Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage
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.
Highlights
AIs derived by statistical extrapolation or read across should be expressed on a molar scale or corrected for MW.
The EMA 18 ng/day regulatory default AI re-calculated on a molar scale is 163 pmol/day.
MW-corrected AIs for selected nitrosamine drug substance related impurities (NDSRIs) are presented.
MW scaling should be applied to all stoichiometric reactivity-mediated toxicological outcomes, even beyond nitrosamines.
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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Jonathan Fine, Leonardo Allain, Joerg Schlingemann, David J. Ponting, Robert Thomas, George E. Johnson, Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage, Regulatory Toxicology and Pharmacology, Volume 145, 2023, 105505, ISSN 0273-2300,
https://doi.org/10.1016/j.yrtph.2023.105505.