Analysis of the indicative value of repeated dose toxicity studies for reproductive toxicity

Assessment of reproductive toxicity is an animal-, time- and cost-consuming process. In order to refine, replace and reduce animal testing, the use of in-silico, in-vitro and alternative in-vivo strategies is tested for their value to predict adverse reproductive outcomes. Due to the complexity of the reproductive cycle, encompassing maturation of gametes, mating, implantation of the conceptus, intra-uterine survival and maturation as well as postnatal development, no alternative testing strategies so far are able to cover all aspects of fertility. One approach should therefore be the use of existing animal study data, especially from repeated dose studies, to analyse indicators for reproductive toxicity. The current versions of OECD Guideline requirements for repeated dose toxicity include structural changes in reproductive organ tissues (mainly testes, epididymides, prostate, seminal vesicles and ovaries and uterus). Based on this information repeated dose toxicity studies are useful for selection of substances for further reproductive toxicity testing, for appropriate dose selection and for selection to incorporate additional parameters, e.g. for endocrine testing, into reproductive toxicity studies. In addition repeated dose studies can have a predictive value for detecting certain impairments of reproductive function. These conclusions have been extended by analysing animal studies from the Fraunhofer ITEM databases RepDose for repeated dose toxicity and FeDTex for reproductive toxicity. Further, based on the analysis of FeDTex, and in view of the development of AOP (adverse outcome pathway)-based approaches it should be considered to enhance the list of mandatory study parameters in repeated dose studies by hormone and sperm parameters and oestrus cyclicity in order to increase the predictivity for reproductive toxicity.