Do you know the “DARAN” approach?
The method was published some days ago in Regulatory Toxicology and Pharmacology, developed in a Ph.D. project, based on their experiences of regulatory submissions to Europe, Brazil, and the United States.
dos Santos, C. E. M., Dorta, D. J., & de Oliveira, D. P. (2022). Setting limits for N-nitrosamines in drugs: A defined approach based on read-across and structure-activity relationship for N-nitrosopiperazine impurities. In Regulatory Toxicology and Pharmacology (Vol. 136, p. 105288). Elsevier BV. https://doi.org/10.1016/j.yrtph.2022.105288
The paper describes DARAN (Defined Approach for Risk Assessment of New Nitrosamines) as a 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.
The approach is based on the regulatory criteria defined in the report EMA/369136/2020 for structure-activity relationship (SAR) and Read-across (RAx):
- Structural similarity criteria
- RAX hypothesis
- Influence of structural differences
- Detailing and assessment basis
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. Publicly available databases and datasets were used to retrieve experimental in vitro mutagenicity and in vivo carcinogenicity data for N-nitrosopiperazine compounds and to form the chemical category for an RAx.
On the basis of the criteria proposed in the Assessment Report EMA/369136/20202 and by using the SAR hypotheses obtained by the analysis, it is obtained a robust RAx, scientifically supported assumptions, which resulted in TD50 values predicted from the closest structurally related compounds and a worst-case approach.
Do you need DARAN to support new limits for N-nitrosamines? Contact us.
