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12 DRINKING WATER AND HEALTH CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARL) Chronic Exposure Long-term (2-year) feeding studies have been con- ducted in rats and dogs. The studies reviewed in the first volume of Drir~k- ing Water arid Health (National Research Council, 1977, pp. 635-693) es- tablished 0.1 mg/kg/day no-adverse-effect levels in both animal species. This resulted in the calculation of an acceptable daily intake (ADI) for aldicarb of 0.007 mg/liter. This value continues to be the recommended SNARL for chronic exposure. Work cited in the first volume indicated that the acute effects of aldicarb toxicity are readily reversible. Unless exposure is sustained, therefore, cumulative effects are unlikely. None of three long- term rodent studies on aldicarb provided evidence of a carcinogenic effect. In fact, no chronic toxicity of any type was observed. This may be attrib- uted to the limited maximum daily dose that could be given because of the potent anticholinesterase activity of aldicarb. Animal studies have pro- vided no indication that aldicarb has any untoward toxicity other than that associated with anticholinesterase activity. Since animal studies of sufficient duration have been conducted and since restrictions on dosage have been imposed by the intrinsic toxicity of the agent, it is unlikely that any further meaningful repeated exposure data will be forthcoming. The best judgment that can be made with the data in hand is that exposure of humans to doses of aldicarb that do not affect cholinesterase will not result in any adverse effects. CARBOFURAN 7-benzofuranol, 2,3~ihydr~2,2~imethyt-, methy~carbamate CAS No. 1563-6~2 OOCNHCH3 ~<CH3 Carbofuran is a systemic insecticide, acaricide, and nematocide, which is applied directly to foliage and soil. The chemical was introduced in 1967 by the FMC Corporation under the trademark Furadan. It is a colorless, crystalline solid that is soluble in water at 700 mg/liter. Its half-life in soil ranges from 30 to 60 days. In alkaline media, the compound is unstable. Carbofuran does not require activation, but is a direct inhibitor of ace- tylcholinesterase. For this reason, symptoms consistent with the toxicity of
Toxicity of Selected Contaminants 13 insecticides of this class appear in mammals immediately after they have been exposed to the compound. METAB OLISM Carbofuran is readily and completely absorbed when administered orally to mice and rats (Ahdaya et al., 1981; Marshall and Dorough, 1979~. In studies of bile-cannulated rats given an oral dose of '4C-ring-labeled carbo- furan, Marshall and Dorough (1979) accounted for 95~o of the dose in the bile and urine within 48 hours. Biliary excretion was quite extensive and comprised about one-third of the dose given. The products of the metabolism of carbofuran have been shown to be similar in plants and mammals (Metcalf et al., 1968~. The most prominent of these products results from the hydroxylation of the dihydrobenzo- furanyl ring to yield 3-hydroxycarbofuran (Dorough, 1968; Ivie and Do- rough, 1968~. In mice and rats, further oxidation to the 3-keto derivative occurs as well as hydrolysis of the carbamate. Studies with ring-labeled carbofuran in rats have shown that more than 90~O of the dose is excreted in the urine and that the material is present primarily as water-soluble con- jugates of the 3-hydroxy and 7-hydroxy metabolites, each of which appears to a limited extent in free form. Sulfate and glucuronide conjugates ac- count for the majority of the urinary metabolites in the rat (Marshall and Dorough, 1979~. The N-methylhydroxy derivative was also found in the urine in small quantities. As would be expected, the urinary product also included derivatives formed by metabolic alteration at more than one site (e.g., hydrolysis at position 7 plus 3-hydroxylation). In another study in rats, the major urinary metabolite was a water-soluble conjugate of 2,3- dihydro-2,2-dimethyl-3-keto-7-hydroxybenzofuran (Dorough, 1968~. In the cow, the metabolic deposition of carbafuran was found to be very simi- lar to that in the rat both in route of excretion and metabolites fanned (Ivie and Dorough, 1968~. HEALTH A SPE CTS Observations in lIumans Tobin (1970) related five case reports of individuals with apparent carbo- furan intoxication. The symptoms that were rapid in onset were character- istic of compounds with anticholinesterase activity: nausea, blurred vision, muscular weakness, and perspiration. The effects subsided shortly after the onset, and all subjects had complete recovery, which was enhanced by the administration of atropine. A committee of the National Research Council (1982) found no evidence l
