An Approach to Flavor Chemical Thermal Degradation Analysis
Juul Labs, Inc., Washington, DC 20004, USA
*
Author to whom correspondence should be addressed.
Toxics 2024, 12(1), 16; https://doi.org/10.3390/toxics12010016
Submission received: 28 November 2023
/
Revised: 14 December 2023
/
Accepted: 20 December 2023
/
Published: 23 December 2023
(This article belongs to the Special Issue Electronic Cigarettes and Heated Tobacco Products Aerosols Emission and Toxicity Evaluation)
Abstract
:Toxicological evaluations of flavor chemicals for use in inhalation products that utilize heat for aerosol generation are complicated because of the potential effect heat may have on the flavor chemical. The objective was to develop a thermal degradation technique to screen flavor chemicals as part of a toxicological testing program for their potential use in ENDS formulations. Based upon published data for acetaldehyde, acrolein, and glycidol from ENDS products (common thermal degradants of propylene glycol and glycerin), the pyrolizer temperature was adjusted until a similar ratio of acetaldehyde, acrolein, and glycidol was obtained from a 60/40 ratio (v/v) of glycerin/propylene glycol via GC/MS analysis. For each of 90 flavor chemicals, quantitative measurements of acetaldehyde, acrolein, and glycidol, in addition to semiquantitative non-targeted analysis tentatively identifying chemicals from thermal degradation, were obtained. Twenty flavor chemicals transferred at greater than 99% intact, another 26 transferred at greater than 95% intact, and another 15 flavor chemicals transferred at greater than 90% intact. Most flavor chemicals resulted in fewer than 10–12 tentatively identified thermal degradants. The practical approach to the thermal degradation of flavor chemicals provided useful information as part of the toxicological evaluation of flavor chemicals for potential use in ENDS formulations.
1. Introduction
Toxicological evaluations of flavor chemicals for use as ingredients in inhalation products that utilize heat to generate an aerosol are complicated because of the potential effect heat may have on the flavor chemical. Sufficient heat may cause pyrolysis or degradation of the flavor chemical, yielding different chemicals. In cigarettes where temperatures can reach 900 °C [1], Dempsey et al. [2] have provided a historical review of these flavor chemical evaluation efforts, which have generally incorporated evaluating the pyrolysis-derived by-products [3,4]. As reported in the literature, electronic nicotine delivery systems (ENDSs) utilize substantially lower temperatures to generate an aerosol, typically under 300 °C [5,6,7,8,9,10]. However, non-temperature-regulated devices may exceed 300 °C, leading to the production of higher levels and different thermal degradation products [11]. Although the lower temperature utilized in ENDS products precludes pyrolysis, thermal degradation of flavor chemicals is still possible. Evaluation of the potential thermal degradation products from flavor chemicals used in ENDSs is consistent with a published ENDS ingredient evaluation program [5] and requirements and guidance from regulatory agencies [12,13,14].
ENDS products generally consist of a base formulation consisting of a mixture of glycerin, propylene glycol, and nicotine, although some formulations consist of only glycerin or propylene glycol and nicotine [15,16,17,18]. In addition to the base formulation, ENDS products contain various flavor chemicals. In a survey of English language websites conducted in 2014 [14], Zhu and colleagues counted 466 separate brands of e-liquid with 7764 unique e-liquid flavors. More recently, several authors have conducted studies identifying flavor chemicals in ENDS products with the majority but not all being used at low levels [19,20,21,22,23,24,25,26,27]. For example, in an examination of 20 refill fluids, the total amount of chemical flavors exceeding 0.1% occurred in only four of the refill fluids [19]. In other reports, most flavor chemicals were used at less than 1% in a brand comparison of menthol- and tobacco-flavored ENDSs [24,25].
The objective of the current work was to develop a thermal degradation technique that could be used to screen flavor chemicals as part of a toxicological testing program for their potential use in ENDS formulations.
2. Materials and Methods
Since the exact temperature (average or maximum) an e-liquid experiences along the coil of an ENDS product throughout a puff cannot be approximated with a single temperature [28,29] in a thermal degradation setup attached to a gas chromatograph/mass spectrometer (GC/MS), a practical approach was used. This practical approach was based upon previous work using propylene glycol showing that although different coil materials can affect the amount of carbonyl production, there appear to be similar thermal degradation processes occurring [30]. The practical approach was based upon targeted chemical analysis of several e-liquids using the Juul device [31], which is a temperature-controlled ENDS product [8,9,31]. Three chemicals (acetaldehyde, acrolein, and glycidol) were selected as indicators of the degradation of glycerin and propylene glycol to set the temperature of the thermal degradation setup attached to the GC/MS. A 60/40 percent ratio (v/v) of USP-grade glycerin and propylene glycol was used to set the analysis temperature in the thermal degradation setup. This ratio of USP-grade glycerin and propylene glycol was consistent with previous reports of commercial ENDS products [9,11,17,18,26,31]. The temperature of the GC/MS setup was tested at 275 °C and in 25 °C steps between 350 °C and 575 °C until the ratio of quantifiable acetaldehyde, acrolein, and glycidol was similar to that reported for currently marketed Juul products [31].
