GENOTROPIN® Nonclinical Toxicology

(somatropin)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with GENOTROPIN. No potential mutagenicity of GENOTROPIN was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact animals (bone marrow cells in rats).

In a fertility study in male and female rats receiving SC doses during gametogenesis (2 weeks prior to mating for females and 9 weeks prior to mating for males) and continuing up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose by body surface area) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. Lower copulation and pregnancy rates were also observed at 3.3 mg/kg/day. At 1 mg/kg/day (approximately 7 times human dose by body surface area), rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted (approximately 2 times human dose by body surface).

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Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with GENOTROPIN. No potential mutagenicity of GENOTROPIN was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (mouse L5178Y cells), and chromosomal damage in intact animals (bone marrow cells in rats).

In a fertility study in male and female rats receiving SC doses during gametogenesis (2 weeks prior to mating for females and 9 weeks prior to mating for males) and continuing up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose by body surface area) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. Lower copulation and pregnancy rates were also observed at 3.3 mg/kg/day. At 1 mg/kg/day (approximately 7 times human dose by body surface area), rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted (approximately 2 times human dose by body surface).

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