Workshop Report

Workshop Report 12 – Workshop on Triggering and Waiving Criteria for the Extended One-Generation Reproduction Toxicity Study

WR 12 : Workshop on Triggering and Waiving Criteria for the Extended One-Generation Reproduction Toxicity Study | August 2008

Under the new chemicals legislation in Europe, REACH (EU, 2006), the two-generation reproductive toxicity study, OECD TG 416, may be required for substances produced or imported at 100 tonnes per annum or more. At 1000 tonnes per annum, this study becomes a default requirement. The one-generation study design, OECD TG 415, is not a standard information requirement under REACH. A proposal has been developed for an extended one-generation study design-to be included in a tiered testing approach-that is intended to address the limitations of the standard design, while significantly reducing the numbers of animals required (Cooper et al, 2006).

The workshop was convened by ECETOC jointly with ECVAM to discuss triggers and waivers within a modular approach to the proposed extended one-generation reproduction toxicity study (ECETOC, 2008). Invited experts were from academia, regulatory authorities, contract research organisations, and industry.

The outcome will be provided to the OECD expert group on the 'extended one-generation reproductive toxicity guideline' for its consideration.

The results of the workshop indicate that on several issues a consensus exists and a common understanding for guidance can be given. These points include:
Study Design

  1. If the second generation is an optional module, then the decision to conduct a second breeding should be made on the strength of the findings. If unequivocally positive or negative findings were obtained, no further work would be required and the substance can be classified accordingly.
  2. The prenatal developmental toxicity (PDT) and developmental neurotoxicity (DNT) modules are based on methods included in guideline studies and, thus, the methods included in the modules are sufficiently validated.
  3. A four weeks' pre-dosing period was considered to be adequate, since this study design is standard for pharmaceuticals (ICH, 2005) and because histopathology and testis weight (measured in the F1 generation following > 70 days of exposure) are amongst the most sensitive endpoints.
  4. If an F1 mating is performed, it should start when the animals are at least 90 days of age.
  5. A PDT module should not be a mandatory requirement of the OECD guideline. However, it may be included in the study design as long as it does not compromise the overall study objectives. In practice, it is likely that this study will be conducted standalone.
  6. It may be premature to include a developmental immunotoxicity (DIT) module in the study design as there is no technical or validated guidance issued for this endpoint.

Triggers and Waivers

  1. For practical reasons the number of triggers for the optional modules coming from within the study should be limited. Exceptions may consist of equivocal breeding results triggering a second generation and functional observation battery (FOB) / motor activity (MA) results triggering morphological and pathological evaluations in the optional DNT module. But a second generation could only be an optional module if questions over the additional information gained from the second breeding can be satisfactorily resolved.
  2. There are no useful internal triggers for a DNT module. Consequently, the decision to include a DNT module needs to be made during the development of the guideline or during the study design phase. There was no consensus as to whether a DNT module should be a default requirement but, if it were to be, then it should be limited to FOB and MA.

Two reviews covering approximately 500 two-generation studies indicate that the second breeding in more than 95% of cases did not add significant new information over and above that found in the first generation (Makris, 2004; Janer et al, 2007). The question as to whether the two-generation study can be replaced by an extended one-generation study was heavily debated in all breakout groups. Two out of the three groups could not reach an agreement on this question. The third group concluded that there was enough information to support the use of the extended one-generation design as a replacement of the two-generation study. However, it was felt that a more thorough review of this information is needed. Several of the participants requested that the exceptions raised by Makris (2004) and Janer et al (2007) be evaluated carefully to more closely examine the endpoints concerned and the chemical classes of these compounds, and to evaluate what the overall outcome of an extended one-generation study design would have been for these compounds. A proposal was made for ECETOC to help facilitate a review of these data and to collect more data, e.g. through a survey of member companies and contract research organisations.