2.1. Analytical Equipment
All work was performed at a contract research organization (RTI, Laboratories, Livonia, MI, USA). This work used a GC (Agilent 6890)/MS (Agilent 5972) with a Frontier Eco-Cup LF pyrolizer (EGNPY-3030D) and a VF-wax (Agilent CP9206) 30 m × 0.25 mm column with a nominal film thickness of 1 µm and helium carrier gas (0.7 mL/min). Based upon preliminary work monitoring acetaldehyde, acrolein, and glycidol levels from 10 µL samples of USP-grade glycerin and propylene glycol in a 60/40 ratio (v/v), a temperature of 475 °C was selected to conduct the subsequent flavor chemical thermal degradation studies. The desorption time was set to 1 min. Each flavor chemical sample was placed directly in the Eco-cup to avoid volatilization that might occur in an autosampler. Quantitative analysis focused on acetaldehyde, acrolein, and glycidol using calibration curves prepared from analytical standards for each compound. The method performance was verified by acceptable recovery of 5 ng of each compound added to the USP-grade glycerin and propylene glycol mixture as samples. In addition to the quantitative determination of acetaldehyde, acrolein, and glycidol from each flavor chemical, a non-targeted semiquantitative analysis was performed using a greater than or equal to 70% match factor with the GC/MS library (Wiley 7/National Institute of Standards and Technology 05 [NIST]) to tentatively identify other potential thermal degradation products from each flavor chemical. After every 10 flavor chemical samples a quantitative standard was desorbed to demonstrate quantitative accuracy for the targeted compounds. Details of the GC separation method are in Table S1.
2.2. Chemical Flavors
A total of 90 flavor chemicals were evaluated using the thermal degradation setup with 5 µL for liquids or 5 µg for solids being used (Table 1). The flavor chemicals were a convenience sample and had been reported in ENDS products [19,20,21,22,23,24,25,26,27]. All flavor chemicals were food grade and compliant with Food Chemical Codex, if available, and their purity was provided by the chemical supplier.
3. Results
The majority of flavor chemicals tested (46) transferred intact at 95% or greater, with 20 transferring at greater than 99% intact (Table 1). Another 15 flavor chemicals tested transferred at greater than 90% intact (Table 1). Most flavor chemicals resulted in fewer than 10–13 chemicals tentatively identified due to thermal degradation, which represented less than 9% of the estimated mass (Table 1). Thermal degradation analysis of a few flavor chemicals resulted in the tentative identification of more than 30 chemicals. For the few flavor chemicals that had zero percent intact transfer, fewer than nine thermal degradation products were identified for each one (Table 1). Chromatograms for six flavor chemicals (4-vinyl guaiacol, cinnamyl isovalerate, delta-3-carene, ethyl cinnamate, methyl-2-methyl-3-furyl disulfide, and methyl benzoate) were not suitable for analysis due to late elution of the compounds as evidenced by carryover into the next injection (Table 1; Figures S1–S9).
A total of 8 of the 90 flavor chemicals produced measurable amounts of acetaldehyde, acrolein, or glycidol (Table 2). Considering that 5 µL for liquids or 5 mg for solids of each flavor chemical was analyzed, the maximum total amount of acetaldehyde, acrolein, or glycidol measured (0.33 ng/µL acetaldehyde, 1.38 ng/µL acetoin, and 1.052 for glycidol) for any flavor ingredient was a low level of thermal degradation for the targeted compounds and represented approximately 0.02–0.07% of the main intact flavor ingredient peak.
4. Discussion
In a few cases the percentage of intact transfer was higher than the purity of the flavor chemical (e.g., Alpha Ionone, Cital, etc.) either due to the minimum purity stated by the manufacturer and/or due to some impurities being below the limit of detection. For two flavor chemicals (2,4-Decadienal, purity 91.93%, and Melonal, purity 85.96%) the levels of the targeted chemicals and the number of tentatively identified thermal degradants may have resulted from the impurities or carrier used for these flavor chemicals, rather than from the flavor chemicals. Some of the tentatively identified thermal degradation products from the flavor chemicals (Table S2) could be of toxicological concern (e.g., pulegone identified from butyl anthranilate or ethylene oxide identified from melonal) and would guide the development of targeted chemical analysis to determine the quantitative levels of these tentatively identified thermal degradation products from flavor chemicals. Alternatively, the most prudent approach would be not to use the flavor chemical in ENDS formulation development. The toxicological evaluation of the tentatively identified chemicals or their confirmation for further toxicological evaluation of the flavor chemical is beyond the scope of this work.
One limitation in this study, as evidenced by the chromatograms for six flavor chemicals (4-vinyl guaiacol, cinnamyl isovalerate, ethyl cinnamate, delta-3-carene, methyl-2-methyl-3-furyl disulfide, and methyl benzoate) not being interpretable, is that it is likely slightly different analytical methods (e.g., different run time, columns, etc.) are required to screen a large range of flavor chemicals. A second limitation is the use of a 70% match factor to the Wiley/NIST database for chemical identification. A higher match factor (>70%) would increase confidence that the tentatively identified chemical is correct but is likely to reduce the number of tentatively identified chemicals, while using a lower match factor (<70%) would have the opposite effect, more tentatively identified chemicals with less confidence in their correct identification. Another limitation is that our use of a practical approach to set the temperature used in the GC/MS setup in this study was designed for the temperature-controlled JUUL device and would need to be adapted to other ENDS devices that have been reported to reach over 500 °C [11]. The practical approach is flexible in that the degradation products of glycerin and propylene glycol can be changed, and their ratios can be adjusted for specific ENDS devices. Finally, single-chemical thermal degradation testing cannot predict what might occur when the flavor chemical is mixed with propylene glycol, glycerin, or other flavor chemicals in an ENDS formulation [31,32], which is why this method is proposed as one screening tool for flavor chemicals, and mechanistic degradation analysis was not performed. To be clear, thermal degradation testing of flavor chemicals is not intended as a substitute for aerosol constituent measurements from the final formulation used in a final ENDS product as has been previously reported [31,33,34].
