MEVINPHOS T. C. Marrs Department of Health, Elephant and Castle, London, United Kingdom Explanation Evaluation for acceptable daily intake Biochemical aspects Absorption, distribution, and excretion Biotransformation Toxicological studies Acute toxicity Short-term toxicity Long-term toxicity and carcinogenicity Reproductive toxicity Developmental toxicity Genotoxicity Special studies Dermal and ocular irritation and dermal sensitization Neurotoxicity Observations in humans Comments Toxicological evaluation References Explanation Mevinphos was evaluated for toxicological effects by the JMPR in 1963 and 1965 (Annex 1, references 2 and 4); in neither case was an ADI assigned. An ADI of 0-0.0015 mg/kg bw was established in 1972 (Annex 1, reference 18). The toxicology of the compound was reviewed at the present Meeting within the CCPR periodic review programme. This monograph summarizes data not previously reviewed and relevant data from the previous monograph on mevinphos (Annex 1, reference 19). Evaluation for acceptable daily intake 1. Biochemical aspects Mevinphos consists of two cis/trans isomers of methyl 3-(dimethoxyphosphinyloxy)-2-butenoate. Commercial preparations vary in the relative amounts of each, but most contain about 65-75% alpha and 10-20% ß isomer (Figure 1). Figure 1. Isomers of mevinphos O " H3C C-OCH3 \ / O C=C " / \ CH3O-P-O H ' OCH3 alpha-; E-; cis-mevinphos H3C H \ / O C=C " / \ CH3O-P-O C-OCH3 ' " OCH3 O ß-; Z-; trans-mevinphos (a) Absorption, distribution, and excretion The penetration of 14C-mevinphos (purity, 96%; 73% alpha and 15% ß isomer) diluted with water across the nonoccluded skin of Crl:CD(SD)BR rats was examined in vivo. The doses were 5, 30, or 150 µg per animal (0.4, 2.5, and 12.5 µg/cm2 of skin). The radiochemical purity of the labelled compound was 87%; this was repurified to > 96%. Absorption, measured as the amount in the skin and that penetrating the skin, was 47-48% of the applied dose; of this, 13-17% crossed the skin (Jeffcoat & Coleman, 1993). After a preliminary study in which it was found that substantial amounts of label were expired, the absorption, distribution, and excretion of mevinphos (75% alpha and 15% ß isomer) was studied in groups of five male and five female Sprague-Dawley (Crl:CD BR) rats. Either a single oral dose of 14C-mevinphos at 0.15 or 1.5 mg/kg bw; multiple doses of 0.15 mg/kg bw, only the last (16th) dose being radiolabelled; or a single intravenous dose of 0.15 mg/kg bw were given. In all cases, the label was rapidly absorbed, transformed, and excreted, predominantly by exhalation, with 77% in the breath of males and 78% in the breath of females after the single oral dose of 0.15 mg/kg bw, and only 14% in the urine over 24 h, mostly within 8 h. At the higher oral dose, 61-62% of the label appeared in the breath and 23% in the urine. After the intravenous dose, about 71% of the label appeared in the breath of animals of each sex and 16 and 17% in the urine of males and females, respectively. After administration of 16 daily oral doses, 75% of the administered dose was found in the expired air of males and 77% in that of females, urinary excretion being 16 and 19%. In all these studies, almost all of the radiolabel (85-96%) was eliminated within 24 h as carbon dioxide and in the urine; < 1.3% was excreted in the faeces. Thus, mevinphos was almost completely absorbed (Reddy et al., 1991). (b) Biotransformation In the study of Reddy et al. (1991), mevinphos was metabolized primarily to carbon dioxide, and only traces of other volatile materials were present. High-performance and thin-layer liquid chromatography of the urine showed four major peaks, representing unmetabolized alpha isomer of mevinphos and the alpha isomers of mevinphos acid and desmethyl mevinphos. A fourth peak may have represented mevinphos diacid. The proposed metabolic pathway for mevinphos in Sprague-Dawley rats is shown in Figure 2. 2. Toxicological studies (a) Acute toxicity The results of studies of the acute toxicity of mevinphos are shown in Table 1.Table 1. Acute toxicity of mevinphos in experimental animals Species Strain Sex Route Purity LD50 (mg/kg bw) Reference (%) or LC50 (mg/litre) (95% CI) Mouse Swiss Webster Male Dermal 99 12 (6-24) Skinner & Kilgore (feet) (1982) Rat Sherman Male Oral NR 6.1 Gaines (1969) Female 3.7 Rat Sprague-Dawley Male Oral NR 4.1 (3.5-5.0) Deenihan (1985) Female 2.2 (1.8-2.6) Rat Sprague-Dawley-derived CD Male Oral 97.7 3.5a Auletta (1988a) Female 2.3 (1.0-3.6) Rat Albino HSD:SD Male Oral Unknownb > 5 Kuhn (1994) Female > 5 Rat Sherman Male Dermal NR 4.7 Gaines (1969) Female 4.2 Rat Sprague-Dawley Crl:CD BR Male Dermal 90 >20 Trimmer (1989) Female >20 Rat Sprague-Dawley CD Male Inhalationc 100 12 Hoffman (1988) Female 7.3 Rabbit New Zealand white Male, Dermal NR 57 (38-86) Deenihan (1985) female Rabbit New Zealand white Male Dermal 99.3 51 (31-71) Auletta (1988b) Female 60 (23-97) Chicken White Leghorn pullets Female Oral approx. 