NTP Toxicology and Carcinogenesis Studies of Chlorobenzene (CAS No. 108-90-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Chlorobenzene is a colorless, volatile liquid under standard environmental conditions (vapor pressure=11.8 mm Hg at 25 degrees C, 760 mm Hg). It is used primarily as a solvent (e.g. resins, dyes, pesticides, and perfumes), a degreasing agent, and a chemical intermediate, particularly in the synthesis of nitrobenzenes. Although still considerable, estimates of the yearly production volume of chlorobenzene in the United States indicate declining use in recent years, due to the reduced demand for organochlorine pesticides utilizing chlorobenzene as an intermediate. Toxicology and carcinogenesis studies of chlorobenzene (<99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 female B6C3F1 mice at doses of 60 or 120 mg/kg. Groups of 50 male B6C3F1 mice received 30 or 60 mg/kg. Chlorobenzene was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls, and additional groups of 50 rats and 50 mice of each sex served as untreated controls. The chlorobenzene doses were chosen on the basis of 90-day studies, in which doses 2-fold or greater in excess of the doses used in the 2-year study caused death, hepatocellular necrosis, renal tubular injury, thymic necrosis, or lymphoid or myeloid depletion of bone marrow, spleen or thymus. Mean body weights of dosed rats and mice were essentially the same or greater than those of the controls during the 2-year studies. Survivals of low dose male rats, dosed female rats, dosed male mice, and dosed female mice were not adversely affected by administration of chlorobenzene. Survival of high dose male rats in the 2-year study was significantly (P=0.033) lower than that of the vehicle controls. No chlorobenzene-induced toxic lesions responsible for this reduction in survival were observed. Based on the prechronic results and on the above data, the doses used in the 2-year study were considered to be adequate for carcinogenicity testing. Male rats dosed with chlorobenzene exhibited a significant (P<0.05) increase in the incidence of animals with neoplastic nodules of the liver (overall incidences: untreated control, 4/50 (8%); vehicle control, 2/50 (4%); low dose, 4/49 (8%); high dose, 8/49 (16)). Increased incidences of hepatocellular carcinomas in male rats or of neoplastic nodules or hepatocellular carcinomas in female rats were not observed. No increased tumor incidences were observed in female rats or in male or female mice. Under the conditions of these studies, chlorobenzene administration increased the occurrence of neoplastic nodules of the liver in high dose (120 mg/kg/day) male F344/N rats, providing some but not clear evidence of carcinogenicity of chlorobenzene in male rats. Carcinogenic effects of chlorobenzene were not observed in female F344/N rats or in male or female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: monochlorobenzene; chlorobenzol; phenyl chloride; benzene monochloride