** Evaluation in CCPR periodic review programme
TOXICOLOGY
Dimethoate was previously evaluated for toxicological effects by the Joint Meeting in 1963, 1965, 1967, 1984, and 1987. In 1987, an ADI of 0-0.01 mg/kg bw was established, on the basis of a no-effect level of 0.2 mg/kg bw per day for the inhibition of erythrocyte acetylcholinesterase in volunteers. The compound was reviewed at the present Meeting within the CCPR periodic review programme.
Omethoate (the oxygen analogue of dimethoate, which has been used as a pesticide in its own right) was evaluated for toxicological effects by the Joint Meeting in 1971, 1975, 1978, 1979, 1981, and 1985. An ADI of 0-0.0003 mg/kg bw was allocated in 1985. The Meeting was informed that the primary manufacturer is no longer producing omethoate; however, since the use of dimethoate on agricultural crops can lead to residues of omethoate in treated produce, the toxicity of omethoate is important in the context of the potential use of dimethoate. Information on the absorption, distribution, excretion, metabolism, and toxicity of omethoate was therefore also considered by the Meeting. These data were taken from published sources such as previous JMPR evaluations of omethoate and national reviews; the original reports were not available for detailed evaluation.
Formothion (an aldehyde derivative of dimethoate, which has also been used as a pesticide in its own right, but is no longer supported by the manufacturer) was evaluated for toxicological effects in 1969 and 1973. An ADI of 0-0.02 mg/kg bw was allocated in 1973. Since the use of dimethoate does not lead to residues of formothion in treated produce, the toxicity of formothion was not considered at the present Meeting.
Preparation of this review was aided by reference to the results of previous reviews conducted by the Pesticides Safety Directorate, United Kingdom.
Dimethoate
Dimethoate was rapidly and extensively absorbed from the gut and rapidly excreted. There was no accumulation in fat tissue. In rats and humans up to 90% of radiolabel was found in the urine within 24 h. The report of a study with methylcarbamoyl-labelled dimethoate indicated that up to 18% of the administered label was excreted in expired air. Four metabolites with anticholinesterase activity have been identified in rats and humans. One seems to result from thiono oxidation, leading to the formation of the oxygen analogue of dimethoate, omethoate; this step was followed by hydrolysis to a thiocarboxyl product, said to be the main metabolite in rats and humans.
Data on the acute oral toxicity of dimethoate gave LD50 values of about 310 mg/kg bw in rats, 150 mg/kg bw in mice, and 55 mg/kg bw in hens. The signs of toxicity were those typical of cholinesterase inhibition. WHO has classified dimethoate as "moderately hazardous".
In short-term and long-term studies at dietary concentrations of 75 ppm or above, there were minor reductions in body-weight gain and food consumption. Apart from the inhibition of cholinesterase activity, dimethoate had no effect on the composition of the blood or urine. The liver weights of animals treated at the higher doses tended to be lower than those of the control groups; there were however no microscopic changes, and the effect is unlikely to be of toxicological significance. Investigations of toxicity at higher doses were limited by effects due to cholinesterase inhibition. The NOAELs were thus generally based on reductions in acetylcholinesterase activity in the brain or erythrocytes. On the basis of minimal reductions in acetylcholinesterase activity of 10-20%, the NOAEL in a 12-month study in dogs at doses of 0, 5, 20, or 125 ppm was 5 ppm, equal to 0.2 mg/kg bw per day; in rats the NOAEL in a life-span study at doses of 0, 1, 5, 25, or 100 ppm was 1 ppm, equal to 0.04 mg/kg bw per day. In mice, an NOAEL was not identified, as cholinesterase activity was depressed at all doses after 52 weeks of treatment in a life-span study at doses of 0, 25, 100, or 200 ppm.
The results of long-term studies of toxicity and carcinogenicity in mice (at 0, 25, 100, or 200 ppm) and rats (at 0, 5, 25, or 100 ppm) reported in 1986 and studies reported in 1977 indicate that dimethoate is not carcinogenic to rodents.
