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The purpose of these studies was to evaluate the short-term toxicity of theophylline, a compound present in tea and used in a variety of clinical applications. Fourteen-day repeated-dose toxicity studies were conducted in B6C3F1 mice and F344 rats of both sexes. Theophylline was administered in feed (0, 500, 1000, 2000, 4000, and 8000 ppm) or by gavage in corn oil (12.5-twice daily, 25, 50, 50-twice daily, 100, 200, 200-twice daily, and 400 mg/kg). Dosed-feed exposure to theophylline at concentrations up to 8000 ppm induced no significant toxicity except for dose-related uterine hypoplasia in rats. Palatability problems at that level precluded administration of higher concentrations. In the gavage study, 400 mg/kg was acutely toxic for both species, but mice and rats differed in that this same daily dose administered as two separate doses of 200 mg/kg was acutely toxic in rats but not in mice. No dose-related weight gain depression was evident in mice; weight gain was depressed in the majority of dose levels in rats and was pronounced at the higher levels. Clinical signs in mice were squinting and distended testes in males, and in rats, rapid respiration (all doses), squinting, and hunching. Gross necropsies, organ weights, clinical pathology, and pathology identified no target organs in mice, while histopathologic observations in rats suggested heart and stomach as possible target organs. Histopathologic effects in a number of other tissues, including lung, thymus, bone marrow, spleen, and uterus, were considered to reflect agonal changes in treated rats, possibly related to inanition. The results suggest that both species and sex differences exist with respect to sensitivity to theophylline toxicity, with F344 rats being more sensitive than B6C3F1 mice and male rats being more sensitive than female rats.