N-Nitrosamine impurities in pharmaceuticals are assessed under the ICH M7 guideline where they are classified as a cohort of concern. Recently, structure-activity relationships (SAR) and read-across 2,3 approaches have been recommended for the determination of data-poor N-nitrosamine TD50 values. Here, it is important to ensure that existing TD50 values for N-nitrosamines are derived using the approach aligned with the guideline for data-poor nitrosamines. The TD50 for N-Methyl-N-nitrosophenethylamine (NMPEA) as described in the Carcinogenicity Potency Database4 did not follow the recommendations of ICH M7, which requires using only the most sensitive organ of effect to calculate the Acceptable Intake value5. A re-examination of the original data indicated that the oesophagus was the most sensitive organ, which resulted in a re-calculated TD50 of 40.1 μg/kg/day (or an AI of 40.1 ng/day)1. This represents a 5-fold increase in the current AI level of 8 ng/day, with substantial implications for impurities assessed based on similarity to NMPEA. Additionally, Benchmark Dose (BMD) modeling of in vivo dose response data is referenced in the ICH M7 guideline5 where the Benchmark Dose Lower Confidence Limit (BMDL10) can be used to calculate the acceptable lifetime risk. The BMD10 range for NMPEA was found to be 3.06–17.6 μg/kg/day, translating to a Permitted Daily Exposure (PDE) range of 306–1760 ng/day1.
The re-assessment of the AI value for NMPEA has the following implications:
- Higher AI values for NMPEA could lead to revised Acceptable Intake limits for Nitrosamine Substance-Related Impurities that use NMPEA as a read-across analog.
- The importance of accurate tissue selection and adhering to guidelines in deriving AI values is highlighted.
- BMD modeling is shown as a complementary approach
It is important to re-evaluate cases where an update to the TD50 value is scientifically justified, as these values can influence the Acceptable Intake values for drug impurities, particularly those established through read-across1.
You can read more about the reassessment of NMPEA in our recent publication here: https://doi.org/10.1016/j.yrtph.2025.105888
References:
- Woolley, D. R., Johnson, G. E., & Cross, K. P. (2025). Risk (Re)assessment of N-Methyl-N-nitrosophenethylamine for use in computing risk levels of N-Nitrosamine drug substance-related impurities. Regulatory Toxicology and Pharmacology, 162, 105888. https://doi.org/https://doi.org/10.1016/j.yrtph.2025.105888
- U.S. Food and Drug Administration (FDA). (2023). Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry. https://www.fda.gov/media/170794/download
- Cross, K. P., & Ponting, D. J. (2021). Developing structure-activity relationships for N-nitrosamine activity. Computational Toxicology, 20, 100186. https://doi.org/https://doi.org/10.1016/j.comtox.2021.100186
- L.S. Gold et al. A carcinogenic potency database of the standardized results of animal bioassays, Environmental Health Perspectives (1984).
- M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance for Industry https://www.fda.gov/media/170461/download
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