Reproductive toxicity dose-response information

Reproductive Toxicity. No information was located regarding reproductive effects in humans. Intermediate-duration inhalation studies in animals (Eustis et al. 1988 Kato et al. 1986) indicate that the testes may undergo degeneration and atrophy at high exposure levels, but the dose- response curve is not well defined. Further studies in animals to identify the threshold for this end point would... 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

Laboratory rodents are the animal models most commonly used to identify hazards in reproductive toxicity. Rodents are used because they are small animals, the assay cost is moderate and there is a large database of toxicology information on these species (e.g., dose-response, metabolism, kinetics, etc.). The rat has proven to be a good model for human reproductive hazard evaluation (Francis et al., 1990). 

A weight of evidence approach to assessing reproductive toxicity requires rigorous evaluation of all available data. However, often only limited information is available, and default assumptions must be made because of uncertainties in understanding mechanisms, dose-response relationships at low dose levels and human exposure patterns. Several of these assumptions are basic to the extrapolation of toxicity data from animals to humans, while others are specific to reproductive toxicity. The general default assumptions for reproductive toxicity stated in the IPCS (1995) report are summarized as follows ... 

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