97 11 (3.2-19) Barrett (1988) CI, confidence interval; NR, not reported a CI could not be calculated owing to distribution of deaths b Phosdrin 4 EC c 4-h exposure; only 3 h at highest dose as all animals had died (b) Short-term toxicity Mice In a three-month range-finding study, groups of 10 male and 10 female CD-1 mice were fed diets containing mevinphos (66.5% alpha, 21.2% ß isomer) at 0, 0.5, 1, 2, or 10 ppm, equal to 0, 0.1, 0.2, 0.4, and 2 mg/kg bw per day for males and 0, 0.1, 0.3, 0.5, and 2.7 mg/kg bw per day for females. Clinical observations, body weight, and food consumption were reported before treatment and weekly after the start of exposure, and plasma and erythrocyte cholinesterase activities were measured in five animals of each sex per group at week 7 and at termination. After three months, the animals were killed and autopsied, and brain acetylcholinesterase activity was measured in five animals of each sex per group. Organs from controls and animals at the high dose were examined grossly, and selected tissues were examined microscopically. Body weight and food consumption were similar in all groups, and no deaths occurred; clinical parameters were similar in all groups. Plasma cholinesterase activity was decreased by 37-49% in animals of each sex at 2 and 10 ppm at week 7. At termination, similar findings were seen in males, but the decreased plasma cholinesterase activity in females was confined to those at 10 ppm. Brain acetylcholinesterase activity was decreased by 16 and 22% in males and females at 10 ppm, respectively, in comparison with controls. The NOAEL was 2 ppm, equal to 0.4 mg/kg bw per day, on the basis of inhibition of brain acetylcholinesterase activity at 10 ppm (Atkinson, 1990). Rats Groups of 10 Sprague-Dawley Crl:CD BR rats received mevinphos (74.5% alpha, 15.1% ß isomer) by gavage for 90 days at doses of active ingredient of 0.056, 0.56, 1.1, or 1.7 mg/kg bw per day for males and 0.011, 0.056, 0.56, or 0.84 mg/kg bw per day for females. Five males at the two highest doses died, and the highest dose was decreased to 1.1 mg/kg bw per day on day 36; the groups at the two highest doses were then combined for most statistical purposes. Additionally, one female at 0.56 mg/kg bw per day died before scheduled termination. Clinical signs, including pinpoint pupils, oral and ocular discharges, and tremors were seen at doses > 0.56 mg/kg bw per day in animals of each sex. No statistically significant differences in body weight or food consumption were noted. Inhibition of plasma cholinesterase activity > 15% was seen at week 7 and terminally in males at doses > 0.56 mg/kg bw per days and in females at doses > 0.056 mg/kg bw per day. Brain acetylcholinesterase activity was inhibited by > 15% at termination in animals of each sex at doses > 0.56 mg/kg bw per day. No significant depression of erythrocyte acetyl- cholinesterase activity was seen. There was a dose-related increase in mean cholesterol levels, which were statistically significantly increased in males at the high dose. No statistically significant differences in absolute or relative organ weights were seen between groups, but a dose-related trend in increased relative liver weights was seen in animals of each sex. Slight vacuolation in centrilobular and midzonal hepatocytes was seen in two male rats at the highest dose. The NOAEL was 0.056 mg/kg bw per day, on the basis of clinical signs and depressed brain acetylcholinesterase activity at higher doses (Keefe, 1992). Dogs Gelatine capsules containing mevinphos (75.1% alpha, 11.8% ß isomer) in corn oil were given to groups of five male and five female beagle dogs at doses of 0 or 0.5 mg/kg bw per day and to four males and four females at 0.025 or 0.25 mg/kg bw per day for one year. No deaths occurred during the study. The only clinical sign attributable to the test material was a higher prevalence of vomiting in the dogs at the high dose than in the controls. No significant differences in body weight or food consumption were noted, and no treatment-related changes were seen at ophthalmoscopic examination at weeks 12, 26, and 52. Blood was taken before treatment and at weeks 6, 12, 39, and 51 for laboratory analyses. No biologically significant haematological or biochemical changes were seen, other than changes in cholinesterase activity. Plasma and erythrocyte cholinesterase activities were determined on blood samples taken before the start of treatment, 3 h after dosing at 4, 12, 39, and 51 weeks, and before dosing at weeks 39 and 51. Brain acetylcholinesterase activity was measured at termination of the study. At many of these time intervals, both erythrocyte and plasma cholinesterase activities were depressed, particularly at the two higher doses. In dogs at the lowest dose, a depression > 15% was seen in erythrocyte enzyme activity at week 25 in males and females, at week 39 in males before treatment and in females before and after treatment, and at week 51 in males before and after treatment and in females after treatment. At this dose, plasma cholinesterase activity was depressed by > 15% at 39 and 51 weeks in females after treatment. Statistically and biologically significant inhibition of brain acetylcholinesterase activity was observed only in males at the highest dose, in which the activity was 77% of that in concurrent controls. Higher absolute thyroid/parathyroid weights were observed in females at the highest dose and higher relative thyroid/parathyroid weights in females at the intermediate dose. No associated histopathological abnormality was discerned, and these findings are considered not to be significant. No treatment-related pathological finding was seen at autopsy. The NOAEL was thus 0.25 mg/kg bw per day, on the basis of clinical signs and a reduction in brain acetylcholinesterase activity at the highest dose (Kangas, 1995). (c) Long-term toxicity and carcinogenicity Mice On the basis of a range-finding study, mevinphos (purity, 87.7%; 66.5% alpha, 21.2% ß isomer) was administered to four groups of 50 CD-1 mice of each sex at dietary concentrations providing doses of 0, 1, 10, or 25 ppm, equal to 0, 0.1, 1.5, and 3.7 mg/kg bw per day for males and 0, 0.1, 1.9, and 4.8 mg/kg bw per day for females, for 18 months. Physical examinations were performed each week and body weight and food consumption before the start of the study, weekly thereafter for 13 weeks