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Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data 

Thresher A; Foster RS; Ponting DJ; Stalford SA; Tennant RE; Thomas R; 

The control of potentially mutagenic impurities in pharmaceutical products is of key importance in assessing carcinogenic risk to humans. The recent discovery of nitrosamine impurities in several marketed pharmaceuticals has increased interest in their mutagenic and carcinogenic potential. This chemical class is considered part of a ‘cohort of concern’, indicating that standard control protocols, such as the use of a threshold of toxicological concern (TTC), cannot be applied. Whilst some nitrosamines are known to be exceptionally potent carcinogens, it’s not clear whether this is a property of all members of the class. To investigate the mutagenic and carcinogenic potential of nitrosamines, data was extracted from published literature to augment that already present in the Vitic and Lhasa Carcinogenicity Databases. This data was analysed to assess the application of the ICH M7 guideline to nitrosamine impurities, with respect to the predictivity of the Ames test for carcinogenic potential and the distribution of carcinogenic potency. It was found that 18% of nitrosamines were considered non-carcinogenic. Nitrosamines showed a greater correlation between mutagenicity and carcinogenicity compared to non-nitrosamine compounds. Whilst nitrosamines, in general, are more potent carcinogens than non-nitrosamines, there is a significant overlap between the two distributions of TD50s for each class.