14 DRINKING WATER AND HEALTH that long-tenn health effects resulted from short-term exposure to a variety of anticholinesterase compounds. That committee did not specifically re- view carbofuran, which is a member of that broad class of chemicals. Nonetheless, this conclusion provides reassurance that short-term expo- sure to carbofuran is unlikely to produce long-term adverse effects on hu- man health. Observations in Other Species Acute Effects The acute oral LDSo of carbofuran has been reported to be less than 20 mg/kg bw for a number of mammalian species (Table II- 11. The committee found no other reports describing the effects of acute treat- ment with carbofuran. Chronic Effects Wolfe and Esher (1980) conducted an 8-month feed- ing study of carbofuran in two species of mice the oldfield mouse (Pero- myscus polionotus) and the cotton mouse (P. gossypinus). They used one dietary concentration of 0.01%. The animals were housed in pairs, and reproductive performance was evaluated in addition to growth and behav- ior. This level of treatment produced no measurable effect on the food con- sumption or growth of the parents, or on reproductive capacity or growth and development of the young. Tobin (1970) reported no-effect levels in the diet of 25 and 20 ppm for the rat and dog, respectively, after conducting 2-year feeding studies with carbofuran. This report contained no other data on the design or the evalu- ation of these studies. Mutagenicity Quarles et al. (1979b) used a transplacental host-medi- ated hamster cell assay to study the ability of carbofuran to induce mor- phological transformation in fetal cell cultures. These cultures were also examined for growth in soft agar (0.3~o) and for their ability to induce tumors in nude mice. Negative results were obtained with carbofuran. Oral administration of sodium nitrite (50 mg/kg) and carbofuran TABLE II-1 LDsos for Carbofuran in Mice, Rats, and Dogs Animal LDsos, mg/kg Reference Mouse 2 Kriegeret al., 1976 Rat 8-14 Tobin, 1970 Rat 4-11 Yuetal., 1972 Rat 1 1-15 Abdel-Aal and Helal, 1980 Dog 19 Tobin, 1970
Toxicity of Selected Contaminants 15 (10 mg/kg) did not result in elevated micronuclei counts in the bone mar- row cells of mice (Seller, 1977~. Negative results were obtained in the Ames Salmonella assay, yeast Saccharomyces cerevisiae D3 mitotic recombina- tion assay, E. cold WP2 assay, and relative toxicity assay with Escherichia cold and Bacillus subtilis (Poole et al., 1977, abstract). Germinating onion bulbs (Allium cepa) were treated with O.l~o carbo- furan for 2 to 4 hours (Sathaiah et al., 1974~. The investigators observed an irregular scattering of chromosomes during the metaphase stage as well as chromosome abnormalities such as fragments, clumping, scattered ana- phases, and contractions. In summary, carbofuran was found to be nonmutagenic in several short- term assays. Although chromosome abnormalities were observed in one plant assay, there is no evidence to suggest that DNA damage was directly involved in producing these effects. Carcinogenicity No data were found by the committee. Teratogenicity McCarthy et al. (1971, abstract) reported that al- though no increase in defects occurred in the offspring of treated rats, rab- bits, and dogs, there was a reduced survival rate in rat offspring exposed to diets containing 100 ppm. Wolfe and Esher (1980) administered the same dietary dose level to mice and found a reduced survival rate, but the differ- ence from controls was not significant, and fetal weights were not reduced. After reviewing these limited data, the committee concluded that carbo- furan does not appear to be teratogenic to mice, rats, rabbits, or dogs. CONCLUSIONS AND RECOMMENDATIONS The published information is not sufficient to permit a calculation of a suggested no-adverse-response level (SNARL) or otherwise to assess the potential hazard of chronic exposure to carbofuran. There is a need for more data on the chronic toxicity, carcinogenicity, and teratogenicity of carbofuran. CARBON TETRACHLORIDE methane, tetrachIorm CAS No. 5~23-5 CCl4 Carbon tetrachloride was evaluated in the first and third volumes of Drink- ing Water and Health (National Research Council, 1977, pp. 703-706;
