Key Milestone Achieved for the OECD Extended One-Generation Reproductive Toxicity Study Test Guideline

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In the Spotlight

Key Milestone Achieved for the OECD Extended One-Generation Reproductive Toxicity Study Test Guideline

Ed Carney, Ph.D., The Dow Chemical Company

Published: January 4, 2011

On November 19, 2010, the Organisation for Economic Cooperation and Development (OECD) announced that the draft Extended One-Generation Reproductive Toxicity Study (EOGRTS) test guideline had been approved by the Joint Meeting of the Working Party on Chemicals, Pesticides and Biotechnology and the Chemicals Committee. While the test guideline still requires official adoption by the OECD Council, the approval by the Joint Meeting represents a critical milestone along what has been a difficult path toward the “2R’s” – reduce and refine – for reproductive and developmental toxicity testing.

So what is this new test guideline with the unwieldy acronym, EOGRTS? Simply stated, the EOGRTS is an integrated protocol which can comprehensively assess reproductive and developmental toxicity within a single study using the same set of animals, but using fewer animals than the current ‘gold standard’ two-generation test. Central to its design is a key refinement which makes much better use of the first generation offspring, and a major reduction in animal use due to the evaluation of one generation, rather than two. The EOGRTS also provides more flexibility than the two-generation test, particularly with respect to the assessment of postnatal developmental toxicity, including developmental neurotoxicity (DNT) and developmental immunotoxicity (DIT).

These enhancements are accomplished in the EOGRTS by the retention of up to three times more of the first generation offspring for assessments at juvenile and/or young adult life stages as compared to the 2-generation study, in which 86% of the offspring are terminated before 3 weeks of age (weaning), with 43% evaluated only until 4 days of age. Furthermore, the pre-weaning offspring data in the two-generation study are limited to general measures such as survival and body weight, whereas the additional offspring retained in the EOGRTS are evaluated for a variety of more specific developmental and functional end points. Thus, the quality and quantity of data obtained from the animals on study is greatly enhanced in the EOGRTS.

The other key design feature of the EOGRTS, namely evaluating one-generation instead of two, yields an unparalleled reduction in animal numbers used for toxicity testing. Conducting separate two-generation reproductive toxicity (DNT and DIT) studies would consume ~5000 rats, whereas similar information can be achieved with the EOGRTS using ~1300 rats. Omission of the second generation is scientifically supported by several retrospective analyses which evaluated up to 498 existing two-generation reproductive toxicity studies and concluded that the second generation data had a minimal impact on risk assessment or chemical classification and labeling (Piersma, et al., Reprod. Toxicol., epub ahead of print, 2010).

Assuming that the EOGRTS becomes formally adopted by OECD, what is the likely path forward? Fortunately several companies in the industrial chemicals and crop protection sectors have already stepped up and have conducted their own EOGRTS studies in an effort to assess feasibility and effectiveness. For example, BASF conducted an EOGRTS study on vinclozolin and confirmed the ability to detect reproductive/development effects (Schneider, et al., Reg. Tox. Pharm., epub ahead of print, 2010), Bayer Crop Sciences has run a study on methimazole to assess DNT effects, and Syngenta sponsored an EOGRTS on lead acetate to address DIT. In addition, the first EOGRTS run for regulatory purposes was conducted by Dow Chemical on behalf of the 2,4-D Task Force. At Dow, we are already receiving new requests for additional EOGRTS studies, and it is suspected that other companies are seeing similar activity. Given the comprehensive nature of toxicity testing requirements for crop protection compounds, it is likely that this sector will be among the first to implement the EOGRTS on a regular basis.

The much larger challenge, but also the greater opportunity, is the acceptance and use of the EOGRTS as an alternative to the two-generation reproductive toxicity study under the European Union’s REACH program. It has been estimated that REACH will ultimately require several hundred new two-generation reproductive toxicity studies on a wide variety of industrial chemicals, consuming a staggering number of animals. If the EOGRTS were to be accepted by the European Chemicals Agency (ECHA) as an alternative to the two-generation study, a reduction on the order of several hundred thousand animals could be achieved.

In addition to ECHA acceptance, another hurdle relates to the cost of the EOGRTS, which is considerably more expensive than the two-generation reproductive toxicity study. However, costs can be reduced if the DNT and DIT cohorts of the EOGRTS can be waived if scientifically justified and/or if the data are not required to meet regulatory requirements. This inherent flexibility of the EOGRTS allows study designs to be tailored to the specific regulatory framework in the most effective and efficient manner possible, and is far preferable to a one-size-fits-all approach in which the two-generation study is the only option. Like most of my colleagues from the OECD Expert Group who worked diligently on the test guideline for more than three years, I sincerely hope that the EOGRTS guideline becomes broadly accepted and utilized, and that its inherent benefits are realized to their fullest potential. In my view, this would be a win for both science and animal welfare.