basis of increased incidences of convulsions, hepatocellular cytoplasmic vacuolation and liver-cell adenomas in males and decreased brain cholinesterase activity in females at 100 ppm. The apparent change in brain cholinesterase activity at the time of the interim kill was considered not to be a true reaction to treatment with phosmet, in view of the absence of a similar effect at the time of the terminal kill, after a longer period of treatment (Katz et al., 1984; Sprague & Turnier, 1986). Rats Groups of 25 male and 25 female albino rats (strain unspecified) received phosmet (purity unspecified) in the diet at concentrations of 0, 20, 40 or 400 ppm, equivalent to 1, 2 or 20 mg/kg bw per day, for two years. Body-weight gain and plasma and erythrocyte cholinesterase activities were depressed at 400 ppm; the cholinesterase activities were decreased throughout the study, and brain cholinesterase activity was lowered at termination. Hepatocyte vacuolation was seen at the highest dose. Pituitary adenomas were more frequent at 40 ppm (46%) and 400 ppm (56%) than in the controls (36%) and in those receiving 20 ppm (21%), but there was not a clear dose-response relationship. The small groups and the small number of survivors at termination made interpretation of the study somewhat difficult and precluded a conclusion being drawn about the carcinogenicity of phosmet. The NOAEL was 40 ppm, equivalent to 2 mg/kg bw per day (Lobdell & Johnston, 1966). Groups of 60 or 70 Sprague-Dawley Crl:CD SD BR rats of each sex received phosmet (purity, 94.3%) in the diet at concentrations of 0, 20, 40 or 200 ppm, equal to 1.1, 1.8 or 9.4 mg/kg bw per day for males and 1.1, 2.1 or 10.9 mg/kg bw per day for females. For interim evaluation, 20 rats of each sex from the control group and 10 of each sex from each test group were killed after 12 months, and the study was continued for a further year. An additional group of 20 rats of each sex received 400 ppm (equal to 23 mg/kg bw per day for males and 27 mg/kg bw per day for females) for 12 months. Exposure did not adversely affect survival; indeed, there appeared to be a dose-related increase in survival. No specific clinical signs were attributable to treatment. Weight gain was reduced throughout the study in animals of each sex at 400 ppm and in the early part of the study at 40 (at 4, 21, 37, 45 and 49 weeks) and 200 ppm (at 1, 2 and 4weeks) in females only. These decreases are unlikely to be biologically significant. Significant reductions in cholinesterase activities were observed: plasma cholinesterase activity was reduced by > 20% at 200 and 400 ppm in males and at 40, 200 and 400 ppm in females; a reduction of 21% was observed at 18 weeks in females at 20 ppm. Erythrocyte cholinesterase activity was reduced by 15-20% at 20 ppm and by > 20% at higher dietary concentrations in males, and by 15-20% at 40 ppm and very considerably at higher concentrations in females. Brain cholinesterase activity was depressed in males at 200 ppm (interim and final kill), although the depression at 24 months was less than 15%. In females, depression of brain cholinesterase activity by > 20% was observed at 200 ppm at both interim and final sacrifice. Brain cholinesterase activity was also depressed in animals of each sex at 400 ppm. An increase in the incidence and severity of fatty liver was seen at 200 ppm. No tumours were seen that were attributable to treatment with phosmet. The NOAEL was 40 ppm, equal to 1.8 mg/kg bw per day, on the basis of an increased incidence of fatty change in the livers of animals of each sex and depressed brain cholinesterase activity in females at 200 ppm (Chang et al., 1991). (d) Embryotoxicity and teratogenicity Rats In Wistar rats given a single dose of 30 mg/kg bw phosmet orally once on day 9 of pregnancy or 1.5 mg/kg bw on alternate days (every day in the summary) throughout pregnancy, post-implantation mortality of embryos was increased. The dose of 30 mg/kg bw on day 9 or 13 caused developmental abnormalities, such as hypognathia and