Reproductive toxicity hazard characterization

The second objective of the hazard assessment concerns characterization of the identified hazards of a particular substance. Under REACH this means that the registrant must define so-called derived no-effect levels., abbreviated DNELs. With respect to human health, these values constitute exposure levels above which humans should not be exposed and below which risks for humans are considered controlled. The DNEL derivation is a complex process which comprises several conversion steps and the application of different assessment factors. In the case of reproductive toxicity, the registrant derives separate DNELs with respect to developmental toxicity on the one hand and to impairment of sexual function and fertility on the other hand. 

The evaluation of dose-response relationships is a critical component of hazard characterization (OECD, 1989 ECETOC, 1992 US , 1997a IPCS, 1999). Evidence for a dose-response relationship is an important criterion in establishing a toxic reproductive effect. It includes the evaluation of data from both human and laboratory animal studies. Because quantitative data on human dose-response relationships are infrequently available, the dose-response evaluation is usually based on the assessment of data from tests performed using laboratory animals. However, if data are available in humans with a sufficient range of doses, dose-response relationships in humans can also be evaluated. 

For most of the other monoclonal antibodies, species cross-reactivity has been limited to nonhuman primates. For these molecules the need to conduct reproductive and developmental studies has to be carefully considered on a case-by-case basis. S5A states that nonhuman primates are best used when the objective of the study is to characterize a relatively certain reproductive toxicant, rather than detect a hazard. The nonhuman primate reproductive toxicity studies are not powered to detect infrequent events. 

Hazard identification is the step in the risk assessment that qualitatively characterizes the inherent toxicity of a chemical. Scientific data are evaluated to establish a possible causal relationship between the occurrence of adverse health effects and chemical exposure. This step includes characterization of acute, subchronic, and chronic effects the potential for local versus systemic effects the influence of the route of exposure the relevance, to humans, of effects seen in animals an evaluation of the biological importance of the observed effects the likelihood of the effects occurring under certain conditions and the potential implications for public health. This step should be based on a thorough review of all the data that may provide information that is relevant to evaluating the potential chemical hazard. This may include data describing the effects on a variety of test animals, in vitro studies that characterize mechanisms of toxicity, metabolism, physiologically based pharmacokinetic studies, structure-activity relationships, short-term human studies, and epidemiological studies. Animal studies may focus on particular types of effects and may include reproductive toxicity studies,... 

A.7.3.3.1 Where the mixture itself has not been tested to determine its reproductive toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data shall be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix Dilution, Batching, and Substantially similar mixtures. 

The risk characterization is carried out by quantitatively comparing the outcome of the hazard (effects assessment) to the outcome of the exposure assessment, i.e., a comparison of the NOAEL, or LOAEL, and the exposure estimate. The ratio resulting from this comparison is called the Margin of Safety (MOS) (MOS = N(L)OAEL/Exposure). This is done separately for each potentially exposed population, i.e., workers, consumers, and man exposed via the environment, and for each toxicological endpoint, i.e., acute toxicity, irritation and corrosion, sensitization, repeated dose toxicity, mutagenicity, carcinogenicity, and toxicity to reproduction. 

No oral MRL has been derived for chromium(VI) or chromium(III) because a NOAEL for reproductive effects has not been adequately characterized. Additional studies are needed to identify a threshold for toxicity and establish dose-response relationships. However, any MRL derived for the oral route would have to take into consideration the essentiality of chromium. No dermal studies of intermediate duration in animals were located. The toxicity of intermediate-duration exposure to chromium compounds is relatively well characterized for the oral and inhalation routes. Dermal studies would be useful to determine possible target organs other than the skin. There are populations surrounding hazardous waste sites that might be exposed to the substance for similar durations. 

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