Risk characterization of N-nitrosodimethylamine in pharmaceuticals.

Area of Science:

• Pharmaceutical Science
• Toxicology
• Risk Assessment

Background:

• N-nitrosodimethylamine (NDMA) has been identified as a contaminant in pharmaceuticals since 2018.
• The FDA previously set an acceptable intake (AI) of 96 ng/day for NDMA based on linear extrapolation from animal studies.
• NDMA is suspected to be a mutagenic carcinogen in animals but is not classified as a known human carcinogen.

Purpose of the Study:

• To re-evaluate the acceptable intake limit for NDMA in pharmaceuticals.
• To propose a threshold-based approach for determining a Permissible Daily Exposure (PDE) for NDMA.
• To assess the risk of liver and other cancers associated with pharmaceutical NDMA exposure in humans.

Main Methods:

• Utilized a threshold-based benchmark dose or point-of-departure (POD) approach.
• Estimated an appropriate POD for NDMA at 29,000 ng/kg/day.
• Calculated a PDE for NDMA assuming a 50 kg average body weight.

Main Results:

• The estimated POD for NDMA was 29,000 ng/kg/day.
• A PDE of 5800 ng/day was calculated based on the POD and average human body weight.
• Human exposure to NDMA below 5800 ng/day is unlikely to increase liver cancer risk.

Conclusions:

• A threshold-based approach is scientifically justified for setting NDMA exposure limits due to likely non-linear dose-response.
• The proposed PDE of 5800 ng/day offers a potentially safer limit for NDMA in pharmaceuticals.
• Current human exposure levels to NDMA in pharmaceuticals are unlikely to pose a significant cancer risk, especially liver cancer.