hydrocephaly. A dose of 0.06 mg/kg bw on alternate days (every day in the summary) had no effect. There was no NOAEL (Martson & Voronina, 1976). Phosmet (purity, 95.8%) was administered in the diet of CD rats at amounts that provided a mean consumption of 0, 10, 22, 27 or 29 mg/kg bw per day on days 6-15 of pregnancy. The size of the groups varied from 47 controls to 17 and 23 at the two higher doses. The rats were killed on day 21. At 22 mg/kg bw per day, food intake and weight gain were reduced. As phosmet was neither teratogenic nor fetotoxic, the NOAEL for maternal toxicity was 10 mg/kg bw per day and the NOAEL for fetal toxicity was the highest dose, 29 mg/kg bw per day. In a similar study, in which phosmet was administered by gavage at doses of 5, 10, 20, 25 or 30 mg/kg bw per day (with no separate control group), survival was affected at the two higher doses. There was a significant reduction in the proportion of rats at 25 mg/kg bw per day that became pregnant, and there was a reduction in food intake at > 10 mg/kg bw per day and a reduction in weight gain at > 20 mg/kg bw per day. In the absence of a suitable control group, there was no NOAEL in this study (Staples et al., 1976). Groups of 24 female alpk:APfSD rats were dosed with phosmet (purity, 96.4%) in corn oil by gavage at 0, 5, 10 or 15 mg/kg bw per day on days 7-16 days of gestation. The rats were killed on day 22 of gestation and the uteruses examined for live fetuses and intrauterine deaths. Maternal toxicity in the form of reduced body-weight gain, reduced food consumption and clinical signs (shaking, piloerection) was seen at the highest dose. As there were smaller but statistically significant effects on body-weight gain at 10 mg/kg bw per day between days 7 and 16, the lowest dose, 5 mg/kg bw per day, was the NOAEL for maternal toxicity. As no teratogenic or fetotoxic effects were seen, the NOAEL for developmental toxicity was 15 mg/kg bw per day (Hodge, 1991). In a three-generation study in CD rats, the F0 generation consisted of two groups of 20 males and two groups of 20 females: One group of each sex received no treatment, while the other received technical-grade phosmet (purity, 99%) in the feed at 40 ppm, equivalent to 2 mg/kg bw per day, or half this concentration during the first three weeks. Animals in each group were mated twice, and the offspring (F1a and F1b) were examined at birth and at weaning, when the F1a rats were killed. The F0 rats were killed but not examined by necropsy. The F1b rats were retained to make up three new groups of 20 rats of each sex, which received phosmet at dietary concentrations of 0, 40 or 80 ppm from weaning until sacrifice. Mating of the F1b rats produced F2a and F2b litters; the F2a rats were sacrificed and the F2b offspring were used, like the preceding generation, to make three new groups of F2a and F2b rats. Offspring were sacrificed at weaning. The treated and control animals were comparable throughout the study. On histopathological examination of the F3b animals, some mild hepatic vacuolation and reduced glycogen content were observed more frequently in treated than in untreated animals; however, the former finding was not frequent in any dose group, and the latter (in adults and therefore presumably in fetuses) was strongly dependent on time since last feed, which may have been different for the various dose groups. In view of the lack of other findings, the Meeting considered the NOAEL to be 40 ppm, equivalent to 2 mg/kg bw per day (Hollingsworth et al., 1965). In a two-generation study, technical-grade phosmet (purity, 95.2%) was administered to Crl:CD(SD)BRVAF/+tm rats at dietary concentrations of 0, 20, 80 or 300 ppm, equal to 1.3, 5.0 or 19.4 mg/kg bw per day in F0 males; 1.5, 6.3 or 24.3 mg/kg bw per day in F1 males; 1.5, 6.0 or 24.4 in F0 females; and 1.5, 6.2 or 26.4 mg/kg bw per day in F1 females. Treatment of the F0 generation was started at 56 days of age, and mating occurred 56 days later. The F1a animals were weaned at 21 days and sacrificed. Shortly