Setting limits for N-nitrosamines in drugs: A defined approach based on read-across and structure-activity relationship for N-nitrosopiperazine impurities.

This paper describes DARAN (Defined Approach for Risk Assessment of New Nitrosamines), an new defined approach that uses lines of reasoning based on structure-activity relationship (SAR) patterns and Read-Across (RAx) to set transparent and acceptable limits for new N-nitrosamines for which no toxicological data exist. We selected the compound 1-methyl-4-nitrosopiperazine (MeNP) as a target to calculate a new acceptable limit on the basis of a more transparent and scientifically reasoned RAx. We used publicly available databases and datasets to retrieve experimental in vitro mutagenicity and in vivo carcinogenicity data for N-nitrosopiperazine compounds and to form the chemical category for an RAx.