on alternate weeks until week 26, and thence monthly. Blood smears for evaluating the differential leukocyte count and erythrocyte morphology were taken from 10 animals of each sex per group at 12 and 18 months. Treatment had few effects, but the survival rate was somewhat reduced in males at the low dose, with only 20 survivors, in comparison with 27 male controls, 26 at the middle dose, and 24 at the high dose. In females, the mortality rate was similar in all groups (36-40%). During the first three months of the study, the mean body weights of animals at the highest dose were lower than those of controls; this effect lasted up to week 16 in males and week 12 in females. Females at the two highest doses had lower leukocyte counts than controls at 18 but not at 12 months. No treatment-related gross or microscopic pathological changes were seen, nor were there treatment-related changes in organ weights. Although tumours were observed in a number of organs, especially the liver and lungs, there was no evidence of treatment-related neoplasia in any treated group. Cholinesterase activity was not measured in this study, as it had been evaluated in the range-finding study, in which the NOAEL for inhibition of brain acetylcholinesterase activity was 2 ppm. The NOAEL in the main study was 25 ppm, equal to 3.7 mg/kg bw per day, as the transient effect on body weight in mice at the high dose can be ignored (Atkinson, 1989). Rats Groups of 80 male and 80 female Crl:CD BR rats were given mevinphos (purity, 85.7%; 74.9% alpha, 10.8% ß isomer) by gavage in water on five days per week for two years at doses of 0, 0.025, 0.35, or 0.70 mg/kg bw per day. In females, the high dose was reduced to 0.60 mg/kg bw per day on day 83 of the study because of signs of acute toxicity. Ten rats from each group were killed at 12 months for histopathological examination, 10 rats from each group were used for clinical chemical determinations, and a further 10 were used to measure cholinesterase activity and were killed at 104 weeks. Clinical examinations were conducted weekly, and body weights were recorded before the start of the study, at the start of dosing, and thereafter weekly for 13 weeks and every four weeks afterwards. Food consumption was also measured weekly for 13 weeks and every four weeks thereafter. Clinical chemical, haematological, and urinary analyses were undertaken and plasma and erythrocyte cholinesterase activities were measured before treatment, at 3, 6, 1,2 and 18 months, and at termination. Brain acetylcholinesterase activity was measured at the interim kill and at the end of the study, but there were too few survivors at the end of the study for useful intergroup comparisons to be made. Ophthalmoscopic examinations were done before the start of the study and before termination. Full histopathological examinations were performed on the 10 animals from each group killed at 12 months and on the survivors at two years. Selected organs were weighed and examined microscopically. Less than 40% of the rats survived to termination at 104 weeks, and there was a dose-related reduction in survival in males, the rate being clearly reduced at the highest dose; there were no significant differences in mortality among female rats. Clinical signs typical of anticholinesterase poisoning, including tremors, were observed after administration of both the medium and high doses. No treatment-related changes in body weight, food consumption, or haematological, clinical chemical, urinary, or ophthalmoscopic parameters were discerned, except for cholinesterase activity. Plasma, erythrocyte, and brain cholinesterase activity was diminished in the animals at the middle and high doses but not in those at the low dose; decreases in erythrocytic acetylcholinesterase activity > 20% were not observed in animals of either sex at any dose, but a depression of 20% was observed at six months in females treated with mevinphos at 0.60 mg/kg bw per day. Although inhibition of plasma cholinesterase activity was not seen at the low dose, reductions of 38-51% were seen in males at the middle dose and 47-61% in males at the high dose; plasma cholinesterase activity was depressed by 50-67% in females at the middle dose and 66-71% at the high dose. Brain acetylcholinesterase activity was depressed by 27% in males at the middle dose, 53% in males at the high dose, 43% in females at the middle dose, and 55% in females at the high dose at the interim kill. No treatment-related effects were seen on histopathological examination. A low incidence of combined incidental and fatal hepatocellular adenomas was seen (0/67, 1/67, 1/69, and 2/68 in males and 1/70, 0.66, 0/67, and 3/67 in females), which gave a dose-response relationship. One female at the high dose had a hepatocellular carcinoma, giving a significant dose-response relationship for all hepatocellular tumours. The numbers involved were small, there was no dose-response relationship for liver carcinomas alone or for adenomas and carcinomas combined in males, and the incidence was well within that of historical controls. Hence, it was concluded that there was no evidence of any treatment-associated tumours. The NOAEL was 0.025 mg/kg bw per day on the basis of inhibition of brain acetylcholinesterase activity and clinical signs at doses > 0.35 mg/kg bw per day (Plutnick, 1994). (d) Reproductive toxicity In a two-generation study, groups of 35 male and 35 female Crl:CD BR (Sprague-Dawley) VAF/Plus rats, seven weeks of age, received mevinphos (purity, 89.6%; 74.5% alpha, 15.1% ß isomer) in water by gavage at doses of 0, 0.05, 0.1, or 0.5 mg/kg bw. Dosing was adjusted to allow for the low purity of the