Implementing the extended one-generation reproductive toxicity study (EOGRTS): important points to consider

Abstract

The hallmark of the extended one-generation reproductive toxicity study (EOGRTS) is that, based on certain criteria or triggers, selected offspring are assigned at weaning to different cohorts for further investigation of sexual maturation, reproductive organ integrity and function, neuropathological and behavioral endpoints, and/or immune function. The triggers allow for a more customizable design based directly on the data, while minimizing animal usage. Compared to the two-generation reproductive toxicity study, the EOGRTS design increases the number, extent, and duration of F₁-offspring assessments resulting in more thorough and efficient utilization of the first generation while excluding the second generation of offspring unless triggered. Therefore, the EOGRTS has the potential to reduce the number of rats required by nearly 1200 animals per study. When performing the EOGRTS, the complexity of this study should not be underestimated and experienced flexible testing laboratories with sufficient resources and historical control data for all parameters are essential. The aim of this review is to discuss the important aspects of this challenging study design and to share our knowledge on the implementation of this study in our laboratories. In addition, we elaborate on the type of criteria for expansion of the study and logistical considerations. Altogether, this review can be used as guidance by other labs, study monitors, and registration officers.

Keywords:

• Developmental immunotoxicity
• developmental neurotoxicity
• extended one-generation reproductive toxicity study (EOGRTS)
• EU B.56
• OECD 443
• 3R’s
• triggers

Acknowledgments

The authors thank their colleagues in Lyon (France), Ashland (OH, USA), Hillsborough (NC, USA), and Den Bosch (The Netherlands) for their valuable contribution in creating one optimal EOGRTS design implemented at all global WIL Research sites.

In addition, the authors would also like to thank all eight reviewers, who were selected by the Editor and anonymous to the authors, for their valuable input and helpful remarks. Their constructive comments and suggestions greatly improved the manuscript.

Ethical standards

The animal studies were performed with approval of the local regulatory agencies, and all study protocols complied with the federal guidelines.

Declaration of interest

The authors are employees of WIL Research, a contract research organization. WIL Research routinely conducts studies of the type described in the paper for a wide range of clients and reports are provided that are routinely submitted to regulatory authorities. The authors have not been involved in any regulatory or legal proceedings related to the contents of the paper. The conclusions drawn and recommendations offered are exclusively the professional opinions of the authors.