Toxicology and carcinogenesis studies of dibromoacetic acid (Cas No. 631-64-1) in F344/N rats and B6C3F1 mice (drinking water studies).
Dibromoacetic acid is a water disinfection by-product. Dibromoacetic acid was nominated to the National Toxicology Program by the United States Environmental Protection Agency for toxicity and carcinogenicity studies in rats and mice because of widespread human exposure and because a related dihaloacetate, dichloroacetate, was found to be carcinogenic to the liver of rats and mice. Drinking water was selected as the route of exposure to mimic human exposure to this chemical. Male and female F344/N rats and B6C3F1 mice were exposed to dibromoacetic acid (greater than 99% pure) in drinking water for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and peripheral blood erythrocytes of exposed mice. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid in drinking water for 2 weeks, equivalent to average daily doses of approximately 17, 32, 67, 134, 270 (males), or 257 (females) mg dibromoacetic acid/kg body weight. All rats survived to the end of the study. Mean body weight gains of 1,000 mg/L males and of 500 mg/L females were significantly greater than those of the controls. Water consumption by exposed and control groups was similar. Liver weights of exposed males and females were significantly increased. Right testis weights of males exposed to 500 mg/L or greater were significantly decreased. The incidences of hepatocytic cytoplasmic alteration were significantly increased in males exposed to 500 mg/L or greater and in 2,000 mg/L females. Testicular lesions, characterized by a delay in spermiation and retained spermatids, were noted in males exposed to 500 mg/L or higher concentrations. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 24, 47, 95, 178, or 370 mg/kg to males and 22, 53, 88, 166, or 309 mg/kg to females) in drinking water for 2 weeks. All mice survived to the end of the study. Mean body weight gains of 250 and 500 mg/L males were significantly greater than those of the controls. Water consumption by exposed and control groups was similar. Liver weights of males and females in the 1,000 and 2,000 mg/L groups were significantly increased. Thymus weights of males and females in the 1,000 and 2,000 mg/L groups were significantly less than those of controls. The incidences of thymus atrophy were significantly increased in 1,000 and 2,000 mg/L males and 2,000 mg/L females. The incidences of morphological changes to the germinal epithelium of the testes were increased in males exposed to 1,000 or 2,000 mg/L. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 10, 20, 40, 90, and 166 mg/kg to males and 12, 23, 48, 93, and 181 mg/kg to females) in drinking water for 3 months. All rats survived to the end of the study. Mean body weights of male and female rats in the 2,000 mg/L group were significantly less than those of controls. Water consumption by the 2,000 mg/L males at weeks 1 and 13 and by females at week 13 was less than that by controls. Small decreases in the erythron and platelet counts occurred in rats exposed to 2,000 mg/L; minimally impaired erythropoiesis was also seen in 1,000 mg/L rats. Liver weights of all exposed groups of males and females were significantly increased. Male rats in the 2,000 mg/L group had significantly decreased testis weights. Testicular atrophy was noted in the 2,000 mg/L group, and retained spermatids were observed in the 500 and 1,000 mg/L groups. In the pituitary gland of male rats exposed to 2,000 mg/L, the incidence of cellular hypertrophy was significantly increased. The incidences of hepatocellular vacuolization were significantly increased in males exposed to 500 mg/L or greater and in females exposed to 2,000 mg/L. Hematopoietic cell proliferation was noted in females in the 2,000 mg/L group. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 125, 250, 500, 1,000, or 2,000 mg/L dibromoacetic acid (equivalent to average daily doses of approximately 16, 30, 56, 115, and 230 mg/kg to males and 17, 34, 67, 132, and 260 mg/kg to females) in drinking water for 3 months. All mice survived to the end of the study. Mean body weights and body weight gains of female mice in the 2,000 mg/L group and the mean body weight gain of 2,000 mg/L males were significantly less than those of controls. Water consumption by males in the 2,000 mg/L group was decreased at weeks 1 and 13 relative to controls. Small decreases in mean cell hemoglobin and platelet counts occurred in 2,000 mg/L male mice. Liver weights of males and females exposed to 500 mg/L or greater were significantly increased. Hepatocellular cytoplasmic vacuolization was present in most mice and the severity was increased in 1,000 and 2,000 mg/L males and females. The incidences of abnormal testicular morphology were significantly increased in 1,000 and 2,000 mg/L males. