Repeated dose toxicity documents

In some cases, evidence can be adduced from blood chemistry results in the repeat-dose toxicity studies to define doses at which toxicity has occurred in adult animals. For example, the concentrations of liver enzymes are frequently increased and could be used to conclude that there was maternal toxicity. However, as with other measures of toxicity, there are many studies in which liver enzymes are elevated but there are no effects on reproduction. Care must be taken in submission documents to justify any conclusion that effects on reproduction can be linked to measures of toxicity and a correlation on an individual animal basis should be demonstrated to assist assessors in evaluating the results. 

In addition to these newly proposed test guidehnes, suggestions are being considered for new parameters to be included in the present repeated dose oral toxicity test (OECD TG 407) with more emphasis to be placed on detection of endocrine effects. The vahdation of the enhanced OECD TG 407 is now being reviewed by an international panel of reviewers. The peer review package, submitted to the panel and available at the OECD Web site for endocrine dismpters (OECD 2007b), includes the validation report, the draft and the current test guidelines, and a Secretariat document to support the peer review panel. 

In most standard development programs, no investigations have been carried out to define the maternal toxicity whether, for example, stress hormones have been increased. If there is reason to believe that maternal toxicity is an important factor, then the submission documents should contain a comparison with the toxicity seen in the repeat-dose toxicology studies and the doses at which the toxicity occurred. If reproductive effects have been found at doses below those found to induce demonstrable toxicity in the repeat-dose studies, care should be taken in concluding that maternal toxicity has been a factor. In this context, the possibility of differences in sensitivity between pregnant and nonpregnant animals should also be considered. 

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