In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of these clinical formulations (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose applied topically, when normalized for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose applied topically is defined as 1 gram of Retin-A Micro® (tretinoin gel) microsphere, 0.1%, applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight).

Dermal carcinogenicity testing has not been performed with Retin-A Micro® (tretinoin gel) microsphere, 0.04% or 0.1%.

Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources.

The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative.

The components of the microspheres have shown potential for genetic toxicity and teratogenesis. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay.

In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topically and normalized for total body surface area) and above were observed. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area.)

Dermal fertility and perinatal development studies with Retin-A Micro® (tretinoin gel) microsphere, 0.1% or 0.04%, have not been performed in any species.