** Evaluation in CCPR periodic review programme
TOXICOLOGY
Carbaryl was evaluated for toxicological effects by the Joint Meeting in 1963, 1965, 1966, 1967, 1969, and 1973. An ADI of 0-0.02 mg/kg bw was established in 1963 on the basis of a one-year study in dogs, and this ADI was confirmed in 1965, 1966, and 1967. In 1969, a temporary ADI of 0-0.01 mg/kg bw was established, using an extra safety factor because of concern about effects on the male reproductive system seen in a one-year study by gavage in rats with an NOAEL of 2 mg/kg bw per day, and because a dose of 0.12 mg/kg bw per day may have affected renal function in a six-week study in volunteers. In 1973, the Meeting established an ADI of 0-0.01 mg/kg bw.
The toxicology of the compound was reviewed by the present Meeting within the CCPR periodic review programme. The evaluation is based on a recent Environmental Health Criteria monograph on carbaryl (EHC 153)1 and is supplemented by newly received studies on metabolism, dermal absorption, chronic toxicity and/or oncogenicity in rats and mice, mechanistic studies, and a report of an epidemiological study on exposed workers.
1 WHO (1994) Carbaryl (Environmental Health Criteria 153), Geneva
Carbaryl is rapidly and almost completely absorbed after oral administration. Excretion is rapid and occurs predominantly via the urine; enterohepatic cycling of carbaryl metabolites is also considerable. There were no significant dose-related or sex-specific differences in elimination patterns, and there was no evidence of bioaccumulation. Dermal absorption in rats was slow; after 24 h, 16-34% of the administered radioactivity had been absorbed. Higher doses were less readily absorbed. In volunteers, 45% of a dose applied to the skin in acetone was absorbed within 8 h. Carbaryl was rapidly absorbed in the lungs.
The metabolism of carbaryl has been studied in various mammals, including humans. The principal metabolic pathways are ring hydroxylation, hydrolysis, and conjugation. There were no species differences. The principal metabolite in humans is 1-naphthol. The hydrolysis product, N-methylcarbamic acid, spontaneously decomposes to methylamine and carbon dioxide. The methylamine is later converted to carbon dioxide and formate, the latter being excreted mainly in the urine. Carbaryl metabolites are also found at small percentages of the absorbed doses in saliva and milk.
Carbaryl is moderately toxic after acute oral administration, the LD50 in rats being 225-721 mg/kg bw. Interspecies differences in toxicity were found, cats (LD50, 150 mg/kg bw) being the most sensitive. The LD50 was increased threefold when animals were pretreated with small doses of carbaryl. The compound is slightly toxic after acute dermal administration, with an LD50 > 2000 mg/kg bw. No LC50 for acute exposure by inhalation was available, but the effects observed in dogs, cats, and rats exposed to dusts or formulations of carbaryl were typical of those resulting from inhibition of cholinesterase activity. In cats exposed to carbaryl dust for 6 h, a concentration of 20 mg/m3 inhibited cholinesterase activity in plasma and erythrocytes. Carbaryl was weakly irritating to the eye but not the skin and was not considered to be a sensitizer. WHO has classified carbaryl as 'moderately hazardous'.
After the oral administration of carbaryl in capsules to dogs at doses of 0.45, 1.8, or 7.2 mg/kg bw per day for one year, slight effects were observed on the kidney at 7.2 mg/kg bw per day; the NOAEL was 1.8 mg/kg bw per day. In two studies in which dogs were fed diets containing carbaryl at 20-125 ppm for five weeks and 125-1250 ppm for one year, the NOAEL was 125 ppm, equivalent to 3.1 mg/kg bw per day, on the basis of effects on liver weight and inhibition of acetylcholinesterase activity in erythrocytes and brain at 400 ppm.
In cats exposed to carbaryl by inhalation, cholinergic signs were observed at 30 mg/m3 after exposure for 30 days; the NOAEL was 16 mg/m3 after exposure for 120 days. In a study in rats, no effects were observed after exposure to 10 mg/m3 for 90 days.