afterwards, the F0 rats were again mated to produce the F1b litters, of which about 25 males and 25 females were used to form the F1 parents. At about 114 days of age, the F1 parents were mated to produce the F2 litters. Toxicity was observed in parents at 80 and 300 ppm in both generations. Reduced body-weight gain and food consumption were observed in animals of each sex at 300 ppm. Males had reduced testicular weights in both generations and reduced spleen weight and hepatocellular vacuolization in the F1 generation. Dehydration was seen in the F0 females at 300 ppm, and chromorhinorrhoea was seen in F1 females at 300 ppm. At 80 ppm, there was reduced body-weight gain in F0 male parents and reduced erythrocyte cholinesterase activity in both generations; in F0 parental females, there was reduced weight gain during lactation and reduced relative liver and adrenal weights. Reduced relative spleen and thymus weights were seen in the F1 generation, and reduced erythrocyte cholinesterase activity was seen in both generations. Plasma cholinesterase activity was reduced in parental F0 males only. Erythrocyte cholinesterase activity, although reduced, was > 80% of that of controls at 20 ppm. Mating and fertility were reduced at 80 and 300 ppm, and there were reduced numbers of pups per litter, reduced pup weight and reduced survival of pups at 300 ppm. The NOAEL for toxicity to the parents and for effects on reproductive performance was 20 ppm (equal to 1.3 mg/kg bw per day), and the NOAEL for developmental toxicity was 80 ppm (equal to 5.0 mg/kg bw per day) (Meyer & Walberg, 1990). Rabbits Phosmet (purity unspecified) was administered by gavage to New Zealand white rabbits at 35 mg/kg bw per day on days 7-12 of pregnancy; the animals were killed at day 28. No embryotoxic effects were detected, although such effects were observed with thalidomide in the same study. The NOAEL for phosmet was 35 mg/kg bw per day; however the treatment period was rather short and included only part of the period of organogenesis (Fabro et al., 1966). Groups of 20 female New Zealand white rabbits were treated with phosmet (purity, 96.4%) at doses of 0, 2, 5 or 15 mg/kg bw per day in corn oil by gavage on days 7-19 of pregnancy. The animals were killed on day 30 of gestation. The highest dose had a slight effect on maternal body-weight gain, and clinical signs thought to be related to treatment (unsteadiness, shaking, salivation and irregular breathing) were seen in four animals. This dose did not affect the number or growth of offspring or survival in utero. The two highest doses increased the number of minor skeletal defects. The Meeting concluded that the NOAEL for maternal toxicity was 5 mg/kg bw per day and that for fetal toxicity was 2 mg/kg bw per day (Moxon, 1991). Monkeys Phosmet (purity unspecified) was administered at doses of 2, 4 or 8 mg/kg bw per day by gastric intubation to groups of seven pregnant rhesus macaques (Macaca mulatta) on days 22-32 of gestation; there were no concurrent controls. Except when resorption or abortion had occurred, the monkeys were delivered by caesarian section after 83-87 days of pregnancy. Fetal mortality was observed, but there was no dose-response relationship and no abnormal fetuses were observed; abortions or resorptions occurred in 2/7 animals at 2 mg/kg bw per day, 0/7 animals at 4 mg/kg bw per day and 1/7 animals at 8 mg/kg bw per day. The rate of fetal mortality in untreated monkeys at the laboratory was stated to be 13.2%. External examination revealed no abnormal fetuses. Thalidomide, which was also tested in the study, induced both fetal mortality and abnormal fetuses, while captan at a dose of 25 mg/kg bw per day induced a high rate of fetal mortality. The NOAEL for phosmet was thus the highest dose, 8 mg/kg bw per day (Courtney & Finkelstein, 1968). (f) Genotoxicity The results of tests for the genotoxicity of phosmet are summarized in Table 2. (g) Special studies (i) Skin and eye irritation and skin sensitization Phosmet is not an irritant in the Draize test. It