Baker and Bishop [3] evaluated the pyrolysis of 291 flavor chemicals, and Purkis et al. [4] evaluated the pyrolysis of 91 flavor chemicals, with both ramping temperatures from 300 to 900 °C in their work. The results from the current thermal degradation study were remarkably consistent with this previous pyrolysis work, especially given the dramatic differences in temperatures used between current and previous studies [3,4] (Table 3). For sixteen of the comparable flavor chemicals, the intact transfer percent was within 3% of the intact transfer percent measured in one of the previous studies; however, for the other eight flavor chemicals, differences in the intact transfer percent exceeded 5%, likely due to the temperature differences between the studies. The purity of the flavor chemicals was slightly higher in the current study compared with the purity used in one of the previous studies [3] and slightly lower compared with the other previous study [4], except for D-limonene. As anticipated due to the differences in the used temperatures, there were differences in the number of and specific degradation products identified in the current study compared with the compounds identified from the two previous pyrolysis studies (Supplemental Table S2). As noted in Baker and Bishop [3], slow or constant heat of a chemical can produce different degradation products compared with rapid heating [35].
5. Conclusions
In summary, a practical approach to thermal degradation testing was used as a screening tool for 90 flavor chemicals consistent with an ENDS ingredient evaluation framework [5]. Over half of the flavor chemicals transferred intact at ≥95%, with another 16% transferring intact at ≥90%. Only eight flavor chemicals produced detectable levels of acetaldehyde, acrolein, or glycidol resulting from thermal degradation. Most flavor chemicals resulted in fewer than 10–12 thermal degradation products that represented less than 9% of the mass. Overall, the practical approach to the thermal degradation of flavor chemicals provided useful information as part of the toxicological evaluation of flavor chemicals for potential use in ENDS formulations.
Supplementary Materials
The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/toxics12010016/s1: Table S1: GC separation parameters; Table S2: Comparison of flavor ingredient degradants; Figure S1: Chromatogram (A) and sample mass spectra (B) for Cinnamyl iso-valerate (CAS# 140-27-2) demonstrating poor chromatography. One unknown peak at 23.078 min. with others eluting in subsequent runs (methyl benzoate and vinyl guaiacol injections); Figure S2: Chromatogram (A) and two sample mass spectra (B,C) for Methyl benzoate (CAS# 93-58-3) demonstrating poor chromatography. Injected after cinnamyl iso-valerate (CAS 140-27-2). Major peaks in this run (peaks 15 and 16 shown above) are identified as cinnamyl iso-valerate eluting late; Figure S3: Chromatogram (A) and mass spectra (B) for Vinyl guaiacol (CAS# 7786-61-0) demonstrating poor chromatography. Injected after cinnamyl iso-valerate and methyl benzoate showing major peak 2 in this run is identified as methyl benzoate eluting late compared the NIST standard mass spectra. Second set of mass spectra shows Peak 6 (RT 31.554) was identified as remaining cinnamyl iso-valerate eluting with a library match score of 95; Figure S4: Chromatogram (A) for delta-3-carene (CAS# 13466-78-9) demonstrating poor chromatography with no real peaks; Figure S5: Chromatogram (A) for ethyl cinnamate (CAS# 103-36-6) demonstrating poor chromatography with no real peaks and eluting in the next run (Methyl-2 methyl-3-furyl disulfide injection); Figure S6: Chromatogram (A) and mass spectra (B) for Methyl-2 methyl-3-furyl disulfide (CAS# 65505-17-1) demonstrating poor chromatography. Injected after ethyl cinnamate (CAS# 103-36-6). Peak 9 (RT 29.849) misidentified due to saturation. Identified as ethyl cinnamate based on comparison to reference spectrum from NIST database; Figure S7: Chromatogram (A) and mass spectra (B) for Tetramethyl pyrazine (CAS# 1124-11-4) demonstrating good chromatography. Sample mass spectra (top) compared to library match mass spectra (bottom) are below the chromatogram; Figure S8: Chromatogram (A) and mass spectra (B) for Propyl caproate (CAS# 626-77-7) demonstrating good chromatography. Sample mass spectra (top) compared to library match mass spectra (bottom) are below the chromatogram; Figure S9: Chromatogram (A) and mass spectra (B) for 2-methyl-2-pentenoic acid (CAS# 3142-72-1) demonstrating good chromatography. Sample mass spectra (top) compared to NIST match mass spectra (bottom) are below the chromatogram. Peak 14 (RT 27.105 min) misidentified due to saturation. Identified as intact 2-methyl-2-pentenoic acid based on comparison to reference spectrum from NIST database.
Author Contributions
Project conceptualization, M.J.O. and I.G.G.; methodology, I.G.G.; formal analysis, L.J.; funding and resources, M.J.O. and I.G.G.; writing—original draft preparation, M.J.O.; writing—review and editing, M.J.O., L.J. and I.G.G. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by Juul Labs, Inc.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data are contained within the article or Supplementary Material.
Conflicts of Interest
All testing was performed at RTI Laboratories and paid for in full by Juul Labs, Inc. All authors were employees of Juul Labs, Inc., and the research was performed as part of their normal responsibilities at Juul Labs, Inc.
