In 2016, the United States (US) Food and Drug Administration (FDA) ruled that Electronic Nicotine Delivery Systems (ENDS) were to be regulated just like more traditional tobacco products, meaning that ENDS (e-cigarettes and e-liquids) are subject to premarket review requirements, despite containing no tobacco. ENDS manufacturers must therefore submit a Premarket Tobacco Product Application (PMTA) to the FDA Center for Tobacco Products (CTP) in order to have any chance of legally marketing their products in the US.

The FDA CTP also needs to authorise the PMTA for each ENDS product before it can reach the US market, which is why a “guidance for industry” document was published in 2019 to assist manufacturers in the construction of a successful PMTA submission. This guidance document provides a useful framework for the overall evaluation of ENDS products and highlights many important aspects that should be considered as part of the assessment. For example, the document indicates that a “full assessment of the toxicological effects of your ENDS (e.g., ingredients, components, use of the product) is important to assess the health effects on users and nonusers”. However, it does not provide detailed guidance on how to approach such assessments (and nor does the March 2023 revision). This is problematic for several reasons. One is that some manufacturers may have little understanding of the scientific research and evaluation requirements expected of them, another is that a wide range of studies and approaches could be adopted by manufacturers that the FDA CTP then needs to interpret and evaluate. Clearly, more detailed guidance is needed.

Perhaps in light of the diversity of data evaluation approaches submitted by industry in the millions of PMTAs for ENDS products, the FDA CTP has issued several “scientific policy memoranda” over the past few years. The memos were originally intended to assist FDA reviewers, but due to “public interest” (or more likely industry calling for more detailed guidance to be released), some are now available on the FDA website at https://www.fda.gov/tobacco-products/market-and-distribute-tobacco-product/regulatory-science-policy-memoranda-about-fda-review-tobacco-product-applications. It should be noted that each memo includes a disclaimer that the any communicated information is subject to change and the documents should not be used as a “tool, guide or manual for the preparation of applications or submissions to FDA”. Nevertheless, the memoranda provide some great insights into the FDA CTP’s evaluation process, and by following similar practices to those described in these memos, manufacturers will presumably increase their chances of regulatory success.

The currently available memos shed light on various topics in the realms of analytical chemistry (e.g. extractables/leachables testing and aerosol yield normalisation) and toxicological assessment. One such memo, released in March 2019, discusses the use of toxicity reference values (TRVs) in the toxicological evaluation of chemical constituents present in inhaled tobacco products. FDA’s thoughts on this topic are described briefly below.

Fundamentally, in any quantitative human health risk assessment, an exposure dose is compared with a safety benchmark (e.g., TRV) in order to estimate whether a health risk is likely to arise. Many chemicals have been subject to evaluation by a number of authoritative and industrial groups, each of which may have established or proposed a different TRV for the same chemical. There could be a variety of reasons for the range of TRVs, from the availability of different datasets and points of departure to the application of different uncertainty factors due to differences in product types. Furthermore, it is critical to understand the intended route and duration of exposure of each of the available TRVs, as well as the exposed population. For example, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) derives Acceptable Daily Intake (ADI) values for food additives that are lifetime oral benchmarks intended for safe use by the general population, whereas Permissible Exposure Limits (PELs) developed by the US Occupational Safety and Health Administration (OSHA) are typically concentrations in air that are deemed acceptable for workers exposed for 8 hours per day, 5 days per week for 40 years. Clearly these two examples could yield vastly different benchmarks, and arguably neither would be directly relevant in the assessment of a chemical found in an ENDS product, where a consumer could be exposed by inhalation on a daily basis throughout their adult life. In 2019, the FDA CTP released a memo on the selection of TRVs. The memo describes many important considerations that should be taken into account when selecting (or deriving) such values, but also defines a “three-tier system” first developed by the US Environmental Protection Agency (EPA). The three tiers in this hierarchy are for:

  1.  Reference Concentrations (RfCs) developed under US EPA’s Integrated Risk Information System (IRIS) program (Tier 1),
  2.  Provisional Peer Reviewed Toxicity Values (PPRTVs) established under the US EPA (Tier 2), and 
  3. “other toxicity values” (Tier 3), which could include inhalation toxicity values for the general population derived by other expert groups and Occupational Exposure Limits (OELs) like PELs that would need to be adjusted or modified to be appropriate for consumers, but also oral values like ADIs. 

Most TRVs would fall into the “Tier 3” category, as the majority of the chemicals involved in ENDS products, notably the e-liquid ingredients, have not been evaluated by the US EPA. 

In addition to this memo on the use of TRVs, the FDA has released in 2024 memos on genotoxicity and carcinogenicity evaluations of chemical constituents in ENDS. Read our blog post describing these two memos in further detail here.

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