is a mild eye irritant (Bullock, 1971). (ii) Delayed neuropathy in chickens Three groups of 10 white Leghorn hens were given phosmet at dietary concentrations of 100, 316 or 1000 ppm, equivalent to 12.5, 39.5 or 125 mg/kg bw per day, for 6-7 weeks; a further group of 10 hens received tri- ortho-cresyl phosphate at 1000 ppm (the oral LD50 of this compound in hens is about 2 g/kg bw), and a fifth group of three hens received normal diet. One of the hens receiving tri- ortho-cresyl phosphate died, and eight of the survivors were paralysed or severely ataxic by the fourth week. One of the birds receiving the highest dose of phosmet was considered to be slightly ataxic, but this was not confirmed by another observer. Spinal axonal degeneration and myelin degeneration were seen in the birds treated with tri- ortho-cresyl phosphate but not in those given phosmet (Johnston, 1963b). Phosmet (purity, 94.7%) was given to groups of 10 white Leghorn hens at 0, 0.02, 0.20 or 2.05 g/kg bw (14 birds at the highest dose) orally in gelatine capsules twice at 21-day intervals, and the birds were killed 21 days after the second dose. Positive controls received 0.5 g/kg tri- ortho-cresyl phosphate. Atropine (118 mg/kg bw) and pralidoxime chloride (55 mg/kg bw) were administered subcutaneously on days 1 and 22 of the study to all birds treated with phosmet, and birds that showed severe clinical signs were further treated with the two antidotes. Transient signs of cholinergic toxicity were observed at the two higher doses; however, there were no clinical signs or histopathological findings suggestive of organophosphate-induced delayed neuropathy, whereas hens treated with tri- ortho-cresyl phosphate had characteristic histological changes (Sprague, 1982). Table 2. Results of tests for the genotoxicity of phosmet End-point Test system Concentration of phosmet Purity (%) Results Reference In vitro Reverse mutation S. typhimurium TA98, 0.156-2.5 mg/plate 95.7 Positivea Majeska & Matheson, 100, 1535, 1537 1986 Reverse mutation S. typhimurium TA1535, Up to 20 µg/plate NR Negative Shirasu, 1975; Shirasu 1536, 1537, 1538 et al., 1976 Reverse mutation S. typhimurium TA98, Up to 5000 µg/plate 95.7 Positivea Moriya et al., 1983 100, 1535, 1537 Reverse mutation B. subtilis H17 rec+ Up to 20 µg/plate NR Negative Shirasu, 1975; Shirasu and 45 rec- et al., 1976 Reverse mutation E. coli B/r WP2hcr+ Up to 20 µg/plate NR Negative Shirasu, 1975; Shirasu and WP2hcr- et al., 1976 Reverse mutation E. coli WP2 hcr approx. 0.100-5000 mg/plate 95.7 Negative Moriya et al., 1983 Cell BALB/3T3 mouse 0.0005-0.014 mg/ml 95.7 Negative Dickey, 1986 transformation cells Forward mutation Mouse lymphoma 0.02-0.1 mg/mlb 95.7 Positiveb Hertzel, 1986 at tk locus cells (L1578Y) 0.004--0.04 mg/mlc Negativec Chromosomal Mouse lymphoma 0.04-0.1 mg/mlb 95.7 Negativea Snyder, 1986a aberration cells (L1578Y) 0.008-0.04 mg/mlc Sister chromatid Mouse lymphoma 0.04-0.1 mg/mlb 95.7 Positivea Snyder, 1986a exchange cells (L1578Y) 0.008-0.040 mg/mlc DNA damage Human fibroblasts 0.25-1 mg/ml 95.7 Negativea Snyder, 1986b and repair (foreskin) Table 2 (contd) End-point Test system Concentration of phosmet Purity (%) Results Reference In vivo Micronucleus Mouse bone marrow 17 mg/kg bw orally 95.5 Negative Gibbs, 1986 formation NR, not reported a In the presence and absence of metabolic activation b In the absence of metabolic activation c In the presence of metabolic activation 3. Observations in humans The frequency of chromatid-type aberrations in peripheral blood lymphocytes taken from workers exposed to phosmet was moderately increased (Király et al., 1979). A number of cases of phosmet poisoning have been reported in the literature. In one, poisoning was associated with decrements in neuromuscular function and ultrastructural abnormalities in the motor end-plate. The subject had been exposed during a five-week spraying operation and had at no time been acutely poisoned. The changes proved to be reversible (Good et al., 1993). Comments Phosmet is rapidly