Evaluating the lifetime cumulative dose as a basis for carcinogenic potency of nitrosamines – a key tenet underpinning less-than-lifetime approaches for establishing acceptable intake limits

Abstract

Potential health risks associated with N-nitrosamine (NAs) impurities in pharmaceuticals have received significant attention. Regulatory guidance recommends methods to establish Acceptable Intake limits (AIs) that are protective for daily lifetime exposure. However, questions remain whether the same limit should apply to NA impurities in drug products used for less than lifetime (LTL). The ICH M7(R2) guidance addresses this for mutagenic impurities by establishing higher AIs for LTL exposures; however, this has not been adopted in current regulatory guidance for NA impurities which fall under the Cohort of Concern (potentially high potency carcinogens). The research described herein addresses one key knowledge gap: that carcinogenic potency of NAs is a function of total exposure rather than dose rate, a fundamental principle underlying the ICH M7(R2) approach for LTL. Data were evaluated from rodent carcinogenicity bioassays for eight NAs and aflatoxin B1 (another high potency carcinogen) involving exposure durations from 21 to 120 weeks. For all case studies, carcinogenic potency was found to be a function of total cumulative dose rather than daily dose, aligning with the ICH M7(R2) guidance, which posits that higher AI limits can be justified for LTL durations. Remaining knowledge gaps will be addressed in a subsequent publication.