How to de-risk OECD 443 studies through optimized dose level selections

5 June 2023

The European Chemicals Agency (ECHA) recently conducted a review project regarding the design of the OECD 443 (Extended One-Generation Reproductive Toxicity Study, or EOGRTS). The project’s goal was to assess the performance of the study in terms of study design, conduct and findings to determine if the study design currently prescribed gives sufficient information for regulatory hazard classification.

Interim findings showed that studies that do not consider sensitive life stages of pregnancy, parturition and lactation are typically not sufficient to inform on dose levels for an OECD 443 study. To properly de-risk performance of such a study, robust dose range finding (DRF) studies must include each of these sensitive life stages.

Determining adequate dose levels

One option is to perform a dedicated stand-alone DRF study designed to incorporate the sensitive life stages of pregnancy, parturition and lactation. This could be implemented in situations where OECD 421 or OECD 422 studies were previously conducted but terminated mid-lactation. The stand-alone DRF study could also be extended to directly dose offspring from postnatal day (PND) 21 through to sexual maturation.

A stand-alone DRF study preceding an OECD 443 could also be enhanced by including additional treatment groups to more comprehensively investigate potential dose levels. However, this option involves more animals than normally required in routine approaches, and would slightly raise costs of the study.

A second option is to extend the duration of studies performed in accordance with Test Guideline OECD 421 and OECD 422 to dose F0—also known as the “founder generation”—parental animals through to weaning, thereby encompassing the entire lactation period. This could be enhanced further by directly dosing the first filial generation, or F1 offspring, from weaning through to sexual maturation. Such an extended study design would fully cover all sensitive life stages and give an early indication of the tolerance of young offspring to dosing from PND 21.

Continuing treatment of young offspring to sexual maturation would also give an early indication of potential adverse effects that could be experienced on a subsequent OECD 443 study. This approach reduces costs, saves on time taken to conduct the package of studies required and minimizes animals required.

Your source in navigating regulatory complexities

EOGRT studies are large and costly studies that utilize a significant number of animals. For best results, the conduct of such studies should be well planned, encompassing selection of appropriate dose levels that yield sufficient information for hazard identification (classification and labeling), risk assessment and substances of very high concern/endocrine disruptor identification.

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