In a multigeneration study of reproductive toxicity conducted in 1989-1990 with doses of 0, 1, 15, or 65 ppm, the reproductive performance of rats was impaired at the high dose. The NOAEL for reproductive toxicity appeared to be 15 ppm (equal to 1.2 mg/kg bw per day) and that for parental toxicity was 1 ppm (equal to 0.08 mg/kg bw per day) on the basis of cholinesterase inhibition, but the Meeting noted that there was some indication that reproductive performance may have been affected at lower doses. In a multigeneration study of reproductive toxicity in mice in 1965 at doses of 0, 5, 15 or 50 ppm, there was no overt effect on reproductive capacity, even in the presence of cholinergic toxicity. In a poorly reported study in rabbits, sperm numbers and quality were adversely affected at doses equivalent to one-tenth and one-hundredth of the LD50.
Studies of developmental toxicity in rats (at 0, 3, 6, or 18 mg/kg bw per day on days 6-15 of gestation) and rabbits (at 0, 10, 20, or 40 mg/kg bw per day on days 7-19 of gestation) provided no evidence of a teratogenic effect, although maternal toxicity was observed at the high dose in rats and at the high and middle doses in rabbits.
After reviewing the available data on genotoxicity the Meeting concluded that although in-vitro studies indicate that dimethoate has mutagenic potential, this potential does not appear to be expressed in vivo.
Undiluted dimethoate formulations were irritating to the eye in rabbits. Skin irritation was minimal and confined to slight, transient erythema. Dimethoate was not a skin sensitizer in guinea-pigs, but a 32.7% emulsifiable concentrate formulation induced sensitization in one of 10 guinea-pigs. In a published paper, dimethoate was cited in four human cases of contact dermatitis, and sensitization was confirmed in these individuals by patch testing.
In hens given a single dose of 55 mg/kg bw by subcutaneous injection or orally, dimethoate did not induce delayed neurotoxicity.
In a 39-day study in nine male and female volunteers, the NOAEL for cholinesterase inhibition was 0.2 mg/kg bw per day. This NOAEL was supported in seven other studies, each involving 6-20 volunteers who received doses ranging from 0.04 to 1.0 mg/kg bw per day for periods up to 57 days.
Omethoate
The oral LD50 of omethoate in rats was approximately 25 mg/kg bw. The signs of reaction to treatment with omethoate were those consistent with cholinesterase inhibition.
In short-term and long-term studies, the potential toxicity of omethoate was limited by the onset of cholinesterase inhibition. In a 12-month study of toxicity in dogs at doses of 0, 0.025, 0.12, or 0.62 mg/kg bw per day by gavage, the NOAEL was 0.025 mg/kg bw per day on the basis of the inhibition of acetylcholinesterase activity. In life-span studies in rats (at 0, 0.3, 1, 3, or 10 ppm) and mice (0, 1, 3, or 10 ppm), there was no evidence of oncogenic potential. The study in mice was unsuitable for deriving an NOAEL because acetylcholinesterase activity was not investigated; the NOAEL in rats was 0.3 ppm (equivalent to 0.015 mg/kg bw per day) on the basis of the inhibition of acetylcholinesterase activity.
In multigeneration studies of reproductive toxicity in rats at 0, 1, 3, or 10 ppm, a dietary concentration of 10 ppm was associated with reduced viability of the pups; there was evidence that this effect extended to animals treated at 3 ppm. The NOAEL was 1 ppm (equivalent to 0.05 mg/kg bw per day). In a further multigeneration study of reproductive toxicity in rats at doses of 0, 0.5, 3, or 18 ppm in the drinking-water, there was evidence of epididymal vacuolation and fewer pups per dam at the high dose; these pups had lower weight gains and were less viable. The precoital time was increased and the number of non-pregnant females was greater than among controls. The NOAEL for reproductive performance was 3 ppm (equivalent to 0.2 mg/kg bw per day), but cholinesterase inhibition was detected at the lowest dose of 0.5 ppm. In studies of developmental toxicity, there was no evidence of teratogenicity in rats given 0, 0.3, 1, or 3 mg/kg bw omethoate per day on days 6-15 of gestation or in rabbits given 0, 0.1, 0.3, or 1 mg/kg bw omethoate per day on days 6-18 of gestation.
Omethoate has been extensively investigated for genotoxicity in vitro and in vivo. The Meeting concluded that it has clear mutagenic potential but that the weight of the evidence observed in vivo was negative; however, the positive result obtained in a mouse spot test could not be completely disregarded.
