Acetaminophen, a nonmutagenic compound as previously concluded from bacteria, in vitro mammalian cell, and in vivo transgenic rat assays, presented a good profile as a nonmutagenic reference compound for use in the international multilaboratory Pig‐a assay validation. Acetaminophen was administered at 250, 500, 1,000, and 2,000 mg·kg⁻¹·day⁻¹ to male Sprague Dawley rats once daily in 3 studies (3 days, 2 weeks, and 1 month with a 1‐month recovery group). The 3‐Day and 1‐Month Studies included assessments of the micronucleus endpoint in peripheral blood erythrocytes and the comet endpoint in liver cells and peripheral blood cells in addition to the Pig‐a assay; appropriate positive controls were included for each assay. Within these studies, potential toxicity of acetaminophen was evaluated and confirmed by inclusion of liver damage biomarkers and histopathology. Blood was sampled pre‐treatment and at multiple time points up to Day 57. Pig‐a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as CD59‐negative RBC and CD59‐negative RET frequencies, respectively. No increases in DNA damage as indicated through Pig‐a , micronucleus, or comet endpoints were seen in treated rats. All positive controls responded as appropriate. Data from this series of studies demonstrate that acetaminophen is not mutagenic in the rat Pig‐a model. These data are consistent with multiple studies in other nonclinical models, which have shown that acetaminophen is not mutagenic. At 1,000 mg·kg⁻¹·day⁻¹, Cmax values of acetaminophen on Day 28 were 153,600 ng/ml and 131,500 ng/ml after single and repeat dosing, respectively, which were multiples over that of clinical therapeutic exposures (2.6–6.1 fold for single doses of 4,000 mg and 1,000 mg, respectively, and 11.5 fold for multiple dose of 4,000 mg) (FDA 2002). Data generated were of high quality and valid for contribution to the international multilaboratory validation of the in vivo Rat Pig‐a Mutation Assay.

中文翻译：

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对乙酰氨基酚的测试支持国际多实验室大鼠体内 Pig-a 测定验证试验。

对乙酰氨基酚是一种非致突变化合物，之前从细菌、体外哺乳动物细胞和体内转基因大鼠测定中得出结论，作为用于国际多实验室Pig-a测定验证的非致突变参考化合物，表现出良好的特性。^{在 3 项研究}（3 天、2 周和 1 个月，1 个月恢复组）中，对雄性 Sprague Dawley 大鼠每天一次给予 250、500、1,000 和 2,000 mg·kg -1 · day ^{-1对乙酰氨基酚。}除Pig-a测定外，为期 3 天和 1 个月的研究还包括评估外周血红细胞中的微核终点以及肝细胞和外周血细胞中的彗星终点；每个测定都包括适当的阳性对照。在这些研究中，通过纳入肝损伤生物标志物和组织病理学来评估和证实对乙酰氨基酚的潜在毒性。在治疗前和直至第 57 天的多个时间点采集血液样本。总红细胞 (RBC) 和网织红细胞 (RET) 中的Pig-a突变频率分别确定为 CD59 阴性 RBC 和 CD59 阴性 RET 频率。在接受治疗的大鼠中，通过Pig-a、微核或彗星终点未发现 DNA 损伤增加。所有阳性对照均做出适当反应。这一系列研究的数据表明，对乙酰氨基酚在大鼠Pig-a模型中不具有致突变性。这些数据与其他非临床模型的多项研究一致，这些研究表明对乙酰氨基酚不具有致突变性。在 1,000 mg·kg ^-1 ·day ^-1时，单次和重复给药后第 28 天对乙酰氨基酚的 Cmax 值分别为 153,600 ng/ml 和 131,500 ng/ml，是临床治疗暴露的数倍 (2.6-6.1单剂量 4,000 mg 和 1,000 mg 分别为 1 倍，多剂量 4,000 mg 则为 11.5 倍（FDA 2002）。生成的数据质量高且有效，有助于体内大鼠Pig-a突变测定的国际多实验室验证。