NTP Toxicology and Carcinogenesis Studies of Benzyl Alcohol (CAS No. 100-51-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Toxicology and carcinogenesis studies of technical-grade benzyl alcohol (99% pure), a textile dye additive, solvent, and food flavoring agent, were conducted by administering the chemical by gavage in corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Short-Term Studies: In 16-day studies, all five male and five female rats and mice dosed with 2,000 mg/kg benzyl alcohol died. Two of five male and 3/5 female rats and 1/5 male and 2/5 female mice dosed with 1,000 mg/kg died. Rats and mice of each sex in the two highest dose groups were lethargic after dosing. Other toxic responses to benzyl alcohol in these dose groups included blood around the mouth and nose, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts of rats and blood in the urinary bladder of mice. Animals administered lower doses of benzyl alcohol (125, 250, or 500 mg/kg) had no compound-related histologic lesions. Doses selected for the 13-week studies were 0, 50, 100, 200, 400, and 800 mg/kg for rats and mice. Eight of 10 male rats dosed with 800 mg/kg died during weeks 7 and 8; four of these deaths were described as gavage related. Rats dosed with 800 mg/kg exhibited clinical signs indicative of neurotoxicity including staggering, respiratory difficulty, and lethargy. Hemorrhages occurred around the mouth and nose, and there were histologic lesions in the brain, thymus, skeletal muscle, and kidney. In mice, deaths were scattered among all dose levels, but none occurred in vehicle controls. Four male and six female mice died after being dosed; all deaths but one were described as gavage related. Staggering after dosing also occurred during the first 2 weeks of the studies in mice dosed with 800 mg/kg. Some of the deaths in the rats and mice may have been caused by a combination of the gavage procedure and chemical toxicity, since there was evidence that benzyl alcohol induced neurotoxic effects. There were reductions in relative weight gain in male rats dosed with 800 mg/kg benzyl alcohol, in female rats dosed with 200 mg/kg or more, in male mice dosed with 400 or 800 mg/kg, and in female mice dosed with 200 mg/kg or more. No notable changes in body weight gain or compound-related histopathologic lesions were observed in rats or mice from the lower dose groups. Based on mortality, reduction in relative body weight gain, and the histopathologic lesions, doses selected for 2-year studies in rats were 0, 200, and 400 mg/kg. Doses selected for 2-year studies in mice were 0, 100, and 200 mg/kg, based on mortality and depression in relative body weight gain. Body Weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered benzyl alcohol in corn oil by gavage 5 days per week for 103 weeks. Administration of benzyl alcohol did not affect survival in male rats (final survival rates: vehicle control, 28/50; low dose, 27/50; high dose, 24/50) but reduced survival of dosed female rats by half (36/50; 18/50; 17/50). Many of the early deaths were considered related to the gavage procedure. Survival in mice was not affected by benzyl alcohol administration (male: 34/50; 33/50; 35/50; female: 26/50; 32/50; 36/50). No effect of benzyl alcohol on body weight gain in rats or mice was observed. In the third month of the studies, clinical signs of sialodacryoadenitis virus infection were observed in rats. A positive serologic reaction for rat coronavirus was observed in sentinel animals at 6 months and again at 18 months. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No apparent compound-related nonneoplastic responses were observed. Dose-related negative trends in the incidences of anterior pituitary gland neoplasms were seen in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49) and of harderian gland adenomas in male mice (8/50; 3/50; 2/50). Adenomas of the adrenal cortex occurred at an increased incidence in high dose male mice (0/48; 0/44; 3/48), but this slight increase was not considered to be related to chemical expcal exposure. Genetic Toxicology: Benzyl alcohol was not mutagenic when tested by the preincubational protocol in the presence or absence of exogenous metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. In the mouse L5178Y/TK&plusmn; lymphoma assay, benzyl alcohol induced an increase in trifluorothymidine (Tft)-resistant cells in the absence, but not in the presence, of S9; the effect was associated with toxicity. In cytogenetic assays with Chinese hamster ovary (CHO) cells, treatment with benzyl alcohol produced an increase in sister chromatid exchanges (SCEs) which was judged to be equivocal both with and without S9; a significant increase in chromosomal aberrations was observed after exposure to benzyl alcohol in the presence, but not the absence, of S9. Audit: The data, documents, and pathology materials from the 2-year studies of benzyl alcohol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50&percnt; that of vehicle controls, primarily due to an increased number of gavage-related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. Synonyms: benzenemethanol; phenylcarbinol; phenylmethanol; a-hydroxytoluene; benzenecarbinol; phenolcarbinol; a-toluenol