In addition to assessing its potential tumorigenic effect, long-term studies in mice have provided important information about the effects of applying topical tretinoin throughout most of the animal's lifetime. Such chronic animal studies should highlight any deleterious cutaneous side-effects that may not become apparent even after 20~30 years of continuous human clinical use.

In mice, two studies have been conducted to assess the lifetime application of tretinoin. The first was a tumorigenicity study performed in Japan by Tsubura and Yamatmoto in 1979, which involved applying 0.03 ml 0.1% tretinoin cream or lotion to ICR mice once or three times daily. Although the dose used was very high, the mice tolerated the treatment, with no evidence of tumour formation after 2 years. A second study was performed by Kligman et al. (unpublished data) to evaluate the effects of lifetime application of 0.025% tretinoin in hairless albino mice. In this study, 36 mice were divided into three treatment groups (tretinoin, vehicle and control) and received treatment three times weekly for 98~103 weeks. After this period, no tumours or other ill effects were noted, and longevity was unaffected. An additional finding for mice in the tretinoin treatment group was that they appeared younger and ther skin was smoother. Microscopic studies confirmed the histological effects of tretinoin therapy. The tretinoin treated skin was characterized by compaction of the stratum corneum, hypergranulosis and increased vascularization. Furthermore, the presence of a repair zone and new collagen formation were detected.