References
- Baker, R.R. Temperature variation within a cigarette combustion coal during the smoking cycle. High Temp. Sci. 1975, 7, 236–247. [Google Scholar]
- Dempsey, R.; Coggins, C.R.E.; Roemer, E. Toxicological evaluation of cigarette ingredients. Regul. Toxicol. Pharmacol. 2011, 61, 119–129. [Google Scholar] [CrossRef] [PubMed]
- Baker, R.R.; Bishop, L.J. The pyrolysis of tobacco ingredients. J Anal. Appl. Pyrol. 2004, 71, 223–311. [Google Scholar] [CrossRef]
- Purkis, S.W.; Mueller, C.; Intorp, M. The fate of ingredients in and impact on cigarette smoke. Food Chem. Toxicol. 2011, 49, 3238–3248. [Google Scholar] [CrossRef] [PubMed]
- Costigan, S.; Meredith, C. An approach to ingredient screening and toxicological risk assessment of flavours in e-liquids. Regul. Toxicol. Pharm. 2015, 72, 361–369. [Google Scholar] [CrossRef] [PubMed]
- Geiss, O.; Bianchi, I.; Barrero-Moreno, J. Correlation of volatile carbonyl yields emitted by e-cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours. Intern. J. Hyg. Environ. Health 2016, 219, 268–277. [Google Scholar] [CrossRef] [PubMed]
- Chen, W.; Wang, P.; Ito, K.; Fowles, J.; Shusterman, D.; Jaques, P.A.; Kumagai, K. Measurement of heating coil temperature for e-cigarettes with a “top-coil” clearomizer. PLoS ONE 2018, 13, e0195925. [Google Scholar] [CrossRef] [PubMed]
- Black, W.; Alston, W.; Holloway, G.; Zhang, J.T. Computational Simulation of Aerosol Generation and Temperature Regulation Performance of Nicotine Salt Pod System. In Proceedings of the CORESTA Conference (Smoke—Technology Joint Study Groups), Hamburg, Germany, 6–10 October 2019; Available online: https://www.coresta.org/sites/default/files/abstracts/2019_STPOST05_Black.pdf (accessed on 2 November 2023).
- Talih, S.; Salman, R.; El-Hage, R.; Karam, E.; Karaoghlanian, N.; El-Hellani, A.; Saliba, N.; Shihadeh, A. Characteristics and toxicant emissions of JUUL electronic cigarettes. Tob. Control 2019, 28, 678–680. [Google Scholar] [CrossRef]
- Mulder, H.A.; Stewart, J.B.; Blue, I.P.; Krakowiak, R.I.; Patterson, J.L.; Karin, K.N.; Royals, J.M.; DuPont, A.C.; Forsythe, K.E.; Poklis, J.L.; et al. Characterization of E-cigarette coil temperature and toxic metal analysis by infrared temperature sensing and scanning electron microscopy—energy-dispersive X-ray. Inhal Toxicol. 2020, 32, 447–455. [Google Scholar] [CrossRef]
- Uchiyama, S.; Noguchi, M.; Sato, A.; Ishitsuka, M.; Inaba, Y.; Kunugita, N. Determination of thermal decomposition products generated from e-cigarettes. Chem. Res. Toxicol. 2020, 33, 576–583. [Google Scholar] [CrossRef]
- European Parliament and of the Council of the European Union, Directive 2014/40/EU on the Approximation of the Laws, Regulations and Administrative Provisions of the Member States Concerning the Manufacture, Presentation and Sale of Tobacco and Related Products and Repealing Directive 2001/37/EC, Official Journal of the European Union, L127, 1–38, 3 April 2014. Available online: https://health.ec.europa.eu/publications/directive-201440eu_en (accessed on 10 November 2023).
- United States Food and Drug Administration, Center for Tobacco Products. Guidance for Industry, Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems, March, 2023. Available online: https://www.fda.gov/media/127853/download (accessed on 22 December 2023).
- United States Food and Drug Administration, Center for Tobacco Products. Final rule, Premarket Tobacco Product Applications and Recordkeeping Requirement. Fed. Regist. 2021, 86, 55300–55439. [Google Scholar]
- Zhu, S.-H.; Sun, J.Y.; Bonnevie, E.; Cummins, S.E.; Gamst, A.; Yin, L.; Lee, M. Four hundred and sixty brands of e-cigarettes and counting: Implications for product regulation. Tob. Control 2014, 23 (Suppl. S3), iii3–iii9. [Google Scholar] [CrossRef] [PubMed]
- Beauval, N.; Antherieu, S.; Soyez, M.; Gengler, N.; Grova, N.; Howsam, M.; Hardy, E.M.; Fischer, M.; Appenzeller, B.M.R.; Goossens, J.F.; et al. Chemical Evaluation of Electronic Cigarettes: Multicomponent Analysis of Liquid Refills and their Corresponding Aerosols. J. Anal. Toxicol 2017, 41, 670–678. [Google Scholar] [CrossRef] [PubMed]
- Oldham, M.J.; Zhang, J.; Rusyniak, M.J.; Kane, D.B.; Gardner, W.P. Particle size distribution of selected electronic nicotine delivery system products. Food Chem. Toxicol. 2018, 113, 236–240. [Google Scholar] [CrossRef] [PubMed]
- Pinto, M.I.; Thissen, J.; Hermes, N.; Cunningham, A.; Digard, H.; Murphy, J. Chemical characterization of the vapour emitted by an e-cigarette using a ceramic wick-based technology. Sci. Rep. 2022, 12, 16497. [Google Scholar] [CrossRef] [PubMed]