Several studies of long-term toxicity or carcinogenicity in mice cited in EHC 153 were not considered to be suitable for evaluation of carcinogenicity by either the Environmental Health Criteria Task Force or the present Meeting, although they were suitable for assessing long-term toxicity. In a recent study of carcinogenicity, mice were given diets providing 0, 100, 1000, or 8000 ppm carbaryl for 104 weeks. Tumours were observed in the liver in females and the kidney in males, and vascular tumours were found in animals of both sexes at the highest dose, which exceeded the maximum tolerated dose (MTD). In male mice, increases in the incidences of vascular tumours were also seen at the two lower doses; after considering all of the available data, the Meeting could not identify an NOAEL for this neoplastic lesion. The NOAEL for non-neoplastic lesions was 100 ppm (equal to 15 mg/kg bw per day), on the basis of inhibition of erythrocyte and brain acetylcholinesterase activity and histopathological changes in the urinary bladder at 1000 ppm. This NOAEL is consistent with the results of the earlier studies. The Meeting concluded that the compound is carcinogenic in mice.
In several studies cited in EHC 153, carbaryl was administered in the diet of rats for 96 days to two years. The most obvious effects were in the kidney at doses of 400 ppm and above. In two one-year studies in rats treated by gavage, effects on the thyroid and on male and female reproductive organs and/or function were observed at doses of 5 mg/kg bw per day and above; the NOAEL was 2 mg/kg bw per day. None of these studies was considered suitable for evaluating carcinogenicity.
In a recent study of long-term toxicity and carcinogenicity, rats were fed diets containing 0, 250, 1500, or 7500 ppm carbaryl for 104 weeks. In animals at the highest dose, which exceeded the MTD, tumours were found in the thyroid in males, in the liver in females, and in the urinary bladder in animals of both sexes. The NOAEL for non-neoplastic findings was 250 ppm, equal to 10 mg/kg bw per day, on the basis of inhibition of erythrocyte and brain acetylcholinesterase and a decrease in mean body weight at 1500 ppm. This NOAEL is consistent with the results of earlier dietary studies. The Meeting concluded that carbaryl is carcinogenic in rats only at levels that exceed the MTD.
The available studies on reproductive toxicity were conducted some time ago and had some deficiencies in relation to currently acceptable scientific standards. In three-generation studies, dietary administration of carbaryl to rats induced reproductive effects (impaired fertility and reduced postnatal survival and growth) at doses above 2000 ppm (equal to 125 mg/kg bw per day); a dose of 100 mg/kg bw per day did not induce maternal toxicity. When carbaryl was administered by gavage, maternal toxicity was not observed at 25 mg/kg bw per day, but both maternal and reproductive toxicity (reduced litter size and viability) were observed at 100 mg/kg bw per day. The Meeting recommended that a new two-generation study of reproductive toxicity be carried out in rats, with special attention to the male reproductive system since effects on this system were observed in some studies of long-term toxicity at gavage doses significantly lower than those evaluated in the dietary studies of reproductive toxicity.
The available studies on developmental toxicity suffered from small group size and had some deficiencies in relation to currently acceptable scientific standards. In two studies in mice, the NOAEL for maternal toxicity was 100 mg/kg bw per day; at 150 mg/kg bw per day, increased litter resorption was found. In rats, administration of carbaryl in the diet for part or all of the gestation period resulted in maternal toxicity at 100 mg/kg bw per day. No overt signs of fetotoxicity were seen at this dose. In a study in which rats were exposed to carbaryl by gavage and then mated, maternal and embryotoxicity were observed at 100 mg/kg bw per day; no effects were observed at 10 mg/kg bw per day. In guinea-pigs, administration of carbaryl during gestation in the diet or by gavage resulted in an NOAEL for maternal toxicity of 100 mg/kg bw per day. No embryo- or fetotoxicity was observed at 300 mg/kg bw per day, the highest dose tested. In rabbits, teratogenic effects were reported after administration of 200 mg/kg bw per day orally; maternal toxicity was also seen at this dose. In two studies in dogs, maternal toxicity (dystocia, at parturition only) was observed at doses of 3.1 mg/kg bw per day. A variety of birth defects was found after exposure to 5 mg/kg bw per day and above. Thus, the LOAEL for maternal toxicity was 3.1 mg/kg bw per day, and this was the NOAEL for birth defects in the offspring.
The Meeting concluded that carbaryl induces developmental toxicity, manifested as deaths in utero, reduced fetal weight, and malformations, but only at doses that cause overt maternal toxicity. The shortcomings of these studies made them inadequate for identifying NOAELs for developmental toxicity that could be used for assessing risk under conditions of exposure other than in the diet.
