NTP Toxicology and Carcinogenesis Studies of Monochloroacetic Acid (CAS No. 79-11-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Monochloroacetic acid, a colorless crystalline material, is used as a postemergence contact herbicide and as an intermediate in the synthesis of other organic compounds. Toxicology and carcinogenicity studies were conducted by administering monochloroacetic acid (99% pure) in deionized water by gavage to groups of F344/N rats and B6C3F1 mice of each sex once daily, 5 days per week for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma L5178Y cells, Chinese hamster ovary cells, and Drosophila melanogaster. 16-Day Studies: Groups of five rats of each sex received 0, 7.5, 15, 30, 60, or 120 mg monochloroacetic acid/kg body weight. Doses administered to mice were 0, 15, 30, 60, 120, or 240 mg/kg to groups of five males and 0, 30, 60, 120, 240, or 480 mg/kg to groups of five females. One of five male rats given 120 mg/kg died during the studies. Clear nasal discharge, lacrimation, or both, were observed in all groups of male and female rats receiving monochloroacetic acid. No compound-related gross lesions were observed in rats. All male mice given 240 mg/kg and all females given 240 or 480 mg/kg died during the studies. Hypoactivity, piloerection, ataxia, and lacrimation were observed in mice given 240 or 480 mg/kg. No compound-related gross lesions were observed in mice at necropsy. 13-Week Studies: Groups of 20 rats of each sex received 0, 30, 60, 90, 120, or 150 mg/kg monochloroacetic acid, and groups of 20 mice of each sex received doses of 0, 25, 50, 100, 150, or 200 mg/kg. Three to five animals in each dose group were killed at weeks 4 and 8 for the evaluation of hematology parameters. Compound-related deaths occurred in rats in the three highest dose groups (all males given 120 or 150 mg/kg, 9/10 males given 90 mg/kg, and all females given 90 to 150 mg/kg) and in mice given 200 mg/kg (all males and 2/10 females). Final mean body weights of surviving rats and mice receiving monochloroacetic acid were similar to those of controls. In rats, dose-related increases in blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase levels were observed, and relative liver and kidney weights were elevated. There were no compound-related changes in the various hematologic or clinical pathology parameters in mice. A dose-related increase in the incidence and severity of cardiomyopathy was observed in male and female rats receiving monochloroacetic acid, and hepatocellular cytoplasmic vacuolization was observed in the high-dose mice that died during the studies. 2-Year Studies: Based on the mortality and compound-related histopathologic lesions observed in the 13-week studies, doses selected for the 2-year studies of monochloroacetic acid were 0, 15, or 30 mg/kg, administered to groups of 70 rats of each sex, and 0, 50, or 100 mg/kg, administered to groups of 60 mice of each sex. Interim evaluations were conducted on 10 rats per dose group after 6 months of treatment with monochloroacetic acid and on seven rats per dose group after 15 months of treatment. Body Weight and Survival in the 2-Year Studies: Mean body weights of low- and high-dose female and low-dose male rats receiving monochloroacetic acid were within 10% of those of controls throughout the studies; however, after week 30, the mean body weights of high-dose male rats were 4% to 8% less than those of controls. In mice, the mean body weights of dosed males were similar to controls, but those of low- and high-dose females were 6% to 10% less than control values after week 52. Survival of high-dose male and dosed female rats and high-dose male mice was significantly lower than that of controls (male rats: control, 27/53; low-dose, 21/53; high-dose, 16/53; female rats: 37/53; 19/53; 26/53; male mice: 46/60; 39/60; 21/60; female mice: 42/60; 40/60; 44/60). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: There was no compound-related increase in the incidence of neoplasms or nonneoplastic lesions in rats given monochloroacetic acid for 2 years. The incidence of uterine stromal polypss. The incidence of uterine stromal polyps in low- and high-dose female rats was slightly higher than that in controls (2/60; 7/57; 10/60). However, the incidence in the controls was unusually low, and those in the dosed groups were well within the range for NTP historical controls (mean: 21&percnt;, range: 10&percnt;-38&percnt;). Further, because the only malignant stromal neoplasm occurred in a control animal, the polyps were not considered to be related to the administration of monochloroacetic acid. Similarly, there was no monochloroacetic acid-related increase in the incidence of neoplasms in male or female mice, and malignant lymphoma occurred with a significant negative trend in dosed female mice. Increases in the incidence of inflammation of the mucosa of the nasal passages, respiratory epithelial metaplasia of the olfactory epithelium of the nose, and focal squamous cell hyperplasia of the forestomach occurred in dosed male and female mice. Genetic Toxicology: Monochloroacetic acid was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98, with or without exogenous metabolic activation (S9). It induced trifluorothymidine resistance in L5178Y cells in the absence of S9 and induced sister chromatid exchanges without S9 in Chinese hamster ovary cells. Monochloroacetic acid did not induce a significant increase in chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Monochloroacetic acid administered in feed was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster; however, when it was administered by injection, the results were equivocal. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity for monochloroacetic acid in male or female F344/N rats given 15 or 30 mg/kg. There was no evidence of carcinogenic activity for monochloroacetic acid in male or female B6C3F1 mice given 50 or 100 mg/kg. Monochloroacetic acid administration was associated with inflammatory lesions of the nasal mucosa, metaplasia of the olfactory epithelium, and squamous cell hyperplasia of the forestomach in male and female mice. Synonyms: Chloroacetic acid, a-chloroacetic acid, chloroethanoic acid