- Hua, M.; Omaiye, E.E.; Luo, E.; McWhirter, K.J.; Pankow, J.F.; Talbot, P. Identification of Cytotoxic Flavor Chemicals in Top-Selling Electronic Cigarette Refill Fluids. Sci. Rep. 2019, 9, 2782. [Google Scholar] [CrossRef] [PubMed]
- Erythropel, H.C.; Anastas, P.T.; Krishnan-Sarin, S.; O’Malley, S.S.; Jordt, S.E.; Zimmerman, J.B. Differences in flavourant levels and synthetic coolant use between USA, EU and Canadian Juul products. Tob. Control 2021, 30, 453–455. [Google Scholar] [CrossRef]
- Jabba, S.V.; Erythropel, H.C.; Torres, D.G.; Delgado, L.A.; Woodrow, J.G.; Anastas, P.T.; Zimmerman, J.B.; Jordt, S.-E. Synthetic cooling agents in US-marketed e-cigarette refill liquids and popular disposable e-cigarettes: Chemical analysis and risk assessment. Nicotine Tob. Res. 2022, 24, 1037–1046. [Google Scholar] [CrossRef]
- Omaiye, E.E.; McWhirter, K.J.; Luo, W.; Pankow, J.F.; Talbot, P. High-nicotine electronic cigarette products: Toxicity of JUUL fluids and aerosols correlates strongly with nicotine and some flavor chemical concentrations. Chem. Res. Toxicol. 2019, 32, 1058–1069. [Google Scholar] [CrossRef]
- Omaiye, E.E.; McWhirter, K.J.; Luo, W.; Tierney, P.A.; Pankow, J.F.; Talbot, P. High concentrations of flavor chemicals are present in electronic cigarette refill fluids. Sci. Rep. 2019, 9, 2468. [Google Scholar] [CrossRef]
- Omaiye, E.E.; Luo, W.; McWhirter, K.J.; Pankow, J.F.; Talbot, P. Electronic cigarette refill fluids sold worldwide: Flavor chemical composition, toxicity, and hazard analysis. Chem. Res. Toxicol. 2020, 33, 2972–2987. [Google Scholar] [CrossRef] [PubMed]
- Omaiye, E.E.; Luo, W.; McWhirter, K.J.; Pankow, J.F.; Talbot, P. Flavour chemicals, synthetic coolants and pulegone in popular mint-flavoured and menthol-flavoured e-cigarettes. Tob. Control 2022, 31, e3–e9. [Google Scholar] [CrossRef] [PubMed]
- Omaiye, E.E.; Luo, W.; McWhirter, K.J.; Pankow, J.F.; Talbot, P. Disposable puff bar electronic cigarettes: Chemical composition and toxicity of e-liquids and a synthetic coolant. Chem. Res. Toxicol. 2022, 35, 1344–1358. [Google Scholar] [CrossRef] [PubMed]
- Omaiye, E.E.; Luo, W.; McWhirter, K.J.; Pankow, J.F.; Talbot, P. Ethyl maltol, vanillin, corylone and other conventional confectionery-related flavor chemicals dominate in some e-cigarette liquids labelled ‘tobacco’ flavoured. Tob. Control 2022, 31, s238–s244. [Google Scholar] [CrossRef] [PubMed]
- Alston, B. Nicotine Salt Pod System Temperature Regulation. In Proceedings of the CORESTA Smoke-Techno Conference, Hamburg, Germany, 6–10 October 2019; Available online: https://www.coresta.org/sites/default/files/abstracts/2019_STPOST03_Alston.pd (accessed on 2 November 2023).
- Dibaji, S.A.R.; Oktem, B.; Williamson, L.; DuMond, J.; Cecil, T.; Kim, J.P.; Wickramasekara, S.; Myers, M.; Guha, S. Characterization of aerosols generated by high-powered electronic nicotine delivery systems (ENDS): Influence of atomizer, temperature and PG:VG ratios. PLoS ONE 2022, 17, e0279309. [Google Scholar] [CrossRef] [PubMed]
- Saliba, N.A.; El Hellani, A.; Honein, E.; Salmon, R.; Talih, S.; Zeaitor, J.; Shihadeh, A. Surface chemistry of electronic cigarette electrical heating coils: Effects of metal type on propylene glycol thermal decomposition. J. Anal. Appl. Pyrol. 2018, 134, 520–525. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Bailey, P.C.; Oldham, M.J.; Yang, C.; Hiraki, B.; Gillman, I.G. Targeted characterization of the chemical composition of JUUL systems aerosol and comparison with 3R4F reference cigarettes and IQOS heat sticks. Separations 2022, 8, 168. [Google Scholar] [CrossRef]
- Erythropel, H.C.; Jabba, S.V.; DeWinter, T.M.; Mendizabal, M.; Anastas, P.T.; Jordt, S.-E.; Zimmerman, J.B. Formation of flavorant-propylene Glycol Adducts with novel toxicological properties in chemically unstable E-cigarette liquids. Nicotine Tob. Res. 2019, 21, 1248–1258. [Google Scholar] [CrossRef]
- Crosswhite, M.R.; Bailey, P.C.; Jeong, L.N.; Lioubomirov, A.; Yang, C.; Ozvald, A.; Jameson, J.B.; Gillman, I.G. Non-Targeted Chemical Characterization of JUUL Virginia Tobacco Flavored Aerosols Using Liquid and Gas Chromatography. Separations 2021, 8, 130. [Google Scholar] [CrossRef]
- Crosswhite, M.R.; Jeong, L.N.; Bailey, P.C.; Jameson, J.B.; Lioubomirov, A.; Cook, D.; Yang, C.; Ozvald, A.; Lyndon, M.; Gillman, I.G. Non-Targeted Chemical Characterization of JUUL-Menthol-Flavored Aerosols Using Liquid and Gas Chromatography. Separations 2022, 9, 367. [Google Scholar] [CrossRef]
- Baker, R.R. Kinetic mechanism of the thermal decomposition of tobacco. Thermochim. Acta 1979, 28, 45–57. [Google Scholar] [CrossRef]
Table 1.