absorbed, distributed and excreted, predominantly in the urine. Less than 1% of the label in the urine was in the form of phosmet or phosmet oxon. In rats, there were two major urinary metabolites, N-(methylsulfinylmethyl)phthalamic acid and N-(methylsulfonylmethyl)-phthalamic acid. The LD50 values have been estimated for a variety of species for most routes. The oral LD50 in mice is 20-50 mg/kg bw and that in rats is 100-300 mg/kg bw. WHO (1992) has classified phosmet as moderately hazardous. In a four-week study of toxicity, mice were fed diets containing 0, 5, 15, 50, 150 or 500 ppm. The NOAEL was 50 ppm, equivalent to 7.5 mg/kg bw per day, on the basis of reduced food intake, reduced body-weight gain and reduced liver and kidney weights. In a 14-week study of toxicity, rats were fed diets containing 0, 20, 100 or 500 ppm. The NOAEL was 20 ppm, equivalent to 1 mg/kg bw per day, on the basis of inhibition of brain cholinesterase activity. In a 14-week study in beagle dogs fed diets containing 0, 10, 75 or 563 ppm, the NOAEL was 75 ppm, equivalent to 1.9 mg/kg bw per day, on the basis of inhibition of brain cholinesterase activity. In a two-year study of toxicity in dogs fed diets containing 0, 20, 40 or 400 ppm, the NOAEL was 40 ppm, equivalent to 1 mg/kg bw per day, on the basis of inhibition of brain cholinesterase activity. The Meeting concluded, however, that the last study was inappropriate for estimation of an ADI in view of the small group size and the large dose interval between the NOAEL and the effect level. In a two-year study of carcinogenicity in mice fed levels of 0, 5, 25 or 100 ppm, there was evidence of hepatotoxicity at the high dose, and a slightly but not statistically significantly increased incidence of hepatic adenomas in comparison with concurrent controls. There was, however, no increase in incidence in comparison with historical controls, and the Meeting concluded that there was no evidence of carcinogenicity in mice. Although brain cholinesterase activities were determined in this study, the results proved difficult to interpret: at the interim kill, brain cholinesterase activity was apparently reduced in each sex in all dose groups; at the terminal kill, brain cholinesterase activity was reduced at the high dietary level in females and not at all in males. The Meeting concluded that the apparent change seen at the interim kill did not represent a true reaction to treatment with phosmet, in view of the absence of a similar effect at the terminal kill, after a longer treatment period. The NOAEL was 25 ppm (equal to 4 mg/kg bw per day) on the basis of hepatotoxicity and brain cholinesterase inhibition at the high dose. In an early, inadequate, two-year study of toxicity and carcinogenicity in rats treated via the diet, the NOAEL was 40 ppm, equivalent to 2 mg/kg bw per day, on the basis of depressed body-weight gain and brain cholinesterase inhibition. In another two-year study of toxicity and carcinogenicity, rats were fed diets containing 0, 20, 40 or 200 ppm phosmet, and a smaller group received 400 ppm. The NOAEL was 40 ppm, equal to 1.8 mg/kg bw per day, on the basis of fatty changes in the liver and reduced brain cholinesterase activity in females. There was no evidence of carcinogenicity in rats. Two multigeneration studies of reproductive toxicity have been conducted with phosmet in rats. In a three-generation study, animals were exposed to dietary levels of 0 or 40 ppm phosmet (first generation) and 0, 40 or 80 ppm (second generation). The NOAEL was 40 ppm, equivalent to 2 mg/kg bw per day. In a two-generation (two litters per generation) study of reproductive toxicity, rats were fed dietary concentrations of 0, 20, 80 or 300 ppm phosmet. The NOAEL was 20 ppm, equal to 1.3 mg/kg bw per day, on the basis of reduced mating and fertility at higher doses. In a study of teratogenicity, rats were dosed orally at 0, 5, 10 or 15 mg/kg bw per day. The NOAEL for maternal toxicity was 5 mg/kg bw per day on the basis of reduced body-weight gain; there was no evidence