Diacetyl is a chemical used as artificial flavor in candy, popcorn and other food items, while also used in e-liquids to provide a butter flavor. However, the inhalation of diacetyl may be associated with permanent lung damage like “popcorn lung” and trigger breathing problems, as well as wheezing or other forms of respiratory disease. Moreover, Khlystov et al. found that the addition of flavoring chemicals significantly increased the emission level of small aldehydes due to the degradation of flavoring molecules. Organic acids additives have also recently been found in e-liquids. Organic acids are used to protonate nicotine to form nicotine salts, which are found naturally in tobacco leaves and are widely used as an alternative to free-base nicotine in e-cigarettes. Nicotine salts are thought to amplify the delivery of nicotine to the user without changing the concentration of added free base nicotine which could cause throat irritation. The speed of e-cigarette nicotine salts uptake in humans is similar to the speed of nicotine uptake in combustible cigarettes. Research on nicotine salts is limited, heavy duty propagation trays and the health risk of persistent inhalation of nicotine salts is unknown at this time. There exist more than 20 nicotine salts available on the market, and the most commonly used weak acid in the formation nicotine salts includes lactic acid, benzoic acid and levulinic acid.
Thechemical structures of representative acids that are used for nicotine salts are shown in Scheme 1.1d.The active ingredient in cannabis e-liquid is tetrahydrocannabinol . Delta-9- tetrahydrocannabinol is the critical component for inducing a psychoactive effect, and is the more popular isomer on the market; however, delta-8 is gaining popularity. THC is found in marijuana, also called weed, herb and some other terms, which is the mixture of dried flowers of cannabis sativa. Cannabis concentrate refers to the product of distilling down the most desired cannabis flowers, but without the undesired part of the plants. THC concentrate is an oil-like extract that contains a high dosage of THC and terpenes from marijuana. Cannabinoids and terpenes are responsible for the psycho-activity, aroma and flavors desired by many e-cigarette users. THC can be absorbed into the bloodstream and transmitted to the brain following smoking or inhaling the aerosol formed by the e-cigarette device, with binding to the endocannabinoid receptors located in the different parts of brain that are responsible for basic function, such as thinking, movement and pleasure. Hemp is also used for oil extraction; it has more cannabidiol content than THC. CBD is one of 113 identified cannabinoids; it does not have the same psychoactivity as THC, and more research is needed to determine its biological effects. The use CBD in e-cigarettes is widespread and CBD in e-cigarettes can act as the precursor to THC. It has been found that 25 – 52% of CBD can transform into other cannabinoids ; THC is the main pyrolysis product of CBD under typical e-cigarette operational temperature ranges under both oxidative and inert conditions.
THC-containing products are generally sold as prefilled cartridge or in dropper bottles for refill. The structures of CBD, THC and corresponding transformation routes are shown in Scheme 1.2a. Beside the psychoactive ingredient, THC cartridges sold on the black market usually contain cutting agents to dilute the THC concentrates; these cutting agents generally have similar viscosity to the THC concentrates to make the mixture appear pure. Since THC is hydrophobic, i.e., not dissolved in water, the typical cutting agents include squalane oil, medium chain triglyceride oil, vitamin E acetate , and triethyl citrate . The safety of these agents has not been fully accessed for vaping inhalation. The structures of these common cutting agents are shown in Scheme 1.2b.Since PG and VG are the main components in the conventional vaping e-liquid, the thermal degradation of PG and VG is important to the fundamental understanding of vaping chemistry. There is a long history of study for PG and VG chemistry. VG was successfully prepared by Scheele in 1779. It has been stated that thermal degradation might happen during the distillation process of VG, where acrolein was identified as the thermal degradation products of VG in 19th century. Subsequently, the American organic chemist John Ulric Nef provided an understanding of the dissociation reaction in the glycol-glycerin series. In the experiments of Nef, the VG sample was heated to 450 °C and carbon monoxide and hydrogen were identified in the collected gas. Furthermore, hydroxyacetone, formaldehyde, acetaldehyde, acrolein and a series of acetals were found in the fractionated residues.
