Abstract
Doxylamine succinate, a commonly used antihistamine, was administered as an admixture in the feed to groups of male and female Fischer 344 rats at dose levels of 0, 500, 1000, and 2000 parts per million (ppm) (based on free amine) for 65 weeks (9 per group) or two years (48 per group). There were no significant treatment-related differences in survival in either sex. Compared to controls, final body weights of rats in the 2000 ppm group were reduced 8.4% and 22.8% in males and females, respectively. Treatment-related, non-neoplastic lesions were found primarily in the liver and parotid salivary gland. Liver lesions consisted of fatty change and degeneration in both sexes; hyperplasia (resulting from degeneration due to leukemia) and atypical cells in males; and hypertrophy, chronic inflammation, and mixed cell foci in females. Both sexes exhibited a treatment-related increase in cytoplasmic alteration in the salivary glands. Liver neoplasms were found only in the highest dose group of male rats. The trend test was significant (p ≤ 0.05) for increased incidence of hepatocellular adenoma and carcinoma with increasing doses of doxylamine, but the increased incidence of either lesion in the high dose group was not significant compared to that in controls. However, when animals with carcinoma or adenoma were combined, the trend test remained significant (p ≤ 0.01), and the incidence of the highest dose group was significantly increased (p ≤ 0.05) over that in controls. No treatment-related increase in neoplasms was found in females, but doxylamine produced a marked dose-related decrease in mammary fibroadenomas. Although not statistically significant, a very rare pineal gland tumor was found in 1 male and 1 female rat in the 2000 ppm group.