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drinking water
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
~
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;
