Over the past 3 years, there has been renewed interest in identifying products which contain nitrosamines.  When, 35 years ago, a widely used agricultural product was found to contain low ppm concentrations, the FDA and the EPA expressed concerns.  Today, the FDA and other agencies around the globe are concerned about the presence of ppb concentrations of nitrosamines in commonly used drugs.  We predict that perhaps dozens of products are going to be targeted and suggest that a high-quality risk assessment is the best way to understand the possible health risks and communicate with agencies, as well as the public.

What are nitrosamines? 

Nitrosamines are a class of chemicals used for research purposes and formed in food by chemical processes in a reaction between nitrite or nitrogen oxides (NOx) and amines. Human exposure to nitrosamines is primarily through tobacco, drinking water, diet, beer, toiletry and cosmetic products, and household goods (ATSDR, 1989). Nitrosamines are also formed endogenously in the human gut from the intake of nitrite containing foods and subsequent reactions with bacteria. Humans are exposed to nitrosamines daily in various concentrations depending on country of residence. 

N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are two types of nitrosamines classified as probable human carcinogens by the FDA based on the results of animal studies. Because it is nearly impossible to account for confounders in epidemiology studies,  the carcinogenic risk to humans exposed to typical concentrations of these compounds is not known (FDA, 2021, ATSDR, 1989).

Why is the FDA Recalling Certain Batches of Valsartan?

In 2021, the FDA issued a recall of Valsartan, a blood pressure medication (e.g., hypertension).  Their interest in this product began in 2018, when they announced that the administration was conducting an investigation of drugs which contained Valsartan’s active pharmaceutical ingredient (API) due to concerns about various impurities (including the nitrosamines).  A few months ago, the FDA reported that certain batches contained NDMA and NDEA and may have been formed as an impurity due to a change in the chemical manufacturing process. The generic drug Valsartan, manufactured by Zhejiang Huahai Pharmaceuticals (China), had been distributed to companies worldwide and recalls were soon widespread. However, not all Valsartan-containing medicines distributed in the United States came from Zhejiang Huahai.

According to the FDA, the nitrosamines may have been present in this drug for up to four years. As is customary, the FDA based their risk estimates on the highest daily dose and an assumption of low-dose linearity of the carcinogenic response.  The FDA estimated that if 8,000 people took the highest Valsartan does (320 mg) containing NDMA from recalled batches daily for four years, there would be one additional case of cancer over the lifetimes of the 8,000 people. They estimated similar risks for NDEA. In our view, the FDA approach produced much higher estimates of risk than would be present for the vast majority of the exposed population (perhaps up to 100-fold higher than the best estimate).

Interim limits for nitrosamine impurities in angiotensin II receptor blockers were set at 96 ng/day for NDMA and 26.5 ng/day for NDEA assuming the maximum daily dose (320 mg) of Valsartan. The acceptable intake was based on posing a risk no greater than 1 in 100,000 assuming 70 years of exposure. 

Since personal injury litigation has already begun, we suggest that those involved conduct a careful analysis of the underpinnings of the FDA risk assessment.  In our view, there are numerous overly conservative assumptions which indicate that ingestion of these nitrosamines could be considerably higher yet would satisfy the FDA’s desire to achieve a 1 in 100,000 risk.

Paustenbach and Associates scientists have extensive experience in conducting consumer product safety assessments and evaluating the potential health risks of possible impurities from consumer products. Specifically, we have assessed the presence of trace quantities of impurities in pharmaceuticals and identified potential long-term health hazards due to those impurities. Our scientists have 50+ years of experience characterizing these hazards and offering a range of possible solutions. Our scientists have published more than 300 papers on relevant topics. Please contact us for more information regarding Paustenbach and Associates’ capabilities.