Chemicals evaluated via thermal degradation analysis.
| Chemical Name | CAS # | FEMA # | Purity (%) | Intact Transfer % | Targeted Chemicals Identified (Yes/No) | Number of Chemicals Tentatively Identified 1 |
|---|---|---|---|---|---|---|
| 2,3,5,6-Tetramethyl pyrazine 2 | 1124-11-4 | 3237 | 99.90 | 99.45 | No | 7 |
| 2-Acetyl pyridine | 1122-62-9 | 3251 | 99.77 | 98.62 | No | 3 |
| 2-isobutyl thiazole | 18640-74-9 | 3134 | 99.54 | 99.34 | No | 9 |
| 2-isopropyl-N,2,3-trimethylbutyramide (WS-23) | 51115˗67˗4 | 3804 | 99.90 | 83.56 | No | 6 |
| 2-Methyl Butyl acetate | 624-41-9 | 3644 | 99.72 | 98.24 | No | 11 |
| 2-Methyl-1-Butanol | 137-32-6 | 3998 | 99.94 | 96.34 | No | 9 |
| 2-Methyl-2-Pentenoic Acid | 3142-72-1 | 3195 | 99.45 | 91.77 | No | 17 |
| 2,4-Decadienal, (E,E)- | 25152-84-5 | 3135 | 91.93 | 75.78 | No | 25 |
| 3-Acetyl pyridine | 350-03-8 | 3424 | 99.97 | 93.52 | No | 8 |
| 3-Methylcyclopentanedione (MCP) | 765-70-8 | 2700 | 99.1 | 96.85 | No | 7 |
| 4-Vinyl guaiacol 3 | 7786-61-0 | 2675 | 98.06 | 3 | 3 | 3 |
| 4-(Para-Hydroxyphenol)-2-Butanone (raspberry ketone) 2 | 5471-51-2 | 2588 | 99.93 | 0 | No | 8 |
| 6-amyl-alpha pyrone | 27593-23-3 | 3696 | 99.25 | 97.73 | No | 20 |
| 6-Methyl coumarin | 92-48-8 | 2699 | 100 | 90.28 | No | 1 |
| Acetoin acetate | 4906-24-5 | 3526 | 99.28 | 99.01 | Yes | 7 |
| Acetophenone 2, 4 | 98-86-2 | 2009 | 99.71 | 99.26 | No | 6 |
| Alpha ionone 2 | 127-41-3 | 2594 | 92.66 | 95.47 | No | 18 |
| Amyl formate | 638-49-3 | 2068 | 100 | 78.93 | No | 20 |
| Anisyl acetone | 104-20-1 | 2672 | 99.78 | 99.08 | No | 7 |
| Benzyl alcohol 2, 4 | 100-51-6 | 2137 | 99.87 | 100 | No | 0 |
| Beta damascenone 2, 4 | 23696-85-7 | 3420 | 95.72 | 80.53 | No | 26 |
| Beta ionone 2, 4 | 79-77-6 | 2595 | 98.9 | 96.96 | No | 21 |
| Bis(2-methyl-3-furyl)disulfide | 28588-75-2 | 3259 | 99.46 | 75.74 | No | 15 |
| Butyl acetate 2 | 123-86-4 | 2174 | 99.78 | 99.53 | No | 5 |
| Butyl anthranilate | 7756-96-9 | 2181 | 99.71 | 71.45 | No | 44 |
| Cinnamyl isobutyrate 2 | 103-59-3 | 2297 | 98.12 | 93.98 | No | 15 |
| Cinnamyl isovalerate 3 | 140-27-2 | 2302 | 96.35 | 3 | 3 | 3 |
| Cis-3-Hexenyl butyrate ((Z)-3-hexen-1-yl butyrate) | 16491-64-4 | 3402 | 98.68 | 89.97 | Yes | 65 |
| Cis-3-Hexenyl caproate | 31501-11-8 | 3403 | 99.85 | 98.97 | No | 5 |
| Cis-6-Nonenol | 35854-86-5 | 3465 | 96.89 | 99.57 | No | 3 |
| Cis-jasmone | 488-10-8 | 3196 | 99.62 | 0 | No | 1 |
| Citral 2, 4 | 5392-40-5 | 2303 | 97.62 | 95.52 | No | 26 |
| Decanal 2 | 112-31-2 | 2362 | 98.33 | 91.95 | Yes | 26 |
| D-limonene 4 | 5989-27-5 | 2633 | 99.45 | 96.7 | Yes | 30 |
| Delta-3-carene 3 | 13466-78-9 | 3821 | 95.76 | 3 | 3 | 3 |
| Diethyl malonate | 105-53-3 | 2375 | 99.61 | 71.86 | No | 8 |
| Diethyl Sebacate | 110-40-7 | 2376 | 99.69 | 98.39 | No | 13 |
| Diethyl succinate | 123-25-1 | 2377 | 99.93 | 99.79 | No | 5 |
| Dimethyl Benzyl Carbinyl Butyrate | 10094-34-5 | 2394 | 99.79 | 79.72 | No | 3 |
| Ethyl acetate 2, 4 | 141-78-6 | 2414 | 99.92 | 99.16 | No | 2 |
| Ethyl benzoate 2, 4 | 93-89-0 | 2422 | 99.34 | 0 | No | 2 |
| Ethyl cinnamate 2, 3 | 103-36-6 | 2430 | 99.68 | 3 | 3 | 3 |
| Ethyl lactate 2 | 97-64-3 | 2440 | 98.88 | 100 | No | 0 |
| Ethyl Methyl Phenyl Glycidate | 77-83-8 | 2444 | 98.67 | 92.78 | No | 17 |
| Ethyl phenyl acetate 2 | 101-97-3 | 2452 | 99.75 | 99.12 | No | 6 |
| Ethyl-3-methylthiopropionate | 13327-56-5 | 3343 | 99.95 | 99.86 | No | 3 |
| Furfuryl thio acetate | 13678-68-7 | 3162 | 99.27 | 94.94 | Yes | 15 |
