The acute toxicity of tamoxifen in experimental animals is low. Furthermore squamous metaplasia and atrophy of the uterine epithelium was observed in chronic studies in rats. Induction of cytochromes P450 and preneoplastic lesions have been detected in the livers of rats. Ocular toxicity, including lipidosis of the retina and cornea and increased incidence of cataract, was reported in studies in rats of chronic exposure to tamoxifen. In the presence of human, mouse, rat and hamster microsomes, tamoxifen binds covalently to protein.
Tamoxifen has oestrogenic effects on human fetal genital tracts grown in athymic mice.
No effects on the fetus have been reported in rabbits, marmosets or cynomolgus monkeys. There is no direct evidence that tamoxifen is active in tests for gene mutation. Preliminary studies indicate that tamoxifen does not give rise to detectable levels of DNA adducts in human liver in vivo or in human endometrium in vitro and in vivo . Mechanistic considerations Tamoxifen increases liver tumour incidence in rats, which may involve both DNA damage leading to increased numbers of initiated cells and oestrogen receptor-mediated clonal expansion of those initiated cells. The available evidence suggests that tamoxifen is carcinogenic in rat liver by a genotoxic mechanism.