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Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) in pharmaceuticals to limit potential carcinogenic risk. The rationales behind the AIs have not been provided to understand the process for selecting a TD50 or read-across analog. In this manuscript we evaluated the toxicity data for eleven common NAs in a comprehensive and transparent process consistent with ICH M7. This evaluation included substances which had datasets that were robust, limited but sufficient, and substances with insufficient experimental animal carcinogenicity data. In the case of robust or limited but sufficient carcinogenicity information, AIs were calculated based on published or derived TD50s from the most sensitive organ site. In the case of insufficient carcinogenicity information, available carcinogenicity data and structure activity relationships (SARs) were applied to categorical-based AIs of 1500 ng/day, 150 ng/day or 18 ng/day; however additional data (such as biological or additional computational modelling) could inform an alternative AI. This approach advances the methodology used to derive AIs for NAs. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Joel P Bercu, Melisa Masuda-Herrera, Alejandra Trejo-Martin, Priyanka Sura, Robert Jolly, Michelle Kenyon, Rob Thomas, David J Ponting, David Snodin, Gregor Tuschl, Stephanie Simon, Kathleen De Vlieger, Richard Hutchinson, Andreas Czich, Susanne Glowienke, M Vijayaraj Reddy, Sandra Johanssen, Esther Vock, Nancy Claude, Richard J Weaver. Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs). Regulatory toxicology and pharmacology : RTP. 2023 Aug;142:105415

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PMID: 37257751

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