Key learnings from ECHA's review of the EOGRTS (OECD Test Guideline 443)

The extended one-generation reproductive toxicity study (EOGRTS) per OECD Test Guideline 443 is a crucial test for evaluating potential reproductive and developmental effects of chemicals. Recently, the European Chemicals Agency (ECHA) conducted an extensive review of EOGRTS  studies to assess the effectiveness of this test guideline and provide recommendations for improvement. This blog post summarizes  key learnings from ECHA's review and the impacts on current and future EOGRTS study design.

ECHA review findings and recommendations 

ECHA reviewed 55 EOGRTS studies in collaboration with member state experts to evaluate the performance of the test in terms of design, conduct, analysis and reporting. The review concluded that EOGRTS was generally effective at identifying substances of concern, noting that including an F2 generation provided useful data. However, ECHA identified some methodological issues related to endocrine disruption assessments like sexual maturation, anogenital distance, nipple/areola counts and estrous cycles. 

To address these issues, ECHA provided a set of recommendations aimed at improving the quality of future EOGRTS studies. A common theme in the recommendations was the need for more robust historical control data and positive control data to demonstrate proficiency in certain measurements. ECHA also called for enhanced guidance on best practices for assessing endpoints related to endocrine disruption.

Impacts on current EOGRTS study design

ECHA's review and recommendations have already influenced changes to current EOGRTS study design and conduct. Some key impacts include the following:

• Adding more animals as a Cohort 1C to have adequate sample sizes for assessing sexual maturation
• Incorporating additional dose groups in dose range-finding studies to optimize selection of doses for the main study
• Making mid-study dose adjustments or adding dose groups when unexpected toxicity occurs
• Placing greater emphasis on generating historical and positive control data to validate methods and demonstrate proficiency

These changes address issues raised in ECHA's review, but they also increase study complexity, timelines and costs. Careful planning is necessary to implement the changes effectively.

The future of EOGRTS studies

Looking ahead, ECHA's focus on improving EOGRTS studies will continue shaping the future direction of this test guideline. Areas of expected focus include:

• Ongoing enhancement of endocrine-related endpoints like anogenital distance and nipple/areola counts
• Expanding guidance on best practices for consistent, accurate methodology 
• Potential additions to the test guideline and guidance documents to further standardize procedures
• Continued discussions around optimizing dose selection and responding to unexpected findings

There is also interest in incorporating assessments of learning and memory to evaluate possible neurodevelopmental impacts related to thyroid disruption. However, determining the best approach to achieve this aim faces scientific and practical hurdles regarding appropriate tests and animal models.

In summary, ECHA's extensive review provided valuable insights that are already improving EOGRTS study quality and will continue to shape best practices. Full implementation of the recommendations will further enhance this vital test to evaluate potential reproductive and developmental effects of chemicals. While challenges remain, enhanced standardization and guidance will lead to more robust, consistent EOGRTS studies.

Learn how the review could shape the future of evaluating developmental and reproductive toxicity in this recording of our JSOT 2024 presentation regarding ECHA's review of the EOGRTS.