E-liquids and aerosols from e-cigarettes contain intentionally added chemicals (referred to as ‘ingredients’). They also contain contaminants and reaction products from chemical reactions occurring during storage of the e-liquid or during heating to form aerosols (described in Sections 18.5.4.3 and 18.5.4.4).1,2
This section focusses on the types of chemicals added on purpose as ‘ingredients’ in e-cigarettes, some of which have toxicity concerns. The toxic chemicals found in e-cigarettes and their aerosols are discussed below in Section 18.5.4.4.
Chemicals in e-liquids include any of hundreds of different intentionally added ‘ingredients’ such as flavours, coolants and solvents (glycerol and propylene glycol) as well as nicotine. Contaminants and products of chemical reactions are also found in e-liquids. The chemicals discussed in this section include only those intentionally added.
Chemicals in e-cigarette aerosols include the chemicals from the e-liquids as well as new products produced by chemical reactions during heating of the e-liquid to form an aerosol.1 Most of the chemical content of the e-cigarette aerosols are ingredients, including glycerol, propylene glycol, water and nicotine, with roughly 3% of constituents being flavours, contaminants and reaction products.
The major classes of the chemical “ingredients” added to e-liquids are described here:
18.5.3.1 Nicotine, nicotine salts, synthetic nicotine and nicotine analogues
Nicotine
Nicotine is a common ingredient in e-liquids and e-cigarette aerosols. As described in Section 18.13.2, most e-liquids and e-cigarettes illegally sold in Australia contain nicotine even if is not included in the labelling. The amount of nicotine in e-cigarettes and e-liquids varies greatly, from none to over 134 mg/ml (13.4%).3 E-cigarettes confiscated from schools in Australia in 2023 contained a range of 16.5 to 63 mg/ml and average of 40 mg/ml (4%) nicotine. Most did not have accurate labelling of the nicotine concentration.4
Nicotine has a harsh bitter flavour, and is detected in the mouth by the taste buds of the gustatory system. Natural or artificial coolants are added to e-liquids to mask this bitter taste potentially increasing the amount of nicotine that is tolerated by the user.5
More information about the addictive effects of nicotine can be found in Chapter 6 and Section 18.4.2. The toxicity concerns of nicotine in e-cigarettes is described in Section 18.5.4.4.
Nicotine salts
E-cigarette devices known as pods and bars (which are usually large pods) (described in Section 18.1.1) often contain ‘nicotine salts’. This form of nicotine is protonated (has a proton added to one of the nitrogen atoms in the nicotine molecule) as opposed to the unprotonated ‘free-base’ nicotine used in the original e-cigarettes. Nicotine salts are made by combining acids such as benzoic acid or levulinic acid with the nicotine, lowering the pH (which increases acidity).6 It is thought that nicotine salts form a less harsh taste for the user, allowing for a much higher concentration of nicotine.7 There is evidence that nicotine salts deliver higher blood levels of nicotine for the same concentration of nicotine in the e-liquid.8 More information about different forms of nicotine is in Section 12.4.3.1.
Synthetic nicotine
Some e-cigarettes contain synthetic nicotine, which is made in chemical reactions rather than purified from tobacco plants. There is no evidence that synthetic nicotine is safer for users than natural nicotine, although some manufacturers make this claim.9 One study has found that synthetic nicotine solutions contain relatively high levels of organic solvent and phthalate residues, compared to tobacco-derived nicotine.10
See InDepth 18C.4.1.3 for more information about synthetic nicotine.
Nicotine analogues and other alkaloids
An analogue is a molecule that is very similar to but not identical to another. Nicotine analogues are molecules with very similar molecular structure to nicotine and therefore may bind to nicotine receptors, leading to similar physiological effects, including toxicity. See InDepth 18C.4.1.4 for more information about nicotine analogues. Nicotine analogues are likely being used in e-cigarettes to circumvent the regulation of products containing nicotine.11,12
A synthetic nicotine analogue called 6-methyl nicotine has been found in numerous e-cigarettes,11 including products sold in Australia.13 6-methyl nicotine is also known as metatine, imotine, hippotine, HYT and nixodine-S. The following is an example of marketing for this type of product:
‘Metatine is a synthetically derived molecule that is structurally similar to, but chemically different from, other vaping alkaloids. Although Metanine produces the same sensation as nicotine and may also be addictive, Metatine is not made or derived from tobacco or nicotine, and Metatine does not consist of or contain nicotine from any source.’
