** Evaluation in CCPR periodic review programme
TOXICOLOGY
Carbofuran was evaluated for toxicological effects by the Joint Meeting in 1976, 1979, 1980, and 1982. The 1980 Meeting established an ADI of 0-0.01 mg/kg bw, which was confirmed in 1982. The compound was re-evaluated at the present Meeting within the CCPR periodic review programme.
Carbofuran is rapidly absorbed, metabolized, and eliminated, mainly in the urine, after oral administration to mice and rats. After oral administration of [phenyl-14C]carbofuran to rats, 92% of the radiolabel was eliminated in the urine and 3% in the faeces. Most of the radiolabel was eliminated within 24 h after treatment. With the [14C]carbonyl-labelled compound, 45% was eliminated as [14C]carbon dioxide. The metabolic pathway involves hydroxylation, hydrolysis, oxidation and conjugation.
Carbofuran is highly toxic after acute oral administration. The oral LD50 values in various species ranged from 3 to 19 mg/kg bw. Carbofuran had no sensitizing potential in guinea-pigs, and no local irritation was found in rabbits after repeated dermal applications over 7 or 21 days. WHO has classified carbofuran as 'highly hazardous'.
In a 13-week study in dogs fed diets providing 0, 10,. 70, or 500/250 ppm carbofuran (dose reduced because of marked toxicity), an NOAEL was not identified because inhibition of erythrocyte acetylcholinesterase activity and some clinical signs were observed at the lowest dose. In a subsequent four-week study in dogs, the only dose administered was 5 ppm, equal to 0.22 mg/kg bw per day, which was the NOAEL for clinical signs, mortality, body weight, food consumption, and cholinesterase activity in plasma and erythrocytes. In a one-year study in dogs at dietary concentrations of 0, 10, 20, or 500 ppm, the NOAEL was 10 ppm, equal to 0.3 mg/kg bw per day, on the basis of histopathological testicular changes in a single male at 20 ppm; similar changes were observed in animals at 500 ppm. There was no inhibition of erythrocyte or brain acetylcholinesterase at concentrations of 10 or 20 ppm. The overall NOAEL in these short-term studies in dogs was 5 ppm, equal to 0.22 mg/kg bw per day.
In two-year studies of toxicity and carcinogenicity at dietary concentrations of 0, 20, 125, or 500 ppm in mice and 0, 10, 20, or 100 ppm in rats the NOAELs were 20 ppm, equal to 2.8 mg/kg bw per day, in mice and 20 ppm, equivalent to 1 mg/kg bw per day, in rats, on the basis of inhibition of erythrocyte and brain acetylcholinesterase activity. There was no evidence of tumorigenicity.
In a three-generation study of reproductive toxicity in rats at dietary concentrations of 0, 20, or 100 ppm, the NOAEL was 20 ppm, equal to 1.6 mg/kg bw per day, on the basis of reduced body-weight gain in parental animals and reduced pup growth and pup survival at 100 ppm.
In an early study of developmental toxicity, rats were given carbofuran at doses of 0, 0.1, 0.3, or 1 mg/kg bw per day by gavage. An NOAEL could not be identified in this study. Dose-dependent transient clinical signs (chewing motions) were observed in the dams. In a later study in rats at oral doses of 0, 0.25, 0.5, or 1.2 mg/kg bw per day the NOAEL for maternal and fetal toxicity was 1.2 mg/kg bw per day, the highest dose tested. In a further study of teratogenicity in rats, with dietary administration of 0, 20, 60, or 160 ppm carbofuran, the NOAEL for maternal toxicity was 20 ppm, equal to 1.5 mg/kg bw per day, on the basis of a reduction in body-weight gain at 60 ppm. The NOAEL for pup toxicity, based on reduced pup weight, was 60 ppm, equal to 4.4 mg/kg bw per day. None of the studies showed teratogenic potential.
