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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage

Jonathan Fine Orcid Logo, Leonardo Allain Orcid Logo, Joerg Schlingemann Orcid Logo, David J. Ponting Orcid Logo, Robert Thomas Orcid Logo, George Johnson Orcid Logo

Regulatory Toxicology and Pharmacology, Volume: 145, Start page: 105505

Swansea University Author: George Johnson Orcid Logo

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Abstract

N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we...

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Published in: Regulatory Toxicology and Pharmacology
ISSN: 0273-2300
Published: Elsevier BV 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa65938
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Abstract: N-nitrosamines (NAs) are a class of compounds of which many, especially of the small dialkyl type, are indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, which are traditionally expressed on a mass basis. Here we demonstrate that AIs that are not experimentally derived for a specific compound, but via statistical extrapolation or read across to a suitable analog, should be expressed on a molar scale or corrected for the target substance's molecular weight. This would account for the mechanistic aspect that each nitroso group can, at maximum, account for a single DNA mutation and the number of molecules per mass unit is proportional to the molecular weight (MW). In this regard we have re-calculated the EMA 18 ng/day regulatory default AI for unknown nitrosamines on a molar scale and propose a revised default AI of 163 pmol/day. In addition, we provide MW-corrected AIs for those nitrosamine drug substance related impurities (NDSRIs) for which EMA has pre-assigned AIs by read-across. Regulatory acceptance of this fundamental scientific tenet would allow one to derive nitrosamine limits for NDSRIs that both meet the health-protection goals and are technically feasible.
Keywords: Nitrosamines; N-Nitrosamine; NDSRIs; Risk assessment; Acceptable intake; Read-across; Carcinogenicity; Percentile; TD50; Toxicology; 18 ng AI default; ICH M7 cohort of concern
College: Faculty of Medicine, Health and Life Sciences
Funders: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. All authors are employed by their respective affiliations.
Start Page: 105505