DOC 045 – Triggering and Waiving Criteria for the Extended One-Generation Reproduction toxicity Study

DOC 045 : Triggering and Waiving Criteria for the Extended One-Generation Reproduction Toxicity Study | March 2008

The current ?gold standard' for the assessment of reproductive toxicity in safety evaluation is the two-generation reproduction study, OECD Test Guideline (TG) 4161. This is a complex study that involves a large number of animals (ca. 2,600), takes nine months from start of treatment to necropsy, and is costly. Under the EU regulation on registration, evaluation, authorisation, and restriction of chemicals (REACH) (EU, 2006), this study may be required for substances produced or imported into the EU at more than 100 tonnes per annum if triggered by findings in other studies, and is a default requirement for substances produced or imported into the EU at more than 1000 tonnes per annum.

The standard one-generation study design (OECD TG 415) is largely disfavoured because it does not cover the full reproductive cycle, and has not been updated with the developing science. For example, many apical endpoints for the evaluation of endocrine active potential could not be evaluated in this study design. Recent developments have, however, led to a re-evaluation of the one-generation study, with the proposal that it could be extended, not only to cover more of the reproductive cycle but also to include additional evaluations of developmental toxicity (Cooper et al, 2006). In parallel to this, re-evaluations of the two-generation study have questioned the value of the second breeding in cases where data are available from other studies (Janer et al, 2007; Makris, 2004). The OECD is now considering a new test guideline describing an extended one-generation study design.

Inclusion of all endpoints suggested by Cooper et al (2006) for the testing of agrochemicals would result in a very complex design for routine evaluation of industrial chemicals far beyond the scope of current testing, as well as increasing the potential for additional animal usage in further studies that may be triggered by type I errors (false positive results) in the main study. Consequently, a modular study design, in which additional evaluations could be triggered or waived in the light of other available information, would appear to be optimal.

If such an extended one-generation study design is to be used within a tiered testing strategy, there must be a formal process for deciding the choice of modules. In this vein, guidance for triggers and waivers for the inclusion or exclusion of modules is required.

This document includes discussion of the following modules that might be included within an extended one-generation study design: second breeding for an F₂generation; developmental neurotoxicity (DNT); prenatal developmental toxicity (PDT); and developmental immunotoxicity (DIT). It gives consideration to the identification and validation of the triggers for these modules, within the framework laid down by the OECD (OECD, 2005). This report also serves as the starting point for a multi-stakeholder workshop for the development of triggering and waiving criteria for the modules of the extended one-generation study.