13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Mutagenicity and carcinogenicity studies have not been conducted on ATGAM.
In fertility studies, ATGAM at doses 10, 20 and 40 mg/kg/day was administered to cynomolgus monkeys (Macaca fascicularis) for 14 days either before (male monkeys) or before and after (female monkeys) cohabitation with untreated mates. ATGAM treatment was not associated with male or female hormonal or copulation behavior changes. A decrease in fertility index in female monkeys receiving ATGAM was seen. Female toxicity, including death, was observed with ATGAM doses of ≥20 mg/kg/day. While the etiology of this toxicity is uncertain, it may be attributed to hemolytic anemia due to cross-reactivity of ATGAM to a monkey red blood antigen.
In embryo-fetal toxicity studies, ATGAM was administered to rats and cynomolgus monkeys for 11 and 16 days, respectively during organogenesis. In rats, hypoplastic cervical vertebrae, a finding consistent with delayed skeletal development, were observed in fetuses whose dams received ATGAM at doses of 100 mg/kg/day during organogenesis. In monkey reproduction studies, maternal toxicity (vaginal bleeding, decreased body weight and loss of appetite) was observed with ATGAM doses ≥20 mg/kg/day after 16 days of dosing. Fetal deaths occurred in dams treated with 20 mg/kg/day ATGAM earlier in organogenesis (days 20–35), but not when treatment was given at a later part of organogenesis (days 35–50). The maternal and fetal deaths were attributed to maternal anemia due to red blood cell antigen that humans do not share. Therefore, this toxicity is not considered relevant to human fetal development.