Utrecht University, Utrecht, the Netherlands.
Charles River Laboratories, Den Bosch, the Netherlands.
Reprod Toxicol. 2022 Sep;112:14-22. doi: 10.1016/j.reprotox.2022.06.006. Epub 2022 Jun 15.
The Extended-One-Generation Study [EOGRTS, OECD 443] is a study in which the toxic effects of test substances on reproduction (Cohort 1), neurodevelopment (Cohort 2), and development of the immune system (Cohort 3) in rats are evaluated. The latter two Cohorts are not always required according to the European Chemicals Agency (ECHA) based on data from previously performed toxicity studies. Although the Cohorts for developmental neurotoxicity (DNT) and developmental immunotoxicity (DIT) are often omitted, the F-animals normally required for these Cohorts are still maintained for evaluation of sexual maturation since three F-animals/sex/litter/group are required according to OECD Guidance Document (GD) No. 151. This review investigates whether two F-animals/sex/litter/group would suffice for this endpoint by investigating the rationale provided by the GD and by comparing results of eighteen EOGRTSs in which three versus two F-animals/sex/litter/group were evaluated. After a comprehensive literature research, we concluded that the rationale in the GD does not substantiate the decision to use three F-animals/sex/litter/group. The scientific papers provided as rationale focused on male observations and the observations discussed do not match the observations for sexual maturation mentioned by the guidelines. The investigation using data from eighteen EOGRTSs showed that the toxicological conclusions, whether the test substance affected sexual maturation or not, matched when comparing data of two F-animals/sex/litter/group to three F-animals/sex/litter/group. To conclude, two F-animals/sex/litter/group would suffice for the evaluation of sexual maturation, which negates the requirement for a so called "Cohort 1 C" (i.e. 160 animals (80 males and 80 females)) per EOGRTS, as well as the number of regulated procedures that need to be performed.
扩展一代研究（EOGRTS，OECD 443）是一项研究，用于评估测试物质对大鼠生殖（第 1 队列）、神经发育（第 2 队列）和免疫系统发育（第 3 队列）的毒性作用。根据欧洲化学品管理局（ECHA）的说法，根据之前进行的毒性研究的数据，后两个队列并不总是必需的。尽管通常会省略发育神经毒性（DNT）和发育免疫毒性（DIT）的队列，但根据 OECD 指导文件（GD）第 151 号的要求，仍需要为这些队列保留 F 代动物，以评估性成熟。本综述通过调查 GD 提供的基本原理并比较其中 18 项 EOGRTS 的结果，研究了每组每性别每窝保留 2 只 F 代动物是否足以满足该终点的要求。在进行了全面的文献研究后，我们得出结论，GD 中的基本原理不能证明使用 3 只 F 代动物/性别/窝/组的决定是合理的。作为基本原理提供的科学论文侧重于雄性观察，所讨论的观察结果与指南中提到的性成熟观察结果不匹配。使用来自 18 项 EOGRTS 的数据进行的调查表明，当比较每组每性别每窝保留 2 只 F 代动物与保留 3 只 F 代动物的数据时，测试物质是否影响性成熟的毒理学结论是一致的。因此，每组每性别每窝保留 2 只 F 代动物足以评估性成熟，这否定了每项 EOGRTS 需保留 160 只动物（80 只雄性和 80 只雌性）（即所谓的“第 1 队列 C”）以及需要执行的监管程序数量的要求。