6-methyl nicotine binds to the same receptors on cells as nicotine.14,15 The relative toxicities of nicotine and 6-methyl nicotine have not been well established, but initial studies indicate similar, if not slightly greater toxicity of 6-methyl nicotine.16 When supplied by inhalation as an aerosol to rats, there were similar behavioural and physiological effects compared to those produced by nicotine, indicating a similar mechanism of action.17
Nicotinamide (also known as niacinamide, nixamide, or nixotin-free base) is a natural nicotine analogue with relatively low toxicity, but it does not bind to the nicotine receptor or produce similar physiological effects to nicotine.16 Some e-cigarettes are advertised as being ‘nicotine free’ and containing nicotinamide as an active ingredient. This advertising may be misleading, as samples of these e-cigarettes have been found to contain a mix of 6-methylnicotine and nicotinamide.11 The 6-methylnicotine is likely to be the active ingredient, which was undisclosed for the products in one study.18
Upon heating and aerosol formation of nicotinamide, it degrades into a chemical called 3-cyanopyridine, which is toxic at quite low doses.19 But no studies have been conducted on the health effects of using nicotinamide in e-cigarettes.
β-nicotyrine is an alkaloid (a basic (i.e. non-acidic) compound containing nitrogen atoms) that is found in tobacco and some e-cigarettes. It has some molecular similarities to nicotine. This chemical does not bind to nicotine receptors and is unlikely to be directly addictive. But it reduces the degradation of nicotine in the body, effectively increasing the presence of nicotine over time. This mechanism of action may increase the abuse potential of nicotine.20,21
18.5.3.2 Solvents
Solvents are liquids that are used to dissolve and carry other chemicals. The main solvents used in e-liquids are chemicals called propylene glycol and glycerol (vegetable glycerine), constituting most of the e-liquid and aerosol emissions produced by e-cigarettes.22-24 Changing the relative percent of these chemicals can change the user experience to a small extent.25 E-cigarette packaging and advertising for illicit products sold in Australia often refers to the ratio between these two solvents as the PG:VG ratio, indicating its importance to consumers.
Although these chemicals are considered safe for ingestion, heating leads to thermal degradation reactions of these solvents into toxic chemicals that may harm the lungs. Both propylene glycol and glycerol are designated by the US Food and Drug Administration (FDA) as harmful constituents of tobacco products. More information about toxicity concerns can be found in Section 18.5.4.4.26
18.5.3.3 Menthol and other coolants
Some natural and synthetic chemicals have a cooling effect on the mouth, throat and airways.5 These chemicals are used in tobacco products and e-cigarettes to enhance the user experience,27 most likely to mask the effects of strong tastes, such as nicotine. Coolants act by binding to specific cell-surface receptors, leading to a localised soothing/cool sensation. This cooling sensation is a type of chemesthesis; a detection of chemicals by the body that is separate from taste and smell.5 Menthol has long been used in cigarettes to mask the harsh taste of nicotine (see Section 12.7.2) and is also found in some e-cigarettes. Other natural coolants have also been found in e-cigarettes, such as carvone (from spearmint oil), menthyl lactate and menthone (from peppermint oil) and methyl lactate.1,28
Synthetic cooling agents that are used in foods, called WS-3 (N-ethyl-p-menthane-3-carboxamide) and WS-23 (2-Isopropyl-N,2,3-trimethylbutanamide), are commonly found in e-liquids.5,28 They may be collectively, or individually, referred to as “koolada”. These synthetic coolants are also sold in separate solutions that can be added to e-liquids that are custom-mixed by the user. They have been found in US e-cigarettes, in those labelled as mint- or menthol-flavoured as well as fruit- and candy-flavoured products. They are also found in popular disposable e-cigarette products.29 WS-23 has also been detected in e-cigarettes found in Australia, and at high levels in some e-liquids and disposable e-cigarettes.30 The long-term safety of frequent inhalation exposure to these coolants has not been determined.
