CTP should finalize its updated list of Harmful and Potentially Harmful Constituents by December 2023

We submitted this comment to the FDA on August 25, 2023. The Regulations.gov tracking number islr-awag-qvw8. A PDF copy is available for download here.

CTP should finalize its updated list of Harmful and Potentially Harmful Constituents by December 2023

Docket No. FDA–2023–N–2873

Developing FDA’s Center for Tobacco Products’ Strategic Plan

Stanton A. Glantz, PhD; Pamela M. Ling, MD, MPH; Lauren Kass Lempert, JD, MPH;
Seyed Mehrdad Mohammadi, MD, MPH, MA; Peyton Jacob, PhD; Sabrina Islam, PhD;
Jennifer Fung, PhD; Suzaynn F. Schick, PhD; Bonnie Halpern-Felsher, PhD;
Sabrina Islam, PhD; Vira Pravosud, PhD; Hai-Yen Sung, PhD;
Janet Wojcicki, PhD, MPH; Karla Llanes, PhD

UCSF TCORS

August 25, 2023

FDA announced[1] a Public Meeting and Listening Session and an opportunity to submit written public comments to obtain feedback on five proposed strategic goals it is using to develop a strategic plan for FDA’s Center for Tobacco Products’ (CTP) comprehensive Strategic Plan. In particular, CTP asked for specific actions it could take in the next 5 years that would have significant impact on reducing tobacco-related death and disease. One of these specific actions should be to immediately complete the process of updating the outdated Harmful and Potentially Harmful Constituents (HPHC) list and commit to revisiting it every three years to ensure that it reflects important potential toxicants in evolving tobacco products and new evidence.

            This principle particularly applies to strategic goals 1 and 2:

