What is Synthetic Nicotine and is it Regulated?

November 10, 2021

By: Bonnie Coffa, PHD

Nicotine is a chiral compound, meaning that there are two enantiomers or different forms of nicotine: (S)-Nicotine and (R)-Nicotine. (S)-Nicotine is the naturally occurring enantiomeric form of nicotine in plants from the Solanaceae family. Tobacco-derived nicotine contains predominantly (S)-Nicotine (~99.3%) and less than 1% (R)-Nicotine, with a small amount of (R)-Nicotine formed during combustion. Tobacco-derived nicotine is regulated under the FDA Center for Tobacco Products and has the CAS# 54-11-5.

Synthetic nicotine on the other hand does not come from the tobacco plant. It is synthesized using either a chemical or an enzymatic process. This is then often followed by a chemical or enantiomeric purification. There are multiple forms of synthetic nicotine. Synthetic nicotine can be identical to tobacco derived nicotine and be >99% (S)-nicotine, or can be a racemic mix of (R)- and (S)- (50/50 with the CAS # 22083-74-5) or vary in the ratios of (R)- and (S)-nicotine; all of which have different CAS numbers as shown below.

Currently there is no FDA regulatory requirement to determine the enantiomeric composition of synthetic nicotine or verify that the synthetic nicotine is indeed synthetic and not mislabeled or adulterated with tobacco derived nicotine.

Is Synthetic Nicotine regulated by FDA?

In 2009, the Family Smoking Prevention and Tobacco Control Act, also known simply as the Tobacco Control Act (TCA), granted FDA broad jurisdiction over tobacco products. The TCA requires that the regulation of tobacco products use a population-level health standard demonstrating appropriate for the protection of public health. In 2016, FDA finalized what is known as the “deeming rule”, that deems any product meeting the statutory definition of a tobacco product, which included e-cigarettes, under the scope of FDA’s regulatory authority. However, this rule only applies to e-cigarettes containing nicotine that are “made or derived from tobacco”, and therefore tobacco products containing synthetic nicotine fall outside of FDA jurisdiction, but on a “case by case basis” can be regulated by FDA as illustrated in FDA Commonly Asked Questions about the Center for Tobacco Products.

“The product I manufacture contains no substance made or derived from tobacco, e.g. is zero-nicotine, or has synthetic nicotine or nicotine made from tomatoes. Is my product subject to FDA regulation?

The definition of “tobacco product” includes any product made or derived from tobacco, including any component, part, or accessory of a tobacco product. E-liquids that do not contain nicotine or other substances made or derived from tobacco may still be components or parts and, therefore, subject to FDA’s tobacco control authorities.

However, it’s possible that a disposable, closed system device that contains an e-liquid with truly zero nicotine (or synthetic nicotine) would not be regulated by the FDA as a tobacco product, if it is not intended or reasonably be expected to be used in such a fashion. FDA intends to make these determinations on a case-by-case basis, based on a totality of the circumstances.” Check out the full list of commonly asked questions here.

In addition, the FDA Center for Drug Evaluation and Research (CDER), which currently regulates nicotine replacement therapy products, also does not have authority over synthetic nicotine and therefore synthetic nicotine is currently seen as a regulatory loophole.

The lack of regulatory oversight enabled companies to bring products back onto the market by replacing the tobacco-derived nicotine with synthetic nicotine. In July 2020, FDA notified companies via warning letters to remove flavored disposable e-cigarettes from the market for marketing unauthorized tobacco products and we have seen companies pivot to synthetic nicotine.

On March 18, 2021, the American Lung Association, Campaign for Tobacco-free Kids, Parents Against Vaping E-cigs and the Truth Initiative sent a letter to FDA Commissioner Janet Woodcock, urging the FDA to take action against disposable synthetic nicotine e-cigarette products. The letter also highlighted the regulatory gap and urged that the agency not allow companies to market nicotine products without FDA review. Read the full letter here.

More recently, U.S. Representative, Raja Krishnamoorthi, sent letters to two companies selling synthetic nicotine to provide all documents and communications referring or relating to the use of synthetic nicotine in their products “including the decision to switch to synthetic nicotine, and all documents relating to the purchase of synthetic nicotine”. You can read the full press release here with links to the letters.

Do you want to know if an e-liquid or an e-cigarette contains synthetic nicotine?

Enthalpy Analytical has been developing and validating methods for the determination of synthetic nicotine in pure nicotine and e-liquid formulations over the past year. We are currently optimizing the methods for use in pouch and other oral nicotine-containing products.

Click the link to view the poster presented on analysis and differentiation of tobacco-derived and synthetic nicotine samples at the 74th Tobacco Science Research Conference (August 2021):

https://www.coresta.org/sites/default/files/abstracts/2021_TSRC19_Campbell.pdf

If you have any questions about nicotine containing products or for more information on our lab testing services, please contact us here.

Bonnie Coffa, PhD
Regulatory Toxicologist
Bonnie is a Regulatory Toxicologist with experience managing in vitro toxicology studies, writing nonclinical sections of FDA PMTA ENDS submissions, and toxicological evaluations of ingredients in tobacco, nicotine, and CBD products.

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