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 50, 500, and 1,000 mg/L dibromoacetic acid for 2 years (equivalent to average daily doses of approximately 2, 20, and 40 mg/kg to males and 2, 25, and 45 mg/kg to females). Survival of exposed rats was similar to that of the control groups. Mean body weights of 1,000 mg/L males and females were less than those of the controls after weeks 29 and 53, respectively, and those of 500 mg/L males and females were less after weeks 57 and 85, respectively. Water consumption by males and females exposed to 1,000 mg/L was less than that by controls during year 2 of the study. The incidence of malignant mesothelioma was significantly increased in 1,000 mg/L male rats. A positive trend in the incidence of mononuclear cell leukemia occurred in female rats, and the incidence in 1,000 mg/L females was significantly increased. The incidences of mononuclear cell leukemia were increased in 50 and 500 mg/L males. The incidences of cystic degeneration of the liver were significantly increased in all exposed groups of male rats. The incidences of alveolar epithelial hyperplasia were significantly increased in 500 and 1,000 mg/L females, and the incidences of nephropathy were significantly increased in all exposed groups of females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to drinking water containing 0, 50, 500, and 1,000 mg/L dibromoacetic acid for 2 years (equivalent to average daily doses of approximately 4, 45, and 87 mg/kg to males and 4, 35, and 65 mg/kg to females). Survival of exposed mice was similar to that of the controls. Mean body weights of 50 and 500 mg/L male mice were greater than those of the controls after week 85. Water consumption by exposed mice was generally similar to that by controls throughout the study. The incidences of liver neoplasms occurred with positive trends in male and female mice. The incidences of multiple hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in all exposed groups of males and in 500 and 1,000 mg/L females. The incidences of hepatoblastoma were significantly increased in 500 and 1,000 mg/L males, and the incidences of hepatocellular carcinoma were significantly increased in 1,000 mg/L males and 500 mg/L females. The incidences of alveolar/bronchiolar adenoma occurred with positive trends in males and females, and the incidence in 500 mg/L male mice was significantly greater than that in controls.


RESULTS
Dibromoacetic acid was mutagenic in Salmonella typhimurium strain TA100 with and without rat or hamster liver metabolic activation enzymes (S9); no activity was detected in strain TA98, with or without S9. Increased frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male, but not female, mice administered dibromoacetic acid in drinking water for 3 months.


CONCLUSIONS
Under the conditions of these studies, there was some evidence of carcinogenic activity of dibromoacetic acid in male rats based on an increased incidence of malignant mesothelioma. The increased incidences of mononuclear cell leukemia in male rats may have been related to dibromoacetic acid exposure. There was some evidence of carcinogenic activity of dibromoacetic acid in female rats based on an increased incidence and positive trend of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of dibromoacetic acid in male and female mice based on increased incidences of hepatocellular neoplasms and hepatoblastoma (males only). Increased incidences of lung neoplasms in male mice were also considered to be exposure related. The slight increased incidence of lung neoplasms in female mice may have been related to dibromoacetic acid exposure. Exposure to dibromoacetic acid for 2 years caused increased incidences of cystic degeneration of the liver in male rats, increased incidences of alveolar epithelial hyperplasia and nephropathy in female rats, and increased incidences of splenic hematopoiesis in male mice.
D000085:Acetates / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D006224:Cricetinae; D003412:Cricetulus; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000139:chemically induced / Q000556:secondary; D051379:Mice; D008815:Mice, Inbred Strains; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009153:Mutagens / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013737:Testis / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests; D014881:Water Supply
D000085:Acetates; D002273:Carcinogens; D004785:Environmental Pollutants; D009153:Mutagens; C088674:dibromoacetic acid