1. Develop, Advance, and Communicate Comprehensive and Impactful Tobacco Regulations and Guidance.

2. Ensure Timely, Clear, and Consistent Product Application Review to Protect Public Health.  

• In April 2012, FDA issued a list of Harmful and Potentially Harmful Constituents (HPHCs)[2] in Tobacco Products and Tobacco Smoke that included 93 HPHCs.
• This list, which is dominated by carcinogens and other toxicants in cigarette smoke, has become the de facto metric for judging the harm of tobacco products.
• The list created in 2012 does not reflect the current range of tobacco products now subject to CTP’s tobacco product authorities including electronic cigarettes and heated tobacco products that deliver toxicants not observed in or at higher levels than in cigarette smoke.
• Use of the 2012 list to judge new products may, therefore, underestimate health effects of new products.
• Recognizing that the list needed to be updated, in August 2019, FDA sought public comment[3]^{, [4]} on its proposal to add 19 particular toxicants, which included constituents in e-cigarettes and e-liquids, to the outdated 2012 list of HPHCs.
• The 19 toxicants FDA proposed to add to the HPHC list are: acetic acid, acetoin, (also known as 3-hydroxy-2-butanone), acetyl propionyl (also known as 2,3-pentanedione), benzyl acetate, butyraldehyde, diacetyl, diethylene glycol, ethyl acetate, ethyl acetoacetate, ethylene glycol, furfural, glycerol, glycidol, isoamyl acetate, isobutyl acetate, methyl acetate, n-butanol, propionic acid, propylene glycol.
• The public comment period closed on October 4, 2019, and only 40 comments in total were submitted (Table 1).
  • 14 endorsed the proposed HPHC update
    1. 6 suggested additional toxicants (48 pages)
    2. 8 endorsed the list without suggesting additions (11 pages)
  • 6 opposed at least some additions (50 pages)
  • 3 submitted information without making specific suggestions about list items (15 pages)
  • 14 did not make specific suggestions about the list (11 pages)
  • 3 were duplicates or endorsements of other comments
• All of these public comments are incorporated by reference.     
• In addition to the 19 additional constituents proposed by FDA, the 6 public comments that urged FDA to add compounds that may cause pulmonary or cardiovascular harms or be carcinogenic when inhaled, especially oils and chemicals and chemical classes found in e-cigarette flavorants, with several commenters suggesting the same additions:
  • UCSF TCORS: pulegone, vitamin E acetate, acetoin, maltol, ortho-vanillin (or “o-vanillin”), coumarin, cinnamaldehyde, menthol, α,β-unsaturated carbonyl compounds, 1,2-dicarbonyl compounds, furans, epoxides
  • AHA Tobacco Regulation and Addiction Center: cinnamaldehyde, menthol, eugenol, citronellol, limonene, vanillin, dimethylpyrazine, eucalyptol, acetylpyridine, and sucralose.
  • American Thoracic Society: chocolate flavor (2,5-dimethypyrazine), 2,3-hexanedione, benzaldehyde, cinnamaldehyde, maltol, mint/menthol, vanillin
  • Ohio State University: furfuryl alcohol, 5-(hydroxymethyl)-2-furaldehyde
  • Schlesinger Law Group: benzo[e]pyrene, N’-nitrosoanabasine, dioxins and di-benzo-furans, 2- and 3-Methylfuran, total particulate matter
  • Respira Technologies: hexavalent chromium
• There were several suggestions for using additional criteria for additions to the HPHC list, including:
  • UCSF TCORS suggested that FDA should use as additional criteria for additions to the HPHC list, including constituents identified by California’s Proposition 65 list of carcinogens and reproductive toxicants and the California Air Resources Board’s list of Toxicant Air Contaminants.
  • AHA Tobacco Regulation and Addiction Center suggested that the FDA should incorporate evidence for cardiac QT-prolonging effects of constituents into their criteria for HPHCs. As well, the potential of e-liquid constituents to generate HPHCs upon heating and aerosolization in ENDS should be added as criteria for HPHCs.
• The 6 critical comments (from industry) often made similar points and were specific enough that FDA can easily respond, including with reference to additional material in the supportive comments.
• The small volume of comments, their brevity and focus, and common themes means that incorporating the information in these public comments is not a major task.
• As a recent paper by Tehrani et al[5] explains, there are thousands of unknown chemicals in e-liquids, and the number of compounds increase significantly in the aerosol. These potential toxicants include hydrocarbon-like compounds that are typically associated with combustion, but which manufacturers say are not produced during vaping. The main take-away from this study is that a large number of different and unknown compounds are present in e-liquids and are formed during the vaping process that may not be present in cigarettes. While e-cigarettes may not contain the same toxicants found in cigarettes, their potential risks must be recognized and studied. The existing list of HPHCs focuses on toxicants found in cigarettes.  The proposed expansion, with the suggested additions, will be an important step toward expanding the HPHC list to include the huge number of compounds found in e-cigarettes that are potential toxicants.
• One of the comments submitted by the Flavor and Extract Manufacturers Association (FEMA)[6] emphasized the fact that the FEMA Expert Panel evaluates the safety of flavor ingredients only under their conditions of intended use in food and only for exposure through ingestion. FEMA does not evaluate flavor ingredients for use in tobacco products including e-cigarettes or any products that result in exposures other than by ingestion. “Therefore, FEMA GRAS status for the use of a flavor ingredient in food does not provide regulatory authority to use the flavor ingredient in e-cigarettes, ENDS devices or other tobacco products in the U.S.”  Further, FEMA referred to its “long-standing statement[7] that flavor ingredients are not evaluated by the FEMA Expert Panel for safety and GRAS status for any uses other than use in food (https://www.femaflavor.org/safety-assessment-and-regulatory-authority-use-flavors-focus- electronic-nicotine-delivery-systems). Therefore, use in ENDS and other tobacco products must have separate safety assessments to assure safety and establish regulatory authority to use flavors in such products.”[8]

In summary, the FDA should immediately act to update the HPHC list, including the additional toxicants recommended in the 2019 public comment period:

• FDA should finalize the updated the HPHC list by December 2023 and begin using the new list to guide product assessments to protect the public health.
• Given its centrality to decision making in the face of a rapidly evolving tobacco product market as well as evidence on toxicants, the FDA CTP Strategic Plan should include regularly reviewing and updating the HPHC list at least every 3 years.