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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
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Leonardo Allain ,
Joerg Schlingemann ,
David J. Ponting ,
Robert Thomas ,
George Johnson
Regulatory Toxicology and Pharmacology, Volume: 145, Start page: 105505
Swansea University Author:
George Johnson
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DOI (Published version): 10.1016/j.yrtph.2023.105505
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...
| Published in: | Regulatory Toxicology and Pharmacology |
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| ISSN: | 0273-2300 |
| Published: |
Elsevier BV
2023
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| Online Access: |
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| 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. |
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| 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 |