Reproductive toxicity experimental studies

The majority of information about male reproductive toxicants has been obtained from studies carried out in the rat, the most common animal model used for reproductive toxicity. Animal studies allow for controlled experimentation where events... 

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. 

Historical control data is an essential component of the study directors toolbox for interpreting reproductive and developmental toxicity data. Scientific judgment and expertise should be used to determine if historical control data is needed for interpretation of study data, which historical control data is appropriate, and how it should be used to support interpretation of a finding. This tool can be a valuable addition to a comprehensive assessment of the study data, which includes determining whether a dose-response is present and whether any statistically significant findings occurred. Sound data interpretation requires that the litter, not the fetus or pup, be used as the experimental unit in developmental and reproductive toxicity studies. For continuous data (e.g., fetal weight). 

The EC funded project CAESAR is developing models for five endpoints specifically related to the REACH legislation [28]. The five endpoints are bioconcentration factor, skin sensitization, carcinogenicity, reproductive toxicity, and mutagenicity (in vivo studies). These five endpoints have been chosen because they are among those that will require more animal tests. Actually, other studies are also supposed to use many animals, but they were excluded because of lack of sufficient experimental values. 

Studies have indicated that repeated exposure of dinitrotoluene has resulted in testicular atrophy and disturbances in the spermatogenesis cycle in experimental mice, rats, and dogs. Female mice also revealed nonfunctioning ovaries 89,90 Conflicting reports regarding the potential reproductive toxicity of dinitrotoluene among workers demand more confirmatory data 91,92 NIOSH has classified technical dinitrotoluene as a human reproductive health hazard in industrial workplaces. Isomers of dinitrotoluene have caused complete liver cancers in animals, but technical-grade dinitrotoluene failed to induce any kind of hepatic cancer in humans.37,93... 

No studies of reproductive toxicity of JP-8 (or other kerosene-based fuels) in experimental animals were found. Ancillary data from other toxicity studies do not suggest an adverse reproductive effect (no effect on fertility in dominant lethal studies in mice and rats (USAF 1978a) and no effect on testis weight or histopathology in a 90-d gavage study in rats (Mattie et al. 1995)). An increase in atrophy of seminiferous tubules in testes of male mice exposed to JP-4 by inhalation for 12... 

Data on the toxicity and disposition of JP-8 in animals are sparse, and no data are available for humans. No reproductive toxicity studies have been done in experimental animals. One adequate study demonstrated developmental toxicity in rats treated orally at 1,500-2,000 mg/kg/d (Cooper and Mattie 1996). A study in a second species should be supplemented with a multiple-generation reproductive toxicity study in rats or mice, including an evaluation of postnatal endpoints, such as developmental neurotoxicity, immunotoxicity, and hematological, hepatic, and renal effects, that could result from prenatal exposures. 

This appendix describes experimental animal and in vitro studies that are used to assess developmental toxicity and male and female reproductive toxicity from exposures to pesticides, industrial chemicals, and food ingredients. The testing of pharmaceutical agents is not described in detail here, but can be found in FDA (1994). A summary of the study types, protocols, endpoints and limitations is presented in Table D-l. A description of the manifestations of each type of toxicity and guidance on the interpretation of results from the studies also are presented. 

CATEGORY IB Presumed human reproductive toxicant The placing of the substance in this category is largely based on evidence fi om experimental animals. Data from animal studies should provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate. 

In some reproductive toxicity studies in experimental animals the only effects recorded may be considered of low or minimal toxicological significance and classification may not necessarily be the outcome. These include for example small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments. 

It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified. 

Prior to initiating these studies, a thorough search of the literature was conducted and the extent of oral toxicity tests was determined. It was found that the colors have a very low order of acute oral toxicity. An experimental design was then developed. Potential reproductive toxicities were evaluated in multigeneration reproductive and teratological studies. No adverse effects were reported at any of the levels examined. 

Bisphenol A causes adverse reproductive and developmental effects in animal studies. But, is the weight of evidence sufficient to consider bisphenol A of high or moderate concern for reproductive and/or developmental toxicity In 2003, the European Union concluded that bisphenol A may adversely affect fertility (reproductive toxic) and that low dose studies indicate bisphenol A may be a development toxicant. Since the EU risk assessment of bisphenol A, a significant body of experimental data has been published evaluating the toxicity potential of bisphenol A at low doses. There is considerable debate on which studies are relevant for evaluating low dose effects of bisphenol A. Issues in the debate include the type of animal studied (the Charles River-Sprague Dawley rat, for example, is the least sensitive test animal to estrogenic chemicals), the... 

The systemic toxicity of CK results from its transformation to free cyanide thus, CK is expected to elicit the same toxic effects as cyanide. Therefore, in the absence of chemical-specific subchronic or chronic human or animal studies for CK, an oral RfDe can be derived based on results of experimental studies with HCN or other cyanides. The nervous system, reproductive system, and thyroid are considered target organs for chronic toxicity of cyanides. 

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