13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

There were no significant increases in tumor incidence in two-year carcinogenicity studies with intranasal administration (0.5, 2.5, and 5 mg/animal/day) of bremelanotide to male and female rats, and subcutaneous administration (3, 9, and 15 mg/kg/day) to male and female mice. Multiples of exposure were calculated based on average Cmax at the high dose over the course of the study and were 1.1-fold and 111-fold the human Cmax for rats and mice, respectively.

Mutagenesis

Bremelanotide was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro chromosomal aberration test in Chinese Hamster Ovary cells, and the in vivo mouse micronucleus assay.

Impairment of Fertility

There were no effects on fertility in male (75 mg/kg/day, approximately 375 times the human AUC) or female (150 mg/kg/day, approximately 760 times the human AUC) mice following subcutaneous administration.