Risk characterization of N-nitrosodimethylamine in pharmaceuticals

Since 2018, N-nitrosodimethylamine (NDMA) has been a reported contaminant in numerous pharmaceutical products. To guide the pharmaceutical industry, FDA identified an acceptable intake (AI) of 96 ng/day NDMA. The approach assumed a linear extrapolation from the Carcinogenic Potency Database (CPDB) harmonic-mean TD₅₀ identified in chronic studies in rats. Although NDMA has been thought to act as a mutagenic carcinogen in experimental animals, it has not been classified as a known human carcinogen by any regulatory agency. Humans are exposed to high daily exogenous and endogenous doses of NDMA. Due to the likelihood of a threshold dose for NDMA-related tumors in animals, we believe that there is ample scientific basis to utilize the threshold-based benchmark dose or point-of-departure (POD) approach when estimating a Permissible Daily Exposure limit (PDE) for NDMA. We estimated that 29,000 ng/kg/day was an appropriate POD for calculating a PDE. Assuming an average bodyweight of 50 kg, we expect that human exposures to NDMA at doses below 5800 ng/day in pharmaceuticals would not result in an increased risk of liver cancer, and that there is little, if any, risk for any other type of cancer, when accounting for the mode-of-action in humans.