NTP Toxicology and Carcinogenesis Studies of Benzaldehyde (CAS No. 100-52-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
Benzaldehyde is an aromatic aldehyde used in the food, beverage, pharmaceutical, perfume, soap, and dyestuff industries. NTP Toxicology and Carcinogenesis studies were conducted by administering benzaldehyde (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Sixteen-Day Studies: All rats that received 1,600 mg/kg died by day 2, and 2/5 males and 2/5 females that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of the 800 mg/kg groups, in which males were 14% lighter and females were 11% lighter than vehicle controls. All mice that received 1,600 or 3,200 mg/kg died by day 3. Final mean body weights of dosed and vehicle control mice were similar. No gross lesions attributable to benzaldehyde were detected upon necropsy. Thirteen-Week Studies: Six of 10 male rats and 3/10 female rats that received 800 mg/kg and 1/10 female rats that received 400 mg/kg died near the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of male rats receiving 800 mg/kg, which were 26% lighter than vehicle controls. Compound-related lesions seen in rats receiving 800 mg/kg, but not in those receiving 400 mg/kg, included degeneration and necrosis in the cerebellum, necrosis in the hippocampus, hyperplasia and/or hyperkeratosis in the forestomach, and degeneration or necrosis of the liver and of the tubular epithelium in the kidney. Nine of 10 male mice and 1/10 female mice that received 1,200 mg/kg benzaldehyde died by the end of the first week. Compound-related renal tubule degeneration and/or necrosis and reduction in final body weight were observed in the 600 mg/kg group of male mice. No reductions in body weight or compound-related lesions were seen in female mice. Based on observations of compound-related lesions involving the brain, forestomach, kidney, and liver of male and female rats and the kidney of male mice in the 13-week studies, 2-year studies were conducted by administering 0, 200, or 400 mg/kg benzaldehyde in corn oil by gavage, 5 days per week for 103 weeks to groups of 50 male and 50 female rats and for 104 weeks to groups of 50 male mice. Based on survival data from the 16-day and 13-week studies, groups of 50 female mice were administered 0, 300, or 600 mg/kg benzaldehyde for 103 weeks. Body Weights and Survival in the Two-Year Studies: Mean body weights of dosed rats and mice were similar to their respective vehicle controls throughout the studies. The survival of the high dose group of male rats was lower than that of the vehicle controls after 1 year; no other significant differences were observed between any groups of rats or mice (survival--male rats; vehicle control, 37/50; low dose, 29/50; high dose, 21/50; female rats: 33/50; 33/50; 29/50; male mice: 32/50; 33/50; 31/50, female mice: 30/50; 27/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The only effects of benzaldehyde were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50). Genetic Toxicology: Benzaldehyde was not mutagenic in six strains of S. typhimurium and did not induce chromosomal aberrations in CHO cells, with or without exogenous metabolic activation. Benzaldehyde induced increases in trifluorothymidine-resistant mouse lymphoma cells in the absence exogenous metabolic activation and increased sister chromatid exchanges in CHO cells in boexchanges in CHO cells in both the presence and absence of metabolic activation. Sex-linked recessive lethal mutations were not induced in the germ cells of adult male D. melanogaster administered benzaldehyde by feeding or by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzaldehyde for male or female F344/N rats receiving 200 or 400 mg/kg per day. There was some evidence of carcinogenic activity of benzaldehyde for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach. Female rats and male and female mice might have been able to tolerate higher doses. Synonyms: artificial almond oil; artificial essential oil of almond; benzenecarbonal; benzene carbaldehyde; benzoic aldehyde; phenylmethanal