Pregnancy Reproductive toxicity

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. 

Box 3.2 shows the toxicity package t)q)ically generated before a Phase I trial. These trials are usually conducted in males, and thus do not require formal reproductive toxicity studies. In the United States, women can be included in early trials without any animal reproductive toxicity if special precautions are taken to ensure that pregnancy does not occur. A histopathological assessment of the effects of the test compound on the male reproductive tract is made in the repeat-dose toxicity tests. 

The FDA allows women to enter carefully controlled and monitored trials in which adequate contraceptive measures and pregnancy testing are performed without requiring results from animal reproductive toxicity tests. In Japan and Europe, because of the high level of concern regarding imintentional exposure of the developing embryo or foetus, an assessment of fertility in a rodent, and embryo/foetal development in a rodent or non-rodent are required if women of childbearing potential are to be included in a Phase I trial. The FDA would expect such results to support Phase II and Phase III studies. 

Methoxyethyl acetate is hydrolyzed in vivo to form 2-methoxyethanol, which is subsequently metabolized to 2-methoxyacetic acid, a proported teratogenic substance. Consequently, the acetate is expected to show profiles of developmental and reproductive toxicity similar to those of 2-methoxyethanol (qv). In a case report, a woman who was extensively exposed to 2-methoxyethyl acetate, both dermally and probably by inhalation during pregnancy, gave birth to two sons with hypospadias. Because family history and medical examination showed no overt risks other than the significant exposure of the mother, and because 2-methoxyethyl acetate can cause teratogenic effects in animals, the malformations were attributed to the exposure. 

Reproductive toxicity data, particularly as relating to treatment during pregnancy, remain relevant throughout the life-time of a compound unless well-designed studies in humans become available either to confirm or negate the animal data. 

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