Carbaryl has been adequately tested in a series of assays in vitro and in vivo. While chromosomal aberrations have been induced in vitro and carbaryl has been shown to disturb spindle fibre mechanisms in vitro, there was no evidence from well-conducted experiments that carbaryl is clastogenic in vivo. The Meeting concluded that carbaryl is not genotoxic.
The effects of carbaryl on the nervous system are primarily related to cholinesterase inhibition and are usually transitory.
Dietary exposure to doses of 10-20 mg/kg bw per day for 50 days was reported to disrupt learning and performance in rats. In chickens given high doses of carbaryl there was no histological evidence of neurotoxicity.
In controlled studies in volunteers, single oral doses of < 2 mg/kg bw were well tolerated. A single oral dose of 250 mg (about 2.8 mg/kg bw) produced moderate cholinergic symptoms.
In volunteers given repeated daily oral doses over six weeks, the NOAEL was 0.06 mg/kg bw per day, on the basis of an increased ratio of amino acid nitrogen to creatinine in the urine at a dose of 0.13 mg/kg bw per day. This effect may represent a decrease in the ability of the proximal convoluted tubule to reabsorb amino acids. The change was reversible. No inhibition of plasma or erythrocyte cholinesterase activity was observed.
An epidemiological study on carbaryl production workers employed between 1960 and 1978 showed no increase in cancer mortality.
An ADI of 0-0.003 mg/kg bw was established on the basis of the LOAEL of 15 mg/kg bw per day in the study of carcinogenicity in mice, using a safety factor of 5000, which includes an extra safety factor of 50 to account for the presence of vascular tumours at all doses in male mice. The resulting ADI provides an adequate margin of safety, taking into account the LOAEL in the study of developmental toxicity in dogs and the uncertainties about the effects on the male reproductive system.
A toxicological monograph was prepared, summarizing the data received since the previous Meeting and information from EHC 153.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Mouse: |
NOAEL not identified. Lowest effective dose: 100 ppm, equal to 15 mg/kg bw per day (two-year study of toxicity and carcinogenicity). |
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Rat: |
250 ppm, equal to 10 mg/kg bw per day (two-year study of toxicity and carcinogenicity). |
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2 mg/kg bw per day (one-year study of toxicity). |
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Dog: |
NOAEL not identified. Lowest effective dose: 3.1 mg/kg bw per day (study of developmental toxicity). |
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1.8 mg/kg bw per day (one-year study of toxicity). |
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Human: |
0.06 mg/kg bw per day (six-week study of toxicity). |
Estimate of acceptable daily intake for humans
0-0.003 mg/kg bw
Studies that would provide information useful for the continued evaluation of the compound
1. Study of reproductive toxicity, with special attention to the male reproductive system.
2. Studies of teratogenicity in rats and rabbits.
3. Completion of on-going studies to elucidate the mechanism of tumour formation.
4. Study of developmental neurotoxicity and/or screening for acute or subchronic neurotoxicity.
5. Follow-up of the epidemiological study in workers, taking into consideration the latent period before development of cancer.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to carbaryl
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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 = 225-721 mg/kg bw |
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Dermal toxicity, rat |
LD50 > 2000 mg/kg bw |
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Dermal irritation, rabbit |
Not 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, five weeks, dog |
NOAEL =3.1 mg/kg bw per day (highest dose tested); no effects on acetylcholinesterase activity |
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Repeated oral, six weeks, human |
NOAEL = 0.06 mg/kg bw per day; increased ratio of amino acid nitrogen to creatinine in urine |
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Inhalation, 90 days, rat |
NOAEL = 10 mg/m3 per day (highest dose tested) |
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Inhalation, 120 days, cat |
NOAEL = 16 mg/m3 per day; cholinergic reactions at 30 mg/m3 after a 30-day exposure |
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Long-term (> one year)
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Repeated oral, two years, carcinogenicity, mouse |
Vascular tumours in males at 15 mg/kg bw per day, the lowest dose tested |
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Repeated oral (gavage), one year, toxicity and carcinogenicity, rat |
NOAEL = 2 mg/kg bw per day, effects on thyroid and male and female reproductive organs and/or function |
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Repeated oral, two years, toxicity and carcinogenicity, rat |
NOAEL = 10 mg/kg bw per day, reduced brain acetylcholinesterase and reduced body weight. Tumours (thyroid, liver, bladder) at 350 mg/kg bw per day, which exceeded the MTD |
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Repeated oral (gavage), one year, toxicity, dog |
NOAEL = 1.8 mg/kg bw per day, effects on kidney |