Nef proposed that glycidol is formed at a relative low temperature, but at an elevated temperature, the glycidol will go through a tautomerization process to form hydroxyacetone or hydroxypropanal. Acrolein can be formed by the dehydration of hydroxypropanal, while hydroxyacetone is further decomposed into acetaldehyde and formaldehyde at the temperature studied by Nef. Hemiacetal and cyclic acetals can be formed by reaction of the thermal degradation carbonyl compounds with excess glycerol. For the thermal degradation of PG, Nef identified propionaldehyde in the fractionated residue. However, there was no acetone found in volatile fraction, which suggested that the propylene oxide may not form as an intermediate during the thermal degradation, or propionaldehyde is the main product fromtautomerization. Generally, Nef provided the fundamental knowledge for the current understanding of PG and VG chemistry. More research about the thermal degradation of PG and VG has been done recently. For example, Laino et al. showed that the thermal degradation of VG can form formaldehyde,acetaldehyde, and acrolein via the formation of glycidol, while PG can generate propionaldehyde and acetone via the intermediate formation of propylene oxide. Diaz et al. suggested PG could also participate in a heat-induced radical-mediated degradation pathway, proposed to be initiated by O2 insertion to C-H bonds to generate the OH radical that further propagates the radical chain, forming at least five products. The radical-mediated pathway of VG has also been proposed by other researchers, and at least seven thermal degradation products have been observed in the process. Some multifunctional degradation products can further react to form simple carbonyls, and accretion reactions between carbon-centered radicals or stable products can further complicate the chemistry of e-cigarette aerosols. The fragmentation of aliphatic alcohols tend to produce compounds that have a carbonyl moeity; however, because PG and VG are polyols, their degradation will also result in carbonyls functionalized with hydroxyl groups in addition to the simple types. Organic acid formation may also occur to a certain degree, possibly as a carbonyl oxidation process. The structures of potential thermal degradation products of PG and VG are shown in Scheme 1.3a. Nicotine may also go through a thermal degradation pathway to form potentially harmful constituents, such as N’-Nitrosonornicotine and the related tobacco constituent 4- -1–1-butanone . NNN and NNK have been regarded as important carcinogenic tobacco-specific nitrosamines , since they are known to induce carcinogenesis through DNA adduction and mutation, as well as to improve tumor growth through receptor-mediated effects. They are present in both the smoke of cigarettes and e-cigarette aerosols, as well as the saliva of tobacco and e-cigarette users. NNN can be formed endogenouslyfrom nornicotine, which is a tobacco constituent and nicotine metabolite. Bustamante et al. has quantified NNN in the saliva of e-cigarette users, ranging from non-quantifiable to 14.6 pg/mL, vertical cannabis while the NNN level in saliva of smokers range from non-quantifiable to 739 pg/mL. Although the total exposure of NNN in e-cigarette users is significantly lower than smokers, the NNN can still be formed through the use of e-cigarettes. Moreover, Farsalinos et al. found that NNK will not formed within the temperature range of e-cigarette operation. However, other research has found that 2.8 ng NNK can be delivered per 15 puffs, and is found in 89% of e-liquids from Korea.91 Moreover, N’-nitrosoanatabine and N’-nitrosoanabasine are also detected in eliquids.