material. The F0 rats were dosed daily for 10 weeks before being assigned randomly, within the dose groups, into mating pairs at least 11 weeks after the start of dosing. Dosing was continued during mating, and the F0 females continued to be treated during gestation and lactation until weaning of the F1 litter 21 days post partum. Offspring were counted, sexed, weighed (excluding postnatal day 0), and examined externally on postnatal days 0, 1, 4, 7, 14, and 21; litters were culled to four males and four females. The F1 litters were dosed from 28 days post partum for at least 11 weeks before mating and also during the mating period. F1 females were dosed during gestation and lactation until weaning on day 21 after birth. Clinical observations were made and body weights measured before selection of the F0 animals on the first day of dosing and thereafter weekly in both generations. Observations were made more frequently in the F0 generation during gestation (days 0, 7, 14, and 21) and on the same days post partum. Erythrocyte, plasma, and brain cholinesterase activity was measured in all animals that survived to termination. Necropsies were performed on all mated animals, all decedent pups, and pups killed in extremis. Histopathological examinations were performed only on the controls and animals at the high dose, except that the ovaries of all F1 females were examined. Treatment-related clinical signs were seen in F0 females at the high dose, which included ataxia, fine or coarse tremors, pinpoint pupils, and oral discharge. The growth of F1 animals of each sex was significantly reduced, and some reduction in the body weights of F1 males and females at the high dose was observed before weaning on postnatal days 4-21. A reduction in the body weights of F1 male offspring at the high dose may represent continuation of the reduction in the F0 males before weaning. The growth of F2 males at the high dose was also reduced. Cholinesterase inhibition was observed in both generations but was generally more severe in F1 animals. Significant inhibition of brain acetylcholinesterase activity was observed in animals of each sex at the high dose, while no significant inhibition of erythrocyte cholinesterase activity was seen at any dose; inhibition of plasma cholinesterase activity extended to animals at the middle dose and to those at the low dose in the F1 generation. F1 animals at the high dose showed a reduction in the absolute weight of the testes or epididymides (12%) and in the relative ovarian weight (17%). The former may be a reflection of the lower total body weight of these animals, but the F1 males in all treated groups had lower mean mating and fertility indices than controls; although these effects were not statistically significant, they may be associated with the lower testicular weight observed. The effect on the ovaries may be a treatment-related effect, as some female rats at the highest dose had fewer or absent corpora lutea. The frequency of this pathological observation did not, however, attain statistical significance, and there were no significant effects on female fecundity or fertility indices; moreover, the live litter sizes of the animals at the high dose and the controls were comparable. The NOAEL was 0.1 mg/kg bw per day on the basis of the presence of clinical signs and reduced brain acetylcholinesterase activity in animals at the highest dose, at which impaired growth, impaired fertility indices, and lower testicular weights were seen in males and lower ovarian weights in females (Beyer, 1991b). (e) Developmental toxicity Rats Mevinphos (65.5% alpha isomer) was administered to four groups of 24 mated CD rats by gavage in water. One group served as controls, while the other groups were given mevinphos at daily doses of 0.2, 0.75, or 1.2 mg/kg bw per day on days 6-15 of gestation. A high mortality rate (29.2%) was observed in rats at the high dose, which was therefore terminated and a new group receiving 1 mg/kg bw per day was added. Females were weighed and examined at regular intervals, while food consumption was recorded on days 0-6, 6-10, 10-15, and 15-20 of gestation. The animals were killed on day 20 of gestation and examined at autopsy; corpora lutea and uterine implantations were counted, and fetuses were weighed, sexed, and examined grossly for malformations. One-half of the fetuses in each litter were processed for visceral examination and the remainder stained for evaluation of skeletal changes. Deaths were observed only in the prematurely terminated group at 1.2 mg/kg bw per day. A dose-related decrease in mean weight gain was seen during days 6-15 of gestation, but none of the decreases attained statistical significance. Clinical signs of cholinergic poisoning (tremors) were seen in about half the animals at the high dose, and excessive salivation was seen in four animals in that group. No indication of maternal toxicity was seen in the other groups, apart from tremor in two rats at the middle dose on day 15. There were no adverse effects on uterine implantation, fetal weight, fetal sex distribution, or the external appearance of fetuses, and there were no visceral or skeletal abnormalities in any treated group. The NOAEL for maternal toxicity was 0.75 mg/kg bw per day on the basis of clinical signs at the next highest dose; the NOAEL for developmental toxicity was 1.0 mg/kg bw per day, the highest dose tested (Schroeder & Daly, 1987). Rabbits Mevinphos (purity, 89.6%; 74.5% alpha, 15.1% ß isomer) was administered in water by gavage to groups of 20 pregnant New Zealand white rabbits at doses of 0, 0.05, 0.5, or 1.5 mg/kg bw per day on days 7-19 of gestation. Surviving animals were