** Evaluation in CCPR periodic review programme
TOXICOLOGY
Mevinphos was evaluated for toxicological effects by the JMPR in 1963 and 1965; in neither case was an ADI assigned. An ADI of 0-0.0015 mg/kg bw was established in 1972. The toxicology of the compound was reviewed at the present Meeting within the CCPR periodic review programme.
Mevinphos is almost completely absorbed when administered orally to rats; a large proportion of the absorbed compound 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 more than in erythrocytes in experimental animals.
The oral LD50 values of mevinphos in laboratory rodents are 2-12 mg/kg bw. WHO has classified mevinphos as 'extremely hazardous'.
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 administered mevinphos by gavage at doses of 0, 0.056, 0.56, 1.1 or 1.7 mg/kg bw per day in males (the highest dose was decreased to 1.1 mg/kg bw per day at day 36 because of high mortality) and at 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 acetylcholinesterase activity at higher doses. Dose-related increases in mean cholesterol levels and increased relative liver weights were also observed.
In a one-year study of toxicity in dogs, mevinphos was administered in corn oil in gelatin 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. Acetylcholinesterase activities were 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 for 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 per day 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 doses of 0, 0.2, 0.75, or 1.25 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 of 1.0 mg/kg bw per day was added. There were no adverse effects on uterine implantation or fetal weight, sex distribution or external appearance, nor visceral or skeletal malformations, in any group. It was concluded that mevinphos is not embryotoxic, fetotoxic, or teratogenic at doses up to 1 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 one study, in which male volunteers were given a dose of 0.025 mg/kg bw per day, plasma and erythrocyte cholinesterase activities 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, 2.0, 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, 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 over four days, using a 10-fold safety factor.
A toxicological monograph was prepared, summarizing the data received since the previous evaluation and including summaries from the previous monograph.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
|
Mouse: |
2 ppm, equal to 0.4 mg/kg bw per day (inhibition of brain acetylcholinesterase in three-month study of toxicity) |
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Rat: |
0.025 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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0.1 mg/kg bw per day (study of reproductive toxicity) |
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Rabbit: |
0.5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) |
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Dog: |
0.25 mg/kg bw per day (one-year study of toxicity) |
|
Human: |
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 the continued evaluation of the compound
Study of micronucleus formation in mice in vivo.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to mevinphos
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EXPOSURE |
RELEVANT ROUTE, STUDY TYPE, SPECIES |
RESULTS/REMARKS |
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Short-term (1-7 days)
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Oral toxicity, rat |
LD50 = 2.2-6.1 mg/kg bw |
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Dermal toxicity, rat |
LD50 >20 mg/kg bw |
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Inhalation, 4 h, toxicity, rat |
LC50 = 7.3-12 mg/m3 |
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Dermal irritation, rabbit |
Slightly irritating |
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Ocular irritation, rabbit |
Slightly irritating |
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Dermal sensitization, guinea-pig |
Not sensitizing |
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Medium-term (1-26 weeks)
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Repeated oral, three months, mouse |
NOAEL = 0.4 mg/kg bw per day, inhibition of brain acetylcholinesterase |
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Repeated oral, 90 days, rat |
NOAEL = 0.056 mg/kg bw per day |
|
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Repeated dermal, 21 days, rabbit |
NOAEL = 1 mg/kg bw per day |
|
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Repeated oral, reproductive toxicity, rat |
NOAEL = 0.1 mg/kg bw per day, maternal and reproductive toxicity |
|
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Repeated oral, developmental toxicity, rat |
NOAEL = 0.75 mg/kg bw per day, maternal toxicity; no developmental toxicity |
|
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 0.5 mg/kg bw per day, maternal toxicity; no developmental toxicity |
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Long-term (> one year) |
Repeated oral, two years, rat |
NOAEL = 0.025 mg/kg bw per day; inhibition of brain acetylcholinesterase activity |
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Repeated oral, one year, dog |
NOAEL = 0.25 mg/kg bw per day; inhibition of brain acetylcholinesterase activity |