They are classified in the Category 3 carcinogens, although the metabolic pathway of NAB has not yet been identified. 87 The structures of NNN, NNK, NAT and NAB and transformation pathways are shown in Scheme 1.3b.Compared to regular e-liquids, there is only very limited research data available for the thermal degradation of cannabis e-liquids, as marijuana are still federally classified as a Category 1 controlled substance by the US Drug Enforcement Administration and access to cannabis samples and analysis in research is greatly restricted. Research on e-liquid diluents or CBD-related vapes do not require a DEA license. Jiang et al. tested seven commonly used e-liquid diluents in an e-cigarette device with a THC-infused cartridge including PG, VG, medium-chain triglyceride oil, squalane oil, vitamin E, VEA, and triethyl citrate . The GC-MS spectra of unvaped e-liquids were compared to the vaping emissions to investigate the thermal degradation products during the vaping process. Generally, significant changes were observed in the GC-MS spectrum with vapingemission condensates compared to unvaped e-liquids, suggesting that the chemical composition of vaping products are very different from the original diluent. The thermal degradation products include carbonyls, alkyl alcohols, esters, carbonxylic acid, and alkanes. Specifically, the main thermal degradation products of MCT oil includes an ester that has the same molecular backbone and precursors in MCT oil, as well as carbonyl compounds generated from the chain breaking. The thermal degradation products of squalane include different alkanes and carbonyls from chain breaking. Alcohols were also identified as oxidation products, presumably through OH chemistry. Acetone, 3,7,11-Trimethyl-1-dodecanol and duroquinone have been found in the e-liquids containing vitamin E and VEA. Durohydroquinone was also identified from the thermal degradation of VEA. Multiple esters were identified from the thermal degradation of triethyl citrate. Moreover, Riordan-Short et al. found the decomposition of VEA could occur within the temperature range of e-cigarette use , even though its boiling point is approximately 485 °C. Most of thermal degradation products are aldehydes and ketones that may come from the oxidation of the aliphatic side-chain of VEA. Ketene , a toxic gas, has also been identified as a potential thermal degradation product of VEA. The structures of potential thermal degradation products of different diluents are shown in Scheme 1.4. The legalization of recreational cannabis use in several states, including California, have significantly increased the popularity of various consumption methods for cannabis extract in ecigarettes . The chemistry of the extracted THC or CBD oil related to dabbing or vaping is very limited due to the aforementioned research restrictions. Moreover, since the extracted cannabis oil is a complex mixture, the source of harmful or potentially harmful constituents in the vaping aerosol of extracted THC orCBD oil is not clear. These constituents may come from cannabinoids, terpenes, extraction solvents or other components that originate from either plants or chemical processing. Meehan-Atrach et al. identified the thermal degradation products of THC to include methacrolein, benzene, and methyl vinyl ketone when using cartridge vaporizer and dabbing. Moreover, four relatively abundant thermal degradation products including isoprene, 2-methyl-2- butene, 3-methylcrotonaldehyde, and 3-methyl-1-butene have been shown to be derived from the common radical intermediate of THC, as THC contains a monoterpene moiety and has been shown to emit similar volatile products to terpenes during the vaping process. Research has also been performed on the pyrolysis of CBD and olivetol derivatives with intact pentyl chains. 95 Terpenes and terpenoids are also present in cannabis extracts since they already exist in cannabis plants. Terpenes and terpenoids are also used as flavoring compounds in both cannabis and conventional vapes. Myrcene is the most abundant terpene in cannabis, followed by limonene,linalool, pinene, caryophyllene, and humulene, in addition to 68 other terpenes found in trace amounts. Monoterpenes, sesquiterpenes alcohols and triterpenes are of particular concern because of their relatively high presence and the potential formation of low molecular weight oxidized thermal degradation products. Tang et al. heated the mixture of 12 terpenoids that usually present in the cannabis extract and identified multiple degradation byproducts, including isoprene, 2,5-dihydroxytoluene, 6-MHO, benzene and some carbonyl products . Meehan-Atrash et al. also identified isoprene, methacrolein, benzene, methyl vinyl ketone and other potential thermal degradation products from myrcene, limonene and linalool. The structures of potential thermal degradation products of THC and representative terpenoids are shown in Scheme 1.5.Many sample collection and analytical methods have been applied for the detection and quantification of components in both the original e-liquid and the e-cigarette aerosol. The collection methods include filter pad collection , adsorbent cartridges, and gas collection bags.