killed on day 29. Body weights were measured on days 0 and 7 of gestation, every three days until day 25, and on day 29 of gestation. Plasma and erythrocyte cholinesterase activity was determined in blood taken from dams about 3 h after treatment on the last day. After the animals had been killed, gross necropsy was carried out, and body weight and the weight of the uterus plus ovary were determined. The uterine contents were examined, live fetuses were killed, and all fetuses were weighed and examined externally. The viscera and skeleton were examined for malformations, and half of the fetuses from each litter were examined for the presence of brain abnormalities. Brain acetylcholinesterase activity was not measured. Maternal toxicity was seen in animals at the high dose, resulting in one death; corrected body weights were also decreased in that group on day 29 of gestation. Erythrocyte acetylcholinesterase activity was statistically significantly reduced in all three treated groups. The decreases were not biologically significantly in those at the medium and low doses (13% and 6%), but the reduction of 18% in animals at the high dose can be considered to be marginally biologically significant. Plasma cholinesterase activity was more sensitive to mevinphos, being significantly reduced at the two higher doses. No significantly different findings among the groups were made at autopsy. Mean fetal body weights and the crown-rump lengths of the treated pups were similar to those of controls. An increased incidence of accessory vessels was seen at 1.5 mg/kg bw per day, which was not considered by the authors to be related to treatment, as these are normal variations. Hypoplastic hyoids and unossified forepaws were also seen at increasing incidence with dose, but the difference in incidence between animals at the high dose and the controls did not achieve clinical significance. The NOAEL was 0.5 mg/kg bw per day on the basis of a marginally biologically significant decrease in erythrocyte acetylcholinesterase activity in animals at the high dose (Beyer, 1991a). (f) Genotoxicity Studies on the genotoxicity of mevinphos in vitro and in vivo are summarized in Table 2. Table 4. Recent tests for the genotoxicity of mevinphos End-point Test system Concentration Purity Results Reference (%) In vitro Reverse mutation S. typhimurium TA98, 100-10 000 µg/plate 89.6 Negative in TA98 San & Schadly TA100, TA1535, (74.5% alpha, with and without (1989) TA1537, TA1538 15.1% ß) S9 Sister chromatid Chinese hamster 10-5-10-3 mol/litre NR Positive Hirka et al. exchange ovary cells (1982) Unscheduled DNA Rat primary hepatocytes 0.0003-0.3 µl/ml NR Negative Curren (1990) synthesis In vivo Chromosomal CF-1 mouse, bone 1.5, 3 mg/kg bw per 70% alpha Negative Dean & Senner aberration marrow day orally (1974) Dominant lethal Mouse 1.5; 3, 6 mg/kg bw NR Negative Dean (1974) mutation NR, not reported (g) Special studies (i) Dermal and ocular irritation and dermal sensitization Slight dermal irritation and erythema were observed in five of six New Zealand white rabbits and oedema in the sixth. Most of the effects had disappeared by 72 h. In the same study, the material produced slight temporary ocular irritation in six New Zealand white rabbits (Deenihan, 1985). Groups of five male and five female New Zealand white rabbits received applications of mevinphos (74.5% alpha, 15.1% ß isomer) on the clipped unabraded skin of the back at doses of 0, 0.1, 1, or 10 mg/kg bw per day, on five days per week for three weeks. The material was not irritating. Males at the highest dose had a significant increase in relative brain weight and a decrease in the liver:brain and kidney:brain weight ratios. A dose-related decrease in brain, erythrocyte, and plasma cholinesterase activity was also seen. Plasma, erythrocyte, and brain cholinesterase activities at termination were inhibited in males and females at the highest dose by > 15% in comparison with concurrent controls. Erythrocyte acetylcholinesterase activity was the least inhibited and brain acetylcholinesterase activity the most inhibited in animals of each sex. The NOAEL for transdermal exposure was thus 1 mg/kg bw per day (Trimmer, 1990b). Mevinphos (purity, 93.6%) did not have dermal sensitization potential in guinea-pigs (Auletta, 1988c). (ii) Neurotoxicity Hens Ten Leghorn hens (Gallus gallus domesticus) were given 12.5 mg/kg bw mevinphos (purity, approx. 97%), this dose being slightly greater than the oral LD50 for hens. Antidotal treatment was required, and 0.625 mg/kg bw atropine was given as clinically indicated; each hen was also treated with 10 mg/kg bw pralidoxime chloride. Three of the treated hens died, despite antidotal therapy; the remainder were treated again on day 21 of the study as they had shown no signs of neurotoxicity. Four positive controls were treated with tri- ortho- tolylphosphate (90% mixture of isomers), but, when no signs of neurotoxicity were seen, material from a different supplier was used to treat the hens again at 21 days. Hens that survived to 42 days were injected with sodium pentobarbital and perfused with neutral buffered formalin. Brain, including the medulla, spinal cord, sciatic nerve, and the proximal parts of the peroneal and tibial nerves, were examined histopathologically. The treated birds had slight weight loss, presumably due to the cholinergic effect of mevinphos, but no evidence of mevinphos-induced delayed polyneuropathy was seen, either clinically or histopathologically, whereas characteristic changes were seen in the positive controls. Neuropathy target esterase was not measured in this study (Barrett, 1988). A single dose of mevinphos (76% alpha, 11% ß