5 Reproductive toxicity, definition

The adverse reproductive effects are considered as being threshold effects, i.e., effects for which there are expected to be a threshold of substance concentration below which the effects will not be manifested. For the hazard and risk assessment, it is important to identify those dose levels at which adverse reproductive effects are observed, and the dose level at which adverse reproductive effects are not observed, i.e., to derive a NOAEL for reproductive toxicity. Crucial in the derivation of the NOAEL and/or LOAEL, is the definition of adverse effects (Section 4.2.2). In the derivation of the NOAEL and/or LOAEL, a number of factors need to be considered these issues are addressed in detail in Sections 4.2.3 and 4.2.4. An alternative approach to the derivation of the... 

In vitro studies will not, in the absence of more definitive data, provide a basis for a firm decision about the reproductive toxicity of a substance. Positive results from such smdies indicate that there may be some concern in relation to the potential for reproductive toxicity, but they can be overridden by clearly negative data from well-conducted test guideline smdies for reproductive toxicity. Negative data from in vitro smdies, if well conducted, may contribute to the weight of evidence. 

Data from repeat-dose toxicity studies are essential for CTAs in the early stages of development of a compound, but are superseded once there is a reasonable amount of human data. Any target organs that are identified in the toxicity studies should be monitored in clinical trials. Definitive data on the effects derived from clinical trials will show whether the animal studies are predictive of the effects in humans. This information can then be used to help interpret findings in reproductive toxicity studies, such as whether general toxicity in the adult is relevant. If adult toxicity in animals is deemed relevant, the exposure at which it occurs can be used to estimate the clinical relevance of any reproductive effects. If toxic effects in animals are induced at exposures greatly in excess of the clinical exposure, then they might not be clinically relevant. 

For the purposes of this chapter, reproductive toxicity will refer to any manifestations of xenobiotic exposure, including endocrine disruption (see discussion below), reflecting adverse effects on any of the physiological processes and associated behaviors and/or anatomical structures involved in animal reproduction or development (Figure 36.1). This is a fairly broad definition which encompasses developmental toxicity, as well as any toxic... 

Agent GB (Sarin). RfDe = 2 x 10 mg kg d". A LOAEL was identified in a 90-d oral study in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), extrapolation from a subchronic to chronic exposure (3), and incomplete data base (3). An uncertainty factor of 3 rather than 10 was used to extrapolate from a subchronic to chronic exposure because of the unlikelihood that the LOAEL would have been substantially lower if the exposure had continued for a longer period of time. The LOAEL-to-NOAEL uncertainty factor of 3 was used because the endpoint, cholinesterase inhibition, was not associated with any physical signs of clinical toxicity. A pilot multigeneration reproductive toxicity study on GB was inconclusive however, because the available evidence indicates that organophosphate cholinesterase inhibitors such as GB are not likely to be reproductive toxins, the lack of definitive results was not considered critical. Therefore, a UFd of 3, not the default value of 10, was applied. 

Select appropriate procedures to minimize exposure. Use the "basic prudent practices for handling chemicals," which are discussed in Chapter 5, section 5.C, for all work with chemicals in the laboratory. In addition, determine whether any of the chemicals to be handled in the planned experiment meet the definition of a particularly hazardous substance due to high acute toxicity, carcinogenicity, and/ or reproductive toxicity. If so, consider the total amount of the substance that will be used, the expected frequency of use, the chemical s routes of exposure, and the circumstances of its use in the proposed experiment. As discussed in this chapter, use this information to determine whether it is appropriate to apply the additional procedures for work with highly toxic substances and whether additional consultation with safety professionals is warranted (see Chapter 5, section 5.D). 

The following is the statutory definition of a Category 3 reproductive toxicant ... 

No definitive, quantitative data were available regarding the potential reproductive and developmental toxicity of arsine in humans. 

The reproductive/developmental toxicity screening test can provide initial information on possible effects on reproduction and/or development and may make it possible to identify a substance as being toxic to reproduction, i.e., the test gives a clear positive result. However, this test offers only limited means of detecting postnatal manifestations of prenatal exposure or effects that may be induced during postnatal exposure. In addition, because of the study design (e.g., relatively small numbers of animals per dose level, relatively short smdy duration), the test will not provide evidence for definite claims of no effects. 

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