NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C12, 60% Chlorine) (CAS No. 108171-26-2*) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis assessments of chlorinated paraffins (C12, 60% chlorine), a material widely used as a flame retardant and extreme-pressure lubricant, were conducted in male and female F344/N rats and male and female B6C3F1 mice in single-administration, 16-day, 13-week, and 2-year studies. Doses used in the 2-year studies were 0, 312, or 625 mg/kg body weight per day administered by gavage in corn oil five times per week to groups of 70 male and female rats and 0, 125, or 250 mg/kg administered to groups of 50 male and female mice. Ten male and 10 female rats were killed after 6 and 12 months of dosing and examined for toxicity. No chemically related toxicity was observed in single-administration studies in which male and female rats received doses of chlorinated paraffins (C12, 60% chlorine) up to 13,600 mg/kg body weight and male and female up to 27,200 mg/kg. In 16-day studies, deaths did occur in groups of male and female rats given 7,500 mg/kg and in groups of male and female mice given doses of 1,875 mg/kg or higher. In 13-week studies, no chemically related deaths occurred among male and female rats given up to 5,000 mg/kg or mice given up to 2,000 mg/kg. Increased liver weights were noted in dosed rats and mice of each sex in the short-term studies, and dosed male rats showed more severe nephropathy than did vehicle controls. Doses selected for the 2-year studies were those that caused a minimal increase in liver weight in the short-term studies. Liver and kidney weights were increased in dosed rats killed at 6 and 12 months. Morphometric measurements demonstrated hepatocyte hypertrophy in the livers of dosed rats. Lesions of the kidney tubules and interstitial inflammation increased with dose in male and female rats. During the 2-year studies, body weights of high dose male rats were 8%-12% lower than those of vehicle controls after week 20, and body weights of dosed female mice were about 10% lower than those of vehicle controls during the second year. Survival of dosed male rats was lower than that of vehicle controls after about week 85, perhaps due to toxicity to the kidney (final survival: vehicle control, 27/50; low dose, 6/50; high dose, 3/50). Survival of low dose female rats was lower than that of vehicle controls (34/50; 24/50; 29/50). Survival of dosed male mice was not significantly different from that of vehicle controls (34/50; 31/50; 31/50). Survival of high dose female mice was lower than that of vehicle controls after about week 75 (final survival: 36/50; 31/50; 25/50). Chemically related nonneoplastic lesions consisted of hypertrophy and minimal focal necrosis of the liver in rats; erosion, inflammation, and ulceration of the glandular stomach and forestomach a in male rats; and formation ofmultiple cysts in the kidney tubules of male rats. The incidence of nephropathy was also increased in dosed female rats and mice. The maximum tolerated dose may have been exceeded in male and female rats. Neoplastic lesions associated with chlorinated paraffins (C12, 60% chlorine) administration were found in the liver of rats and mice of each sex (see table p. 12 of Technical Report) Dosed male rats showed increased incidences of kidney tubular cell hyperplasia (1/50; 9/50; 12/49) and of tubular cell adenomas (0/50; 7/50; 3/49); two low dose males had tubular cell adenocarcinomas. The incidences of mononuclear cell leukemia were increased in dosed male rats (7/50; 12/50; 14/50) and in low dose female rats (11/50; 22/50; 16/50). Pancreatic acinar cell tumors occurred at increased incidences in low dose male rats (11/50; 22/50; 17/50). Follicular cell adenomas or carcinomas (combined) of the thyroid gland were found at increased incidences in both female rats (0/50; 6/50; 6/50) and female mice (8/50; 12/49; 15/49). Chlorinated paraffins (C12, 60% chlorine) was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley or male Syrian hamster liver S9 when tested according to the preincubational protocol. An ed according to the preincubational protocol. An audit of the experimental data was conducted for these 2-year studies on chlorinated paraffins (C12, 60% chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for F344/N rats based on increased incidences of hepatocellular neoplasms (primarily neoplastic nodules) in male and female rats, of adenomas or adenocarcinomas (combined) of the kidney tubular cells in male rats, and of follicular cell adenomas or carcinomas (combined) of the thyroid gland in female rats. Mononuclear cell leukemia in dosed male rats may have been related to administration of chlorinated paraffins (C12, 60% chlorine). There was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of adenomas or carcinomas (combined) in dosed male and female mice and increased incidences of adenomas and of adenomas or carcinomas (combined) of thyroid gland follicular cells in dosed female mice.