isomer) was given by gavage to groups of 27 male and 27 female Sprague-Dawley Crl:CD BR rats at doses of 0, 0.025 (17 rats of each sex), 0.1, 2, or 3.5 mg/kg bw. Seven animals of each sex per group were allocated for neuropathological examination and underwent a functional observation battery and tests for locomotor activity before treatment, at the time of the peak effect (about 45 min after dosing), and on days 7 and 14. These animals were killed at 15 days, and their brains were perfused in situ and weighed; neuropathological examination was then carried out on five rats of each sex in the control group and those at the highest dose. The other 20 animals in each group (10 at 0.025 mg/kg bw) were allocated for determinations of cholinesterase activity; viability, clinical signs, and body weight were recorded, and the functional observation battery and tests for locomotor activity were conducted on five rats of each sex per group. Plasma, erythrocyte, and brain (including regional) cholinesterase activities were measured before treatment, at the time of the peak effect (about 45 min after dosing), and on days 7 and 15 in five animals of each sex per group, except for those at the lowest dose, in which activity was measured only at the time of peak effect and on day 15. The numbers of animals available for determination of cholinesterase activity were also reduced in the group at the high dose because of mortality (see below). One male and five females at the highest dose died, and clinical signs, including gait alterations, tremors, salivation, and lacrimation, were observed in those at 2 or 3.5 mg/kg bw only on the day of dosing. Major disturbances in the locomotor test battery were observed in animals at these doses but not in controls. The alterations included lacrimation, salivation, impaired mobility and gait, clonic and tonic convulsions, tremors, bizarre behaviour, and altered reflexes. No treatment-related signs were seen in animals at 0.025 or 0.1 mg/kg bw. On the first day of the study, plasma cholinesterase activity was reduced by 36-39% in rats at 2 mg/kg bw and by 41-50% in those at 3.5 mg/kg bw in comparison with concurrent controls. Erythrocyte acetylcholinesterase activity was unaffected, while reductions of 20-25% were seen in acetylcholinesterase activity in the brain stem and/or cerebral cortex, hippocampus, and olfactory region of animals at 2 mg/kg bw and 19-36% in those at 3.5 mg/kg bw. The only statistically significant reductions in activity were those in the brain stem and cortex in males and in the hippocampus and brain stem in females. Plasma and brain cholinesterase activities were normal on days 7 and 14. No adverse effects were seen on body or brain weight. All signs of neurotoxicity had reversed by the end of day 1, and no treatment-related neuropathological signs were seen at any dose. The NOAEL was thus 0.1 mg/kg bw, on the basis of clinical effects and reduced brain acetylcholinesterase activity at higher doses (Lamb, 1993). Mevinphos was given by gavage in water to groups of 25 male and 25 female Sprague-Dawley Crl:CD BR rats for 91 days. The initial doses for all animals were 0.025, 0.035, or 0.70 mg/kg bw per day, but the dose for females at the high dose was reduced to 0.60 mg/kg bw per day on day 32 because of the deaths of two animals. Controls received the vehicle only. Viability, clinical signs, body weights, and food consumption were recorded for all animals, and a functional observational battery and locomotor activity tests were conducted on 10 animals of each sex per group. Necropsy was performed on all animals that died during the study. Neuropathological changes were evaluated in five animals of each sex in the control group and those at the high dose, and, because of the mortality at the high dose, in the females at the intermediate dose. The remaining 20 animals in each group were evaluated for plasma, erythrocyte, and brain cholinesterase activity in groups of five animals during weeks 3, 7, and 12 of the study. The main clinical sign was tremor in animals at the high dose 45 min after treatment, even after the dose for the females had been lowered. Excessive salivation was seen in animals of each sex at this dose, and lacrimation and râles were seen in females. Treatment- related declines of 32-56% were seen in erythrocyte and plasma cholinesterase activities in animals of each sex at the intermediate and high doses; the decreases in erythrocyte acetylcholinesterase activity were slightly greater (34-62%). Regional brain acetyl- cholinesterase activity showed some variation, with decreases of 9-21% in animals at the intermediate and high doses. If decreases of 15% are biologically significant, the decreased acetylcholinesterase activity of 21% in the mid-brain of males at the middle dose and of 17% in females would result in a NOAEL at 0.025 mg/kg bw per day. No treatment-related neuropathological change was seen (Lamb, 1994). Administration of a single dose of mevinphos (purity, 89.6%) to Crl:CD Br rats transdermally did not induce statistically or biologically significant depressions in erythrocyte acetyl- cholinesterase activity. A significant depression of plasma cholinesterase activity occurred at 20 mg/kg bw (29% of control value) and a marginal fall at 5 mg/kg bw (11% of control). Significant depressions of brain acetylcholinesterase activity occurred at 20 mg/kg bw (18% of control) (Trimmer, 1989, 1990a). The effects of mevinphos on flash-evoked potentials were studied in gerbils, pigeons, cats, and squirrel monkeys, through electrodes placed in the superior colliculus. Mevinphos reduced the inhibitory pause in pigeons at doses of 0.1-0.15 mg/kg bw. This effect could not be prevented by pretreatment with atropine methylnitrite (Revzin, 1978). Electroretinograms of Swiss white mice were examined after injection of organophosphates, including mevinphos at an intraperitoneal dose of 0.015 mg. Mevinphos was found to interfere with retinal function by a direct action on the photoreceptor, by inhibition of cholinesterase at synapses, and possibly by damaging the bipolar and/or ganglion cells (Carricaburu et al., 1980). 