NTP Toxicology and Carcinogenesis Studies of 1,2-Dichlorobenzene (o-Dichlorobenzene) (CAS No. 95-50-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
The major use of 1,2-dichlorobenzene is as an intermediate in the synthesis of several organic compounds (e.g. 3,4-dichloroaniline) and in the syntheses of the herbicides propanil, diuron, and neburon. It is used as an industrial solvent for toluene diisocyanate, an additive to degreasing agents, a heat exchange medium, a deodorant for garbage and sewage, an ingredient in paint removers, an engine cleaner and de-inking solvent, and a solvent and intermediate in dye manufacture). 1,2-Dichlorobenzene is also used as an insecticide and a fumigant to control peach tree borers, bark beetles, grubs, and termites and to kill mites and other insects in poultry houses and animal sleeping quarters. Because of its properties as both an insecticide and a solvent, 1,2-dichlorobenzene has been used in low-pressure aerosol formulations of insecticides. Approximately 49 million pounds of 1,2-dichlorobenzene were produced in the United States in 1980. First reported commercial production began in 1921. In 13-week studies using F344/N rats and B6C3F1 mice, 500 mg/kg of 1,2-dichlorobenzene (<99% pure) decreased survival in male and female mice and female rats when administered in corn oil by gavage five times per week. At this dose, 1,2-dichlorobenzene produced centrolobular necrosis of the liver, hepatocellular degeneration, and depletion of lymphocytes in the thymus and spleen of both sexes of rats and mice. At a dose of 250 mg/kg, necrosis of individual hepatocytes was observed in both sexes of rats and in male mice. Minimal hepatocellular necrosis was observed in a few rats at a dose of 125 mg/kg, but no hepatic alterations were observed in mice at this dose. Renal tubular degeneration was observed in male rats at 500 mg/kg, and multifocal mineralization of the myocardial fibers of the heart and skeletal muscle were seen in mice. The only hematologic changes considered notable were slight decreases in hemoglobin and hematocrit in the 500 mg/kg male and female rats and in red blood cell counts in the 500 mg/kg male rats; no other marked hematological changes were observed in either species. Two-year toxicology and carcinogenesis studies of 1,2-dichlorobenzene were conducted by administering the test chemical in corn oil gavage five times per week for 103 weeks to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 60 and 120 mg/kg. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Survivals of female rats, male mice, and female mice were comparable to those of the corresponding vehicle controls in the 2-year study, but survival of high dose male rats was (P<0.001) shorter than that of the vehicle controls. In this group there were three accidental deaths and five deaths probably due to the gavage process; in addition aspiration of 1,2-dichlorobenzene in corn oil into the lungs may have been a contributing factor to the deaths of 12 high dose male rats. The 120 mg/kg dose level of 1,2-dichlorobenzene did not affect body weight in rats or mice of either sex or survival of mice or female rats. An increase in tubular regeneration in the kidney of high dose male mice was observed in the 2-year study (control, 8/48, 17%; low dose, 12/50, 24%; high dose, 17/49, 35%). No other compound-related nonneoplastic histological lesions were noted in the 2-year study. The incidence of pheochromocytoma of the adrenal gland in low dose male rats was elevated (P<0.05, life table test) relative to controls (9/50, 16/50, 6/49). However, the incidence in the high dose group was lower than that of the controls and the dose-response trend was not statistically significant. Therefore, the increase in pheochromocytoma in the low dose male rats is not regarded as related to administration of 1,2-dichlorobenzene. A dose-related increase (P<0.05) in malignant histiocytic lymphoma was observed in male mice (control, 0/50, 0%; low dose, 1/50, 2%; high dose, 4/50, 8%) and in female mice (0/49, 0%; 0/50, 0%; 3/49, 6%); however, comparisons of the numbers of animals with all typnt;; 3/49, 6&percnt;); however, comparisons of the numbers of animals with all types of lymphomas is considered to be a more appropriate comparison. 1,2-Dichlorobenzene did not increase the incidence of all types of lymphomas (combined) in male mice (8/50, 16&percnt;; 2/50, 4&percnt;; 4/50, 8&percnt;) or female mice (11/49, 22&percnt;; 11/50, 22&percnt;; 13/49, 27&percnt;). Therefore, the increase in histiocytic lymphomas was discounted. Under the conditions of these two-year gavage studies, there was no evidence of carcinogenicity of 1,2-dichlorobenzene for male or female F344/N rats or B6C3F1 mice receiving 60 or 120 mg/kg per day. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: o-dichlorobenzene