The results of an early study of developmental toxicity in rabbits at oral doses of 0, 0.2, 0.6, or 2 mg/kg bw per day showed an NOAEL of 0.6 mg/kg bw per day for maternal toxicity on the basis of clinical signs, and an NOAEL of 2 mg/kg bw per day for fetotoxicity and teratogenicity. In a subsequent study in rabbits at doses of 0, 0.12, 0.5, or 2 mg/kg bw per day, the NOAEL was 0.5 mg/kg bw per day on the basis of slightly reduced body-weight gain in dams and a slightly increased incidence of skeletal variations in pups at 2 mg/kg bw per day. These studies provided no evidence of teratogenicity.
In a 90-day study of neurotoxicity in rats at dietary concentrations of 0, 50, 500, or 1000 ppm, systemic toxicity (reduction in body-weight gain) was observed at all doses. Clinical signs of neurotoxicity were observed at 500 and 1000 ppm. No histopathological lesions in the nervous system were observed.
In a study of developmental neurotoxicity, carbofuran was administered in the diet to provide concentrations of 0, 20, 75, or 300 ppm from gestation day 6 through lactation day 10. Reductions in body-weight gain in dams and pups and in pup survival and some evidence of delayed pup development were found at 75 ppm and higher. The NOAEL was 20 ppm, equal to 1.7 mg/kg bw per day, on the basis of reduced body-weight gain in dams and signs of fetotoxicity at higher doses.
Carbofuran has been tested for genotoxicity in a wide range of tests in vivo and in vitro. The Meeting concluded that it is not genotoxic.
An ADI of 0-0.002 mg/kg bw was allocated on the basis of the NOAEL for erythrocyte acetylcholinesterase inhibition of 0.22 mg/kg bw per day in a four-week study in the most sensitive species, the dog, using a 100-fold safety factor. The use of a short-term study to determine the ADI was justified because the effect observed was reversible and acute.
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
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Mouse: |
20 ppm, equal to 2.8 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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Rat: |
20 ppm, equivalent to 1 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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20 ppm, equal to 1.2 mg/kg bw per day (three-generation study of reproductive toxicity) |
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1.2 mg/kg bw per day (highest dose tested in a study of developmental toxicity) |
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20 ppm, equal to 1.5 mg/kg bw per day (study of developmental toxicity) |
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20 ppm, equal to 1.7 mg/kg bw per day (study of developmental neurotoxicity) |
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Rabbit: |
0.6 mg/kg bw per day (study of developmental toxicity) |
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Dog: |
5 ppm, equal to 0.22 mg/kg bw per day (four-week study of toxicity) |
Estimate of acceptable daily intake for humans
0-0.002 mg/kg bw
Studies that would provide information useful for the continued evaluation of the compound
Further observations in humans.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to carbofuran
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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 =6-14 mg/kg bw |
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Dermal toxicity, rat |
LD50 >500 mg/kg bw |
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Inhalation toxicity, rat |
LC50 = 0.088-0.1 mg/litre |
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Dermal irritation, rabbit |
Not irritating |
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Ocular irritation, rabbit |
Not available |
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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, 4 weeks, toxicity, dog |
NOAEL = 0.22 mg/kg bw per day |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 1.6 mg/kg bw per day, parental and pup toxicity |
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Repeated oral (gavage), developmental toxicity, rat |
NOAEL = 1.2 mg/kg bw per day (highest dose tested). No evidence of teratogenicity |
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Repeated oral (feeding), developmental toxicity, rat |
NOAEL = 1.5 mg/kg bw per day, maternal toxicity |
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 0.6 mg/kg bw per day, maternal toxicity. No evidence of teratogenicity |
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Repeated oral, developmental neurotoxicity, rat |
NOAEL = 1.7 mg/kg bw per day |
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Long-term (> one year) |
Repeated oral, two years, carcinogenicity, mouse |
NOAEL = 2.8 mg/kg bw per day, cholinesterase inhibition. No evidence of carcinogenicity |
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Repeated oral, two years, carcinogenicity, rat |
NOAEL = 1 mg/kg bw per day, reduced body-weight gain and cholinesterase inhibition. No evidence of carcinogenicity. |