| Heptanal | 111-71-7 | 2540 | 94.48 | 0 | No | 6 |
| Hexyl alcohol 2 | 111-27-3 | 2567 | 98.55 | 95.99 | No | 14 |
| Hexyl 2-methylbutanoate | 10032-15-2 | 3499 | 99.56 | 90.9 | No | 10 |
| Hexyl Caproate | 6378-65-0 | 2572 | 99.86 | 98.49 | No | 7 |
| Hexyl isobutyrate | 2349-07-7 | 3172 | 99.64 | 99.51 | No | 7 |
| Isoamyl phenyl acetate 2 | 102-19-2 | 2081 | 98.42 | 92.31 | No | 11 |
| Isobutyl acetate 2 | 110-19-0 | 2175 | 99.78 | 88.63 | No | 3 |
| L-Menthyl acetate | 2623-23-6 | 2668 | 99.98 | 92.48 | No | 6 |
| Linalool oxide 2 | 1365-19-1 | 3746 | 99.59 | 89.69 | No | 25 |
| Melonal | 106-72-9 | 2389 | 85.96 | 76.81 | Yes | 18 |
| Methyl 3-nonenoate | 13481-87-3 | 3710 | 98.08 | 95.37 | No | 21 |
| Methyl benzoate 2, 3, 4 | 93-58-3 | 2683 | 99.62 | 3 | 3 | 3 |
| Methyl caproate | 106-70-7 | 2708 | 99.75 | 99.1 | No | 3 |
| Methyl furfuryl disulfide | 57500-00-2 | 3362 | 99.25 | 30.54 | No | 26 |
| Methyl heptanone | 110-93-0 | 2707 | 99.43 | 98.72 | No | 20 |
| Methyl nonyl ketone | 112-12-9 | 3093 | 99.82 | 94.42 | No | 5 |
| Methylphenyl acetate 2 | 101-41-7 | 2733 | 99.99 | 99.61 | No | 2 |
| Methyl thiobutyrate | 2432-51-1 | 3310 | 99.94 | 99.78 | No | 2 |
| Methyl-2-furoate | 611-13-2 | 2703 | 99.85 | 99.3 | No | 6 |
| Methyl-2 methyl-3-furyl disulfide 3 | 65505-17-1 | 3573 | 98.57 | 3 | 3 | 3 |
| Milk lactone (5,6-decenoic acid) | 72881-27-7 | 3742 | 87.51 | 91.08 | No | 14 |
| N-((Ethoxycarbonyl)methyl)-p-menthane-3-carboxamide (WS-5) | 68489-14-5 | 4309 | 99.64 | 95.05 | Yes | 20 |
| Neofolione | 111-79-5 | 2725 | 99.06 | 94.33 | No | 35 |
| Neryl acetate 2 | 141-12-8 | 2773 | 98.83 | 91.36 | No | 30 |
| N-ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-3) | 39711-79-0 | 3455 | 99.70 | 96.30 | Yes | 19 |
| Nona-2-Trans, 6-Cis-Dienal | 557-48-2 | 3377 | 98.94 | 0 | No | 2 |
| Nootkatone | 4674-50-4 | 3166 | 99.16 | 99.68 | No | 6 |
| Octanone-2 (Methyl Hexyl Ketone) | 111-13-7 | 2802 | 98.80 | 98.91 | No | 5 |
| Phenylethyl phenylacetate 2 | 102-20-5 | 2866 | 99.20 | 96.44 | No | 11 |
| Propyl acetate | 109-60-4 | 2925 | 99.70 | 98.49 | No | 6 |
| Propyl caproate | 626-77-7 | 2949 | 99.91 | 99.88 | No | 4 |
| Sulfurol (4-methyl-5-thiazole ethanol) | 137-00-8 | 3204 | 99.86 | 43.11 | No | 6 |
| Sulfuryl acetate | 656-53-1 | 3205 | 99.60 | 0 | No | 9 |
| Styrallyl Acetate (alpha-methylbenzyl acetate) | 93-92-5 | 2684 | 99.75 | 96.85 | No | 24 |
| T,T,2,4, undecadienal | 30361-29-6 | 3422 | 97.75 | 97.32 | No | 12 |
| Thiomenthone | 38462-22-5 | 3177 | 97.66 | 87.46 | No | 21 |
| Trans-2-decenal | 3913-81-3 | 2366 | 97.55 | 98.62 | No | 15 |
| Trans-2-nonenal | 18829-56-6 | 3213 | 95.58 | 87.03 | No | 23 |
| Trithioacetone | 828-26-2 | 3475 | 99.55 | 83.57 | No | 20 |
| Valencene | 4630-07-3 | 3443 | 65-90 | 90.95 | No | 22 |
| Vanillyl Ethyl Ether | 13184-86-6 | 3815 | 98.32 | 98.95 | No | 8 |
| Veratraldehyde 2, 4 | 120-14-9 | 3109 | 99.99 | 97.79 | No | 18 |
| Whiskey lactone | 39212-23-2 | 3803 | 98.62 | 97.64 | No | 6 |
CAS—Chemical Abstract Services; FEMA—Flavor and Extract Manufacturers Association. 1 Match factor greater than 70%. 2 Thermal degradation also evaluated by Baker and Bishop [3]. 3 Flavor chemicals that had unacceptable chromatography resulting in unusable data. 4 Thermal degradation also evaluated by Purkis et al., 2011 [4].
Table 2.
Amount of acetaldehyde, acrolein, and glycidol resulting from thermal degradation of tested flavor chemicals.
Table 2.
