The definitions of the chemical classes in the Cohort of Concern (CoC) by Kroes and co-workers are based on broad structural alerts, in particular for N-nitroso compounds─for which the alert consists essentially of the N–N═O substructure without further refinement. Recent pharmaceutical recalls have focused on the presence of dialkyl N-nitrosamine impurities, some of which are exceptionally potent carcinogens─2 orders of magnitude more potent than the pharmaceutical Threshold of Toxicological Concern (TTC), 1.5 μg/day. However, the class of “N-nitroso compounds” is potentially significantly broader. This Perspective looks at the N-nitroso compounds that are at the edges of the cohort, where changes in mechanism, metabolic activation potential, stability, or indeed toxicity data lead to questions about whether these compounds should be classed as CoC. The critical mechanism of action, metabolic α-hydroxylation leading to a diazonium ion, is presented, along with the pathways by which N-nitroso compounds that are not dialkyl N-nitrosamines can lead to comparable DNA adducts.

中文翻译：

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划清界限：关注的群体可能会在哪里结束？

Kroes 及其同事对关注队列 (CoC) 中化学类别的定义基于广泛的结构警报，特别是N -亚硝基化合物，该警报基本上由 N–N=O 子结构组成，没有进一步细化。最近的药品召回主要集中在二烷基N-亚硝胺杂质的存在上，其中一些是极强的致癌物质，比药物毒理学关注阈值 (TTC) 1.5 微克/天强 2 个数量级。然而，“ N-亚硝基化合物”的类别可能要广泛得多。本观点着眼于该群体边缘的 N-亚硝基化合物，其中机制、代谢活化潜力、稳定性或毒性数据的变化引发了关于这些化合物是否应归类为 CoC 的问题。介绍了产生重氮离子的代谢 α-羟基化这一关键作用机制，以及非二烷基N-亚硝胺的N-亚硝基化合物可产生类似 DNA 加合物的途径。