Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs)

Area of Science:

• Pharmaceutical chemistry
• Toxicology
• Regulatory science

Background:

• Low levels of N-nitrosamines (NAs) detected in pharmaceuticals necessitate regulatory limits.
• Health authorities (HAs) established acceptable intakes (AIs) to mitigate carcinogenic risks.
• The scientific rationale for current AIs and the selection of TD50 values or read-across analogs remain unclear.

Purpose of the Study:

• To transparently evaluate toxicity data for eleven common NAs.
• To establish a clear methodology for deriving acceptable intakes (AIs) consistent with ICH M7 guidelines.
• To address the lack of rationale behind existing NAs AIs.

Main Methods:

• Comprehensive evaluation of toxicity data for eleven common N-nitrosamines (NAs).
• Application of International Council for Harmonisation (ICH) M7 principles.
• Calculation of AIs using TD50 values from the most sensitive organ site for substances with sufficient data.
• Utilizing structure-activity relationships (SARs) and available carcinogenicity data for substances with insufficient experimental data to assign categorical AIs (1500, 150, or 18 ng/day).

Main Results:

• A transparent methodology for deriving acceptable intakes (AIs) for N-nitrosamines (NAs) was developed.
• AIs were calculated based on TD50 values for NAs with robust or sufficient carcinogenicity data.
• Categorical AIs were assigned for NAs with insufficient carcinogenicity data, with potential for refinement through additional studies.

Conclusions:

• The developed approach provides a clear and consistent method for deriving acceptable intakes (AIs) for N-nitrosamines (NAs).
• This methodology enhances the scientific basis for regulatory limits of NAs in pharmaceuticals.
• Further data, including biological and computational modeling, can refine the proposed AIs.