of fetotoxicity or teratogenicity at the highest dose tested. In a study of teratogenicity in rabbits dosed at 0, 2, 5 or 15 mg/kg bw per day, the NOAEL for maternal toxicity was 5 mg/kg bw per day on the basis of reduced body-weight gain, while the NOAEL for fetotoxicity was 2 mg/kg bw per day on the basis of the presence of minor skeletal anomalies. The Meeting concluded that phosmet was not clastogenic but that its mutagenic potential is unclear. In an attempt to address this issue, studies of DNA binding in vivo are being requested. In two studies, phosmet did not cause delayed neuropathy in chickens; however, the Meeting considered a summary of a study in which some inhibition of brain neuropathy target esterase was observed at a dose below the LD50. It therefore concluded that phosmet may have the potential to cause delayed neuropathy, although at doses higher than the unprotected LD50. A further study is being requested to clarify this issue. An ADI was allocated on the basis of the NOAEL in the multigeneration study in rats (20 ppm, equal to 1.3 mg/kg bw per day) and a 100-fold safety factor. Toxicological evaluation Levels that cause no toxic effect Mouse: 25 ppm, equal to 4 mg/kg bw per day (two-year study of carcinogenicity) Rat: 40 ppm, equal to 1.8 mg/kg bw per day (two-year study of toxicity and carcinogenicity) 20 ppm, equal to 1.3 mg/kg bw per day (two-generation study of reproductive toxicity) 5 mg/kg bw per day (study of teratogenicity, maternal toxicity) 15 mg/kg bw per day (study of teratogenicity, developmental toxicity) Rabbit: 5 mg/kg bw per day (study of teratogenicity, maternal toxicity) 2 mg/kg bw per day (study of teratogenicity, fetotoxicity) Estimate of acceptable daily intake for humans 0-0.01 mg/kg bw Studies that would provide information useful for continued evaluation of the compound 1. Long-term study of toxicity in dogs 2. Study of DNA binding in vivo 3. Study of delayed neurotoxicity in chickens at an appropriately high dose, with estimation of neuropathy target esterase 4. Further observations in humans In order to maintain the ADI, these data should be submitted in 1997, in time for review in 1998. References Ackermann, H., Seidler, H., Kagan, Y.S. & Voronina, V.M. (1976) Metabolic and toxic behaviour of phthalimide derivatives. 1. Fate of Imidan in the fetus. Arch. Toxicol., 36, 127-137. Bullock, C.H. (1971) Imidan (EDC process). Unpublished report T-1666, dated 27 May 1971 from Stauffer Chemical Co. Western Research Center. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Bullock, C.H. (1972) Unpublished report T-4035, dated 18 August 1972 from Stauffer Chemical Co., Western Research Center. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Castles, T.R. (1977) Unpublished report T-6123, dated 3 August 1977 from Stauffer Chemical Co., Western Research Center. 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Unpublished report, dated 7 May 1965, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Izmerov, N.F. (1983) Scientific Reviews of Soviet Literature on Toxicity and Hazards of Chemicals, Moscow, Centre of International Projects. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Johnston, C.D. (1962) Imidan: an evaluation of safety of Imidan in the rat and the dog. Unpublished report, dated 21 February 1962, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Johnston, C.D. (1963a) Further evaluation of the safety of Imidan in the rat. Unpublished report, dated 27 February 1963, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Johnston, C.D. (1963b) Imidan: demyelination study in the chicken. Unpublished report, dated 27 February 1963, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Johnston, C.D. (1966) Imidan: single dose oral toxicity in mice. Unpublished report, dated 22 November 1966, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Jones, N.B., Sauerhoff, M.W., Thomassen, R.W. & Zwicker, G.M. (1981) Four week dietary range-finding study in mice with Imidan technical. Unpublished report No. T-10704, dated July 1981 