In studies in hens given single oral doses of 20-300 mg/kg bw, omethoate did not induce delayed neurotoxicity.
Conclusions
An ADI of 0-0.002 mg/kg bw was established for dimethoate on the basis of the apparent NOAEL of 1.2 mg/kg bw per day for reproductive performance in the study of reproductive toxicity in rats, applying a safety factor of 500. Although a safety factor of 100 would normally be used in deriving an ADI from a study of this type, the Meeting was concerned about the possibility that reproductive performance may have been affected at 1.2 mg/kg bw per day in this study and therefore used a higher-than-normal safety factor. No data were available to assess whether the effects on reproductive performance were secondary to the inhibition of cholinesterase. The Meeting concluded that it was not appropriate to base the ADI on the results of the studies of volunteers since the crucial end-point (reproductive performance) has not been assessed in humans.
This ADI would usually be used only when assessing the intake of dimethoate itself. As the use of dimethoate on crops can give rise to residues of omethoate, and omethoate has been used as a pesticide in its own right, previous Joint Meetings have allocated an ADI to omethoate; however, the primary manufacturer is no longer producing omethoate. The Meeting noted that omethoate is considerably more toxic than dimethoate; however, the levels of residues of omethoate resulting from the use of dimethoate on crops are likely to be low. The Meeting therefore recommended that residues of dimethoate and omethoate resulting from the use of dimethoate be expressed as dimethoate and be assessed in comparison with the ADI for dimethoate.
As the primary manufacturer is no longer producing either omethoate or formothion, toxicological data on these compounds were not made available to the Meeting. The previous ADIs of 0-0.0003 mg/kg bw for omethoate and 0-0.02 mg/kg bw for formothion were therefore withdrawn.
There may be a need to re-evaluate the toxicity of dimethoate after the periodic review of the residue and analytical aspects of dimethoate has been completed if it is determined that omethoate is a major residue.
A toxicological monograph on dimethoate was prepared, summarizing the data received since the previous evaluation and including summaries of the data presented in previous monographs and monograph addenda.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect (dimethoate)
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Rat: |
1 ppm, equal to 0.04 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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15 ppm, equal to 1.2 mg/kg bw per day (reproductive performance in a study of reproductive toxicity) |
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1 ppm, equal to 0.08 mg/kg bw per day (parental toxicity in a study of reproductive toxicity) |
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6 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) |
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Rabbit: |
10 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) |
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Dog: |
5 ppm, equal to 0.2 mg/kg bw per day (52-week study of toxicity) |
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Human: |
0.2 mg/kg bw per day (39-day study of cholinesterase inhibition) |
Estimate of acceptable daily intake for humans
0-0.002 mg/kg bw (sum of dimethoate and omethoate expressed as dimethoate)
Studies that would provide information useful for the continued evaluation of the compound:
1. Further multigeneration study of reproductive toxicity in rats using dimethoate.
2. Mouse spot test using dimethoate.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to dimethoate
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EXPOSURE |
RELEVANT ROUTE, STUDY TYPE, SPECIES |
RESULT/REMARKS |
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Short term (1-7 days)
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Oral toxicity, rat |
LD50 = 310 mg/kg bw |
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Dermal toxicity, rat |
LD50 > 7000 mg/kg bw |
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Dermal irritation, rabbit |
Slightly irritating |
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Ocular irritation, rabbit |
Slightly irritating |
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Dermal sensitization, human |
Positive |
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Medium term (1-26 weeks)
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Repeated dermal, 21 days, toxicity, rabbit |
NOAEL = 1000 mg/kg bw per day (highest dose tested) |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 1.2 mg/kg bw per day, reproductive toxicity NOAEL = 0.08 mg/kg bw per day, parental toxicity |
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Repeated oral, developmental toxicity, rat |
NOAEL = 6 mg/kg bw per day, maternal toxicity. No evidence of embryotoxicity or teratogenicity at 18 mg/kg bw per day (highest dose tested) |
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 10 mg/kg bw per day, maternal toxicity. No evidence of embryotoxicity or teratogenicity at 40 mg/kg bw per day (highest dose tested) |
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Long term (> one year) |
Repeated oral, toxicity and carcinogenicity, rat |
NOAEL = 0.04 mg/kg bw per day, cholinesterase inhibition |