3. Observations in humans A number of incidents of poisoning with mevinphos have been reported through the US pesticide incident monitoring scheme (Hodgson & Smith, 1993). Poisoning with this compound is reported to be amenable to treatment with oximes (Bismuth et al., 1993). After administration of 25 µg/kg bw per day mevinphos to eight male volunteers for 28 days, plasma and erythrocyte cholinesterase activity fell throughout the study, with mean decreases of 12.6 and 19% of the respective pretreatment levels. Plasma cholinesterase activity had returned almost to pretreatment levels within seven days after the end of treatment, whereas the levels of erythrocyte activity showed no sign of recovery at follow-up to 14 days. A decrease in slow fibre motor conduction was also seen; there was an increase in Achilles tendon reflex force but no effect on neuromuscular transmission (Verbeck, 1977; Verbeck & Sallé, 1977). Mevinphos was given to groups of five male volunteers at doses of 1, 1.5, 2, or 2.5 mg per day for 30 days. Plasma cholinesterase activity was slightly affected by the highest dose, while the mean erythrocyte acetylcholinesterase activity was depressed by 20% on one occasion each at 1.5 and 2 mg per day. Consistent, significant inhibition of cholinesterase activity was seen only at the highest dose, at which the erythrocyte acetylcholinesterase fell consistently to a minimum of 25% at 27 days (Rider et al., 1975). In agricultural workers with cholinergic symptoms and with mean inhibition of plasma and erythrocyte cholinesterase activity of 15.6 and 5.6%, respectively, cholinesterase activity recovered at a daily rate of 1.2 and 0.43% of the respective final levels of activity of the enzyme over the 14 days after cessation of exposure (Coye et al., 1986). Higher rates of recovery were observed during the first 11 days after poisoning with a mixture of mevinphos and phosphamidon: the plasma activity increased by 3% per day and erythrocyte activity by 0.8% per day. The workers were, however, treated with pralidoxime. As noted previously, inhibition of plasma cholinesterase activity was greater than that of erythrocytic enzyme (Midtling et al., 1985). Human erythrocyte acetylcholinesterase is susceptible to reactivation in vitro by a variety of pyridinium oximes, including pralidoximes and obidoxime (Woreck et al., 1996). Comments Mevinphos is almost completely absorbed when administered orally to rats; a large proportion of the absorbed material is biotransformed to carbon dioxide. Both metabolites and unchanged mevinphos are observed in the urine but very little in the faeces. Mevinphos depresses cholinesterase activity in the plasma mre than in the erythrocytes in experimental animals. The oral LD50 values for mevinphos in laboratory rodents are 2-12 mg/kg bw. WHO has classified mevinphos as 'extremely hazardous' (WHO, 1996). In a three-month range-finding study, mice were fed diets containing mevinphos at concentrations of 0, 0.5, 1, 2, or 10 ppm. The NOAEL was 2 ppm, equal to 0.4 mg/kg bw per day, on the basis of inhibition of brain acetylcholinesterase activity at 10 ppm. In a 90-day study of toxicity, rats were given mevinphos by gavage at doses of 0, 0.056, 0.56, 1.1, or 1.7 mg/kg bw per day were used in males (the highest dose was decreased to 1.1 mg/kg bw per day at day 36 because of high mortality) and 0, 0.011, 0.056, 0.56, or 0.84 mg/kg bw per day in females. The NOAEL was 0.056 mg/kg bw per day, on the basis of clinical signs and depressed brain acetyl- cholinesterase activity at higher doses. Dose-related increases in mean cholesterol levels and increased relative liver weights were also observed. In a one-year study in dogs, mevinphos was administered in corn oil in gelatine capsules at doses of 0, 0.025, 0.25 or 0.5 mg/kg bw per day. The NOAEL was 0.25 mg/kg bw per day on the basis of clinical signs and a reduction in brain acetylcholinesterase activity at the highest dose. In an 18-month study of toxicity and carcinogenicity, mice were fed dietary concentrations of 0, 1, 10, or 25 ppm; cholinesterase activity was not measured. There was no evidence of carcinogenicity. In a two-year study of toxicity and carcinogenicity, rats were given mevinphos by gavage in water on five days per week at doses of 0, 0.025, 0.35, or 0.70 mg/kg bw per day. On day 83 of the study, the high dose of the females was reduced to 0.60 mg/kg bw per day because of signs of toxicity. The NOAEL was 0.025 mg/kg bw per day on the basis of inhibition of brain acetylcholinesterase activity and clinical signs at higher doses. There was no evidence of carcinogenicity. A two-generation study of reproductive toxicity was carried out in which rats were treated by gavage at doses of 0, 0.05, 0.1, or 0.5 mg/kg bw mevinphos in water. The NOAEL was 0.1 mg/kg bw per day on the basis of clinical signs and reduced brain acetylcholinesterase activity at the highest dose. This dose also impaired growth and fertility indices and lowered testicular weights in males and ovarian weights in females. In a study of developmental toxicity in rats, groups were given mevinphos at daily doses of 0, 0.2, 0.75, or 1.2 mg/kg bw per day on days 6-15 of gestation. High mortality (29%) was observed in the high-dose group, which was therefore terminated; accordingly, a new high-dose group at 1 mg/kg bw per day was added. There were no adverse effects on uterine implantation or on fetal weight, sex distribution, external appearance, or visceral or skeletal malformations in any group. It was concluded that mevinphos is not embryotoxic, fetotoxic, or teratogenic at doses < 1.0 mg/kg bw per day. The NOAEL for maternal toxicity was 0.75 mg/kg bw per day on the basis of clinical signs at higher doses. In a study of developmental toxicity, mevinphos was administered by gavage to pregnant rabbits at doses of 0, 0.05, 0.5, or 1.5 mg/kg bw per day on days 7-19 of gestation; surviving animals were killed. The NOAEL was 0.5 mg/kg bw per day, on the basis of maternal toxicity. Mevinphos was neither teratogenic nor fetotoxic. There was some evidence of genotoxic potential in vitro, but the limited studies available indicate that such potential is not exhibited in vivo. In a study in hens, the oral dose of 12 mg/kg bw that was administered was slightly greater than the oral LD50 value, and antidotal treatment was required. There was no evidence of delayed polyneuropathy, either clinically or histopathologically, whereas characteristic changes were seen in positive controls. Neurotoxic target esterase was not measured during this study. Two studies of humans were available. In male volunteers given a dose of 0.025 mg/kg bw per day, plasma and erythrocyte cholinesterase activity decreased throughout the 28 days of the study to 13% and 19% less than the respective pre-dose levels. In the second study, daily doses of 1, 1.5, 2 or 2.5 mg were given to male volunteers for 30 days, and an NOAEL of 1 mg/day, equivalent to 0.016 mg/kg bw per day, was derived; however, only five people, all men, per dose were studied. An ADI of 0-0.0008 mg/kg bw was established on the basis of the NOAEL of 0.016 mg/kg bw per day in the 30-day study in volunteers, using a 20-fold safety factor because of the small numbers in each group. This ADI is supported by the LOAEL in rats of 0.35 mg/kg bw per day and the NOAELs of 0.5 mg/kg bw per day in rabbits and 0.25 mg/kg bw per day in dogs. An acute reference dose for humans was derived from the 28-day study in volunteers, on the basis of a dose of 0.025 mg/kg bw per day, using a 10-fold safety factor. Toxicological evaluation Levels that cause no toxicological effect Mouse: 2 ppm, equal to 0.4 mg/kg bw per day (inhibition of brain acetylcholinesterase activity in a three-month study of toxicity) Rat: 0.025 mg/kg bw per day (two-year study of toxicity and carcinogenicity) 0.1 mg/kg bw per day (study of reproductive toxicity) Rabbit: 0.5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) Dog: 0.25 mg/kg bw per day (one-year study of toxicity) Human: 1 mg per day, equivalent to 0.016 mg/kg bw per day (inhibition of cholinesterase activity in a 30-day study of toxicity) Estimate of acceptable daily intake for humans 0-0.0008 mg/kg bw Acute reference dose 0.003 mg/kg bw Studies that would provide information useful for continued evaluation of the compound Study of micronucleus formation in mice in vivo Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to mevinphos Exposure Relevant route, study type, species Results, remarks Short-term (1-7 days) Oral, toxicity, rat LD50 = 2.2-6.1 mg/kg bw Dermal, toxicity, rat LD50 > 20 mg/kg bw Inhalation, 4 h, toxicity, rat LD50 = 7.3-12 mg/m3 Dermal, irritation, rabbit Slightly irritating Ocular, irritation, rabbit Slightly irritating Dermal, sensitization, guinea-pig Not sensitizing Medium-term (1-26 weeks) Repeated oral, 3 months, mouse NOAEL = 0.4 mg/kg bw per day, inhibition of brain acetylcholinesterase activity Repeated oral, 90 days, rat NOAEL = 0.056 mg/kg bw per day Repeated dermal, 21 days, rabbit NOAEL = 1.0 mg/kg bw per day Repeated oral, reproductive toxicity, rat NOAEL = 0.1 mg/kg bw per day, maternal and reproductive toxicity Repeated oral, developmental toxicity, rat NOAEL = 0.75 mg/kg bw per day, maternal toxicity; no developmental toxicity Repeated oral, developmental toxicity, rabbit NOAEL = 0.5 mg/kg bw per day, maternal toxicity; no developmental toxicity Long-term (> 1 year) Repeated oral, 2 years, rat NOAEL = 0.025 mg/kg bw per day; inhibition of brain acetylcholinesterase activity Repeated oral, 1 year, dog NOAEL = 0.25 mg/kg bw per day; inhibition of brain acetylcholinesterase activity References Atkinson, J.E. 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(1988b) Acute dermal toxicity study in rabbits with mevinphos. Unpublished report dated 23 March 1988, Project No. 4645-87 from BioDynamics Inc., East Millstone, NJ, USA. Submitted to WHO by Amvac Chemical Corp., City of Commerce, CA, USA. Auletta, C.S. (1988c) Dermal sensitization study in guinea pigs with mevinphos. Unpublished report dated 23 March 1988, Project No. 4648-87 from BioDynamics Inc., East Millstone, NJ, USA. Submitted to WHO by Amvac Chemical Corp., City of Commerce, CA, USA. Barrett, D.S. (1988) Acute delayed neurotoxicity study in mature hens with mevinphos. Unpublished report dated 26 July 1988, Project No 4685-87 from BioDynamics Inc., East Millstone, NJ, USA. Submitted to WHO by Amvac Chemical Corp., City of Commerce, CA, USA. Beyer, B.K. (1991a) Teratology study in rabbits. Study No. MRD-88-331. Unpublished report dated 22 February 1991 from Exxon Biomedical Sciences Inc, East Millstone, NJ, USA. 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See Also: Toxicological Abbreviations Mevinphos (FAO Meeting Report PL/1965/10/1) Mevinphos (WHO Pesticide Residues Series 2) Mevinphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)