Toxicology and Carcinogenesis Studies of Chlorendic Acid (CAS No. 115-28-6) in F344/N Rats and B6C3F1 Mice (Feed Studies)
Chemical Formula: C9H4O4Cl6
Chlorendic acid is a chemical intermediate used in the preparation of fire-retardant polyester resins and plasticizers. Toxicology and carcinogenesis studies of chlorendic acid (greater than 98% pure) were conducted by administering the chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at concentrations of 0, 620, or 1,250 ppm for 103 weeks. The estimated mean daily consumption of chlorendic acid was 27 and 56 mg/kg body weight for low dose and high dose male rats and 39 and 66 mg/kg for low dose and high dose female rats. In mice, the estimated daily consumption was 89 and 185 mg/kg for low dose and high dose males and 100 and 207 mg/kg for low dose and high dose females. These concentrations were selected because higher levels in the 14-day and 13-week studies caused decreased mean body weights, more deaths, and increased incidences of liver lesions (rats: centrilobular cytomegaly, mitotic alterations, bile duct hyperplasia; mice: centrilobular cytomegaly, mitotic alterations, coagulative necrosis) relative to control groups.
Survival and feed consumption of dosed male and female rats and mice in the 2-year studies were similar to those of controls. Mean body weights of high dose male and female rats and mice were lower than those of controls. Mean body weights of high dose female rats were 16%-24% lower than those of controls during the second half of the study.
In the 2-year chlorendic acid feed studies, incidences of nonneoplastic lesions of the liver in dosed male rats (cystic degeneration) and dosed female rats (granulomatous inflammation, pigmentation, and bile duct hyperplasia) were increased. The incidences of neoplastic nodules of the liver were significantly increased in dosed male rats (control, 2/50; low dose, 21/50; high dose, 23/50) and high dose female rats (1/50; 3/39; 11/50). The incidence of hepatocellular carcinomas was also increased in high dose female rats (0/50; 3/49; 5/50). In mice, the incidences of nonneoplastic lesions of the liver were increased in dosed males (coagulative necrosis) and high dose females (mitotic alterations). The incidences of hepatocellular adenomas (5/50; 9/49; 10/50), hepatocellular carcinomas (9/50; 17/50; 20/50), and hepatocellular adenomas or carcinomas (combined) (13/50; 23/49; 27/50) were increased in dosed male mice. Hepatocellular carcinomas metastasized to the lung in 2/50 control, 4/49 low dose, and 7/50 high dose male mice. Hepatocellular adenomas or carcinomas (combined) were not significantly increased in female mice (3/50; 7/49; 7/50).
The incidences of acinar cell hyperplasia (0/49; 4/50; 4/50) and acinar cell adenomas (0/49; 4/50; 6/50) of the pancreas were increased in dosed male rats relative to those of controls. Pancreatic acinar cell adenoma is an uncommonneoplasm in untreated control F344/N rats in NTP studies (3/1,667).
In dosed male rats, incidences of alveolar/bronchiolar adenomas of the lung (0/50; 3/50; 5/50) were increased. The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in dosed female mice were also increased (1/50; 5/50; 6/50). Preputial gland carcinomas occurred at a greater incidence in low dose male rats (1/50; 8/50; 4/50) than in controls. An adenoma and a squamous cell papilloma were observed in two low dose male rats. The incidences of sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) of the salivary gland (1/50; 2/49; 4/50) were increased in dosed male rats. The incidences in the dosed groups were not significantly different from that in the controls, but these tumors are uncommon in F344/N rats receiving no treatment (3/1,689).
Chlorendic acid was not mutagenic in strains TA100, TA98, TA1535, or TA 1537 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver activation when tested according to the preincubational protocol. Chlorendic acid was mutagenic in the L5178Y/TK+/- mouse lymphoma cell forward assay (in the absence of activation) at a dose resulting in toxicity.
An audit of the experimental data was conducted for the 2-year studies of chlorendic acid. No data discrepancies were found that influenced the final interpretations.
Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenicity of chlorendic acid for male F344/N rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female F344/N rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver. There was clear evidence of carcinogenicity of chlorendic acid for male B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of hepatocellular carcinomas. There was no evidence of carcinogenicity of chlorendic acid for female B6C3F1 mice given chlorendic acid in the diet at concentrations of 620 or 1,250 ppm for 103 weeks.
Synonym: 1,4,5,6,7,7-hexachloro-5-norbornene-2,3-dicarboxylic acid
Report Date: April 1987