Amount of acetaldehyde, acrolein, and glycidol resulting from thermal degradation of tested flavor chemicals.
| Chemical Name | CAS # | Amount Detected (ng/µL) | ||
|---|---|---|---|---|
| Acetaldehyde | Acrolein | Glycidol | ||
| Acetoin Acetate | 4906-24-5 | <LOQ | ND | 0.526 |
| Cis-3-Hexenyl Butyrate ((Z)-3-hexen-1-yl butyrate) | 16491-64-4 | <LOQ | 0.568 | ND |
| D-limonene | 5989-27-5 | <LOQ | ND | 0.158 |
| Decanal | 112-31-2 | <LOQ | 0.368 | ND |
| Furfuryl thio acetate | 13678-68-7 | ND | ND | 0.118 |
| Melonal | 106-72-9 | <LOQ | 0.668 | ND |
| N-((Ethoxycarbonyl)methyl)-p-menthane-3-carboxamide (WS-5) | 68489-14-5 | 0.166 | 0.688 | ND |
| N-ethyl-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide (WS-3) | 39711-79-0 | 0.112 | ND | ND |
CAS—Chemical Abstract Services. LOQ—limit of quantification. ND—not detected, meaning no peaks were detected.
Table 3.
Comparison of purity and intact transfer % of selected flavor chemicals.
| Chemical Name | CAS # | Current Study | Baker and Bishop, 2004 [3] | Purkis et al. 2011 [4] | |||
|---|---|---|---|---|---|---|---|
| Purity (%) | Intact Transfer % | Purity (%) | Intact Transfer % | Purity (%) | Intact Transfer % | ||
| 2,3,5,6-Tetramethyl pyrazine | 1124-11-4 | 99.90 | 99.45 | 98 | 100 | N/A | N/A |
| 4-(Para-Hydroxyphenol)-2-Butanone (raspberry ketone) | 5471-51-2 | 99.93 | 0 | 98 | 96.8 | N/A | N/A |
| Acetophenone | 98-86-2 | 99.71 | 99.26 | 98 | 99.8 | 99.9 | 98.7 |
| Alpha ionone | 127-41-3 | 92.66 | 95.47 | 90 | 91.8 | N/A | N/A |
| Benzyl alcohol | 100-51-6 | 99.87 | 100 | 99 | 95.2 | 100 | 94.2 |
| Beta damascenone | 23696-85-7 | 95.72 | 80.53 | 95 | 94.2 | 100 | 99.4 |
| Beta ionone | 79-77-6 | 98.9 | 96.96 | 97 | 95.4 | 100 | 100 |
| Butyl acetate | 123-86-4 | 99.78 | 99.53 | 99 | 100 | N/A | N/A |
| Cinnamyl isobutyrate | 103-59-3 | 98.12 | 93.98 | 97 | 94.0 | N/A | N/A |
| Citral | 5392-40-5 | 97.62 | 95.52 | 96 | 93.7 2 | 100 | 94.4 |
| Decanal | 112-31-2 | 98.33 | 91.95 | 95 | 94.8 | N/A | N/A |
| D-limonene | 5989-27-5 | 99.45 | 96.7 | N/A | N/A | 98.7 | 100 |
| Ethyl acetate | 141-78-6 | 99.92 | 99.16 | 99 | 100 | 100 | 100 |
| Ethyl benzoate | 93-89-0 | 99.34 | 0 | 99 | 100 | 100 | 98.7 |
| Ethyl cinnamate 1 | 103-36-6 | 99.68 | 1 | 98 | 98.7 | N/A | N/A |
| Ethyl lactate | 97-64-3 | 98.88 | 100 | 98 | 73.4 | N/A | N/A |
| Ethyl phenyl acetate | 101-97-3 | 99.75 | 99.12 | 98 | 98.5 | N/A | N/A |
| Hexyl alcohol | 111-27-3 | 98.55 | 95.99 | 98 | 96.3 | N/A | N/A |
| Isoamyl phenyl acetate | 102-19-2 | 98.42 | 92.31 | 98 | 94.7 | N/A | N/A |
| Isobutyl acetate | 110-19-0 | 99.78 | 88.63 | 98 | 99.8 | N/A | N/A |
| Linalool oxide | 1365-19-1 | 99.59 | 89.69 | 97 | 95.1 | N/A | N/A |
| Methyl benzoate 1 | 93-58-3 | 99.62 | 1 | 98 | 99.6 | 100 | 100 |
| Methylphenyl acetate | 101-41-7 | 99.99 | 99.61 | 98 | 98.4 | N/A | N/A |
| Neryl acetate | 141-12-8 | 98.83 | 91.36 | 98 | 82.0 | N/A | N/A |
| Phenylethyl phenylacetate | 102-20-5 | 99.20 | 96.44 | 98 | 82.1 | N/A | N/A |
| Veratraldehyde | 120-14-9 | 99.99 | 97.79 | 98 | 99.6 | 100 | 100 |
CAS—Chemical Abstract Services; N/A = not applicable. 1 Flavor chemicals that had unacceptable chromatography resulting in unusable data. 2 Combination of E & Z-Citral.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Oldham, M.J.; Jeong, L.; Gillman, I.G. An Approach to Flavor Chemical Thermal Degradation Analysis. Toxics 2024, 12, 16. https://doi.org/10.3390/toxics12010016
AMA Style
Oldham MJ, Jeong L, Gillman IG. An Approach to Flavor Chemical Thermal Degradation Analysis. Toxics. 2024; 12(1):16. https://doi.org/10.3390/toxics12010016
Chicago/Turabian StyleOldham, Michael J., Lena Jeong, and I. Gene Gillman. 2024. "An Approach to Flavor Chemical Thermal Degradation Analysis" Toxics 12, no. 1: 16. https://doi.org/10.3390/toxics12010016
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