18.5.3.4 Flavours and sweeteners
Most of the chemicals added to e-liquids are flavourants. These chemicals may be naturally occurring or synthetic. They are usually active at very low concentrations, due to the high sensitivity of the human body for detection of flavours. In a major report, 243 chemicals were identified that were considered ingredients added to e-cigarettes, and 237 of these were designated as flavourants.1 Individual flavouring chemicals are commonly detected at between 1 mg/ml and 10 mg/ml, but the highest (limonene) was found at over 70 mg/ml (7% by weight) in one report. Typical total proportion of flavourings in e-liquids constituted between 0.26% to 4.3% of the contents.31 Some of the flavourants in e-cigarettes have toxicity concerns, particularly as they can break down into toxic chemicals upon heating of the e-liquid, see Section 18.5.4.4.
Flavours are detected by the human body via specific interactions of these chemicals with cells in the mouth, nose or airways. The sense of taste involves chemicals binding to taste buds in the mouth, that can detect sweet, bitter, sour, umami (savoury) and salty chemicals. Menthol and other coolants are detected by chemesthesis, whereas nicotine is detected as a bitter taste in the mouth, which is often aversive. The nose contains hundreds of different cell surface receptors that detect flavour chemicals (sense of smell). Chemicals are also detected in the mouth and nose (any many other regions) by other receptors by chemesthesis. The integration of signals from taste in the mouth, sense of smell in the nose and chemesthesis in various regions of the body produces an overall flavour perception during e-cigarette use. Many different chemicals in e-cigarettes are likely to partially contribute to the overall flavour.1,5 One study predicted that, on average, e-liquids contained 10 different flavourants chemicals.32
Examples of flavourant chemicals found in e-cigarettes are cinnamaldehyde (cinnamon), diacetyl (buttery), vanillin (vanilla), limonene (lemon), eugenol (clove) and camphor (woody).1 A study of e-liquids sold in Europe found 219 unique chemicals identified as added flavourants. The most commonly detected flavourants were vanillin (artificial vanilla flavour) in 35% of e-liquids, ethyl maltol (sweet caramel flavour) in 32% and ethyl butyrate (fruity flavour) in 28% of e-liquids.32 The e-liquid flavour categories identified in this study were tobacco, menthol/mint, nuts, spices, coffee/tea, alcohol, other beverages, fruit-berries, fruit-citrus, fruit-tropical, fruit-other, dessert, candy, other sweets, other flavours and unflavoured.32
Animal exposure studies have shown that some flavourants can modulate e-cigarette/nicotine use and addiction effects. In mice, green apple and vanilla flavorants are able change the reward-related behaviours in the absence of nicotine.33 A flavourant called β-damascone, present in tobacco-flavoured e-cigarettes, can increase the consumption of nicotine in mice.34
Sweeteners are flavourants that impart a sweet taste. Natural sweeteners include glucose, sucrose and fructose, whereas artificial sweeteners include aspartame. A study of e-cigarettes sold in the US found the artificial sweetener neotame in 57 disposable e-cigarettes and products labelled as nicotine free, or containing nicotine analogues (see 18.5.3.1 above), but not in JUUL e-cigarettes or FDA-approved e-cigarettes.35 Another study has found the artificial sweetener sucralose present in 45% of e-liquids sampled.36 See Section 18.5.4 for toxicity concerns for sweeteners used in e-cigarettes.
18.5.3.5 Other drugs and bioactive molecules
A survey study detailed peoples’ reports of exposure to a variety of different drugs in e-cigarettes. These include amphetamines, caffeine, cannabinoids (chemicals from cannabis), fentanyl, ketamine, kratom (a herbal substance with opioid-like effects) and opiates.37,38 Etomidate (a hypnotic agent used in anaesthetics) and heroin have also been found in e-cigarettes.39,40 In addition, herbal substances and vitamins in e-cigarettes have also reported.37
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References
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