We members are interested in how to apply the read-across method to unknown nitrosamines. However, the number of cases available is not so large. So I want to pick posts related to Read-across/ SAR from our previous discussion. We have learned a lot and understand applying Read-across/ SAR to unknown nitrosamines is not a simple road. I hope it will help you.
Are all N-nitrosamines a concern? April 2021 @David mentioned the importance of alpha hydrogen here.
Q&A Nitrosamine SAR working group (23 companies and universities) July 2021 @Naiffer_Host shared @kpcross and @David 's excellent slides. And @kpcross shared other recordings.
AIs for Complex Nitrosamines by MW Adjustments, any experience? December 2021 @Naiffer_Host introduced the concept of MW adjustment for determining the AI of complex nitrosamines. @SusanFelter and @conudel justified the application of MW adjustment. I’m not sure current discussion in the regulatory, but it may disclose in the future.
Update of the CMDh’s Q&A Document on Nitrosamine Impurities January 2022
@conudel pointed out lots of problems with guidance. We don’t have clear guidance on how to perform acceptable QSAR/read-across analysis to set acceptable intakes; the molecular weight adjustment method is not yet accepted; the criteria for the selection of adequate surrogates for the read-across method is not clear.
N-nitroso-propranolol? March 2022
Fantastic literature “Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities” was firstly introduced on this topic. But I am sorry whether this approach can apply to your nitrosamines is not clear.
Using SAR to evaluate hazard and potency (Recording) June 2022 @Naiffer_Host shared the recording of @David’s presentation, "How Concerning is your nitrosamine? Using SAR to evaluate hazard and potency”
Calculating Nitrosamine Limits (MasterClass) June 2022 @Naiffer_Host shared the recording of @conudel 's presentation, “Setting Limits for Complex Nitrosamines”. You can understand how to decide the limit of NDSRIs.
Nitroso Flecainide July 2022
N-nitrosoamides - a horse of a different color July 2022
We discussed the difference between nitrosamines and nitrosamides/carbamates/urea/guanidine. These look confusing, but they should be distinguished.
Officially used surrogates for read-across method July 2022
I visualized surrogate compounds used for read-across by EMA. I think we need more examples.
AI Limit for Nitroso Nebivolol August 2022 @David shared deep insight for selecting a suitable read-across analog. I think the current read-across surrogates in 10 focus mainly on local similarity. I hope it will be improved in the future.
If you want to add your favorites, please do not hesitate to post. Let’s enjoy this journey with us!
AI for small nitrosamines not listed in EMA, FDA or Health Canada October 2022
Points to note for calculating TD50 are shared in this thread. As @SusanFelter focused, a robust bioassay is important. NDBA and NDPA with TD50 values are in LCDB, but limits are extrapolated from NDEA.
Sharing our paper about DARAN (Defined Approach for Risk Assessment of New Nitrosamines). This defined approach uses lines of reasoning based on structure-activity relationship (SAR) patterns and Read-Across (RAx) to set transparent, interpretable, 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
Influence of structural differences
Detailing and assessment basis
We used an example case with not API-like, but we are working with
Nitrosamine drug substance-related impurities (NDSRIs), proposing some additional SAR steps and methods.
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*
Thank you for asking me. I searched the following compound on the substructure search of LCDB.
18 compounds are included in LCDB but do not look good as a surrogate for N-Nitroso-N-methyl benzylamine. Then CPCA is a better way compared to read-across from NMPEA. 18ng or 26.5ng/day is applicable.
As far as I know, there is no clear line between NDSRIs and small nitrosamines. The AI of MeNP(1-methyl-4-nitroso piperazine) contained in Rifampin was calculated as 26.5 ng/day by read-across in the previous version of EMA Q&A, but now CPCA is available, 400 ng/day. Unless there is an appropriate surrogate, I expect the application of CPCA justified.
In this case, I believe that the change also comes from the fact that non-compliance of “26”.
Applying any of these limits implies recall from the market. And they (EMA FDA etc) must have been thinking about what to do with this structure.
I am also referring to nitrosopiperazine, which comes from something as common in pharma as piperazine solvent.