from Environmental Health Center, Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Katz, A., Frank, D.W., Zwicker, G.M., Sprague, G.L., Turnier, J.C. & Freudenthal, R.I. (1984) T(TM)10719. Two-year dietary oncogenicity study in mice with Imidan technical. Unpublished report, dated May 1984, from Environmental Health Center, Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Király, J., Szentesi, I., Ruzicska, M. & Czeize, A. (1979) Chromosome studies in workers producing organophosphate insecticides. Arch. Environ. Contam. Toxicol., 8, 309-319. Lee, H. & Miaullis, J.B. (1969) The effect of imidan on cholinesterase and aliesterase activity in rats. Unpublished report No. 004571 from Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Lobdell, B.J. & Johnston, C.D. (1966) Imidan: safety evaluation by two-year feeding studies in the rat and the dog. Unpublished report, dated 21 July 1966, from Woodard Research Corp., Herndon, VA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. McBain, J.B., Menn, J.J. & Casida, J.E. (1968) Metabolism of carbonyl-C14-labelled Imidan, N-(mercaptomethyl)phthalimide- S-(O,O-dimethylphosphorodithioate), in rats and cockroaches. J. Agric. Food Chem., 16, 813-820. Majeska, J.B. & Matheson, D.W. (1986) Imidan: mutagenicity evaluation in Salmonella typhimurium Unpublished report No. T-12819, dated 4 March 1986 from Environmental Health Center, Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Martson, L.V. & Voronina, V.M. (1976) Experimental study of the effect of a series of phosphoroorganic pesticides (Dipterex and Imidan) on embryogenesis. Environ. Health Perspectives, 13, 121-125. Meyer, L.S. & Walberg, J.A. (1990) A two generation reproduction study in rats with R-1504. Unpublished report No. T-13260, dated 18 May 1990, from Environmental Health Center, Ciba-Geigy Corp., Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. 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Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Snyder, R.D. (1986b) Effects of imidan on human fibroblast DNA. Unpublished report No. T-12823, dated 30 May 1986, from In Vitro Toxicology Section, Environmental Health Centre, Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Sprague, G.L. (1982) Acute delayed neurotoxicity study with Imidan technical in adult hens. Unpublished report No. T-10910, dated 9 August 1982, from Richmond Toxicology Laboratory, Toxicology Department, Stauffer Chemical Co., de Guigne Technical Center, Richmond, CA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Sprague, G.L. & Turnier, J.C. (1986) T-10719. Addendum: Two-year dietary oncogenicity study in mice with Imidan technical. Unpublished addendum, dated 22 May 1986, from Environmental Health Center, Stauffer Chemical Co., Agrochemical Division, Farmington, CT, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Staples, R.E., Kellam, R.G. & Haseman, J.K. (1976) Developmental toxicity in the rat after ingestion or gavage of organophosphate pesticides (Dipterex, Imidan) during pregnancy. Environ. Health Perspectives, 13, 133-140. Tarr, J.B. & Hemingway, R.J. (1993a) The nature of the residues of orally administered [carbonyl-14C]-phosmet in tissues and milk of lactating goats. Unpublished report RR 92-103B, study No. PMS-352, dated 22 January 1983, from Zeneca Agricultural Products, Western Research Center, ICI Americas Inc., Richmond, CA, USA. Submitted to WHO by Zeneca Agrochemicals, Haslemere, Surrey, United Kingdom. Tarr, J.B. & Hemingway, R.J. (1993b) The nature of the residues of orally administered [carbonyl-14C]-phosmet in tissues and eggs of laying hens. 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See Also: Toxicological Abbreviations Phosmet (ICSC) Phosmet (JMPR Evaluations 2003 Part II Toxicological) Phosmet (Pesticide residues in food: 1976 evaluations) Phosmet (Pesticide residues in food: 1978 evaluations) Phosmet (Pesticide residues in food: 1979 evaluations) Phosmet (Pesticide residues in food: 1981 evaluations) Phosmet (Pesticide residues in food: 1984 evaluations)