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    man primate that is metabolically similar to humans, would be needed to confirm the lack of reproductive and developmental toxicity.

  • As they are performed today, in vitro studies will not by themselves provide sufficient evidence of no adverse effect.

  • Studies in two species are often available in which pregnant females were exposed during pregnancy and killed just before parturition. This permits full evaluation of adverse effects on mother and fetus. Such prenatal developmental toxicity studies designed to determine a substance's potential to cause structural abnormalities, growth deficits, or death are available in two species for many agents, drugs and pesticides, in particular. When such studies demonstrate no adverse effects, one might conclude that the data are sufficient to indicate that there is little or no risk that the agent might cause developmental toxicity manifested at birth. However, it is important to recognize the limitations of these studies and that if dosing stops at the end of major organogenesis (gestation day 15 in rats and mice, day 19-20 in rabbits), later fetal exposures might result in further growth retardation and in other developmental defects (e.g., those occurring in late-developing reproductive organs such as hypospadias). In addition, there is no information from such studies on the postnatal effects of prenatal exposures, including possible neurobehavioral deficits or other impaired organ system function.

Similarly, the absence of adverse effects in a two-generation reproductive study would not preclude the possibility of significant reproductive toxicity that is not manifested as a fertility problem, unless more detailed sperm evaluations, estrous cycling, ovarian histology, and endocrine function were included. Detailed description of animal testing protocols, and their qualifications and limitations are discussed in Appendix D.

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