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Abstract
Introduction
Prohibited and High-Risk Substances
Regulatory Limits on Toxic and Harmful Substances in Various Countries
Table 1: Limits for Common Prohibited Substances in E-Cigarette Liquids
Summary and Outlook
In recent years, cases of Vape or vaping product use-associated lung injury (EVALI) have been increasingly reported. This review surveys and summarizes common toxic and harmful substances in Vapes, while compiling and discussing limit requirements from global regulations. The aim is to provide references for enterprises in developing reasonable lists for controlling prohibited and high-risk substances, thereby enhancing product safety and compliance.
Vapes have developed rapidly in recent years. Since the first report of EVALI in 2012, the number of cases has risen annually. Starting in 2019, the United States has seen frequent cases of acute lung injury due to Vape use, where inhaled Vape aerosol deposits in the distal small airways and alveoli, causing airway inflammation, reduced gas exchange, and eventual lung damage. A key factor is the use of prohibited or potentially toxic substances in Vapes. E-liquids have complex compositions with diverse additives; excessive or illegal additions of toxic components can severely harm users. Each incident of exceeding toxic substance limits can trigger industry-wide disruptions,warranting high attention from manufacturers.
Global regulations on prohibited and restricted substances in Vapes vary. The European Union's Tobacco Products Directive (TPD) is one of the earliest Vape regulations worldwide, transposed into national standards by member states, with the UK, France, and Germany having more comprehensive implementations that have influenced regulations globally. TPD prohibits substances such as: (1) vitamins or other additives implying health benefits or reduced risks in tobacco products; (2) caffeine, taurine, or other stimulants associated with energy and vitality; (3) color-emitting additives; (4) additives facilitating nicotine inhalation or absorption; and (5) substances with CMR (carcinogenic, mutagenic, reprotoxic) properties in unburned form. This article reviews common toxic and harmful substances in Vapes over the past decade, summarizes regulatory limits, and provides a basis for product development and quality standards.
[Note: The original text has a continuation here, but it aligns with the abstract's content. For clarity, the introduction is integrated above.]
Diacetyl, also known as 2,3-butanedione, imparts a buttery flavor and is commonly used in e-liquids for cake and cream profiles. Reports indicate that inhalation of such substances poses potential lung toxicity, possibly leading to obliterative bronchiolitis, or "popcorn lung." The American E-Liquid Manufacturing Standards Association (AEMSA) in its E-Liquid Manufacturing Standards (Version 2.3) and the British Vape Industry Association in PAS 54115:2015 explicitly classify diacetyl as a prohibited substance. China's national standard for Vapes lists it as a pollutant and impurity, with a limit not exceeding 22 mg/kg, aligning closely with France's XP D90-300-2:2021 standard (22 μg/mL).
2,3-Pentanedione is often used in chocolate and cream flavors and poses similar potential hazards in e-liquids; AEMSA recommends its removal from products. Acetyl propionyl, used for cream, dairy, and yogurt flavors, serves as a diacetyl substitute. Research by Yang et al. examined the stability of butanedione and acetyl propionyl in Vapes, finding butanedione less stable, with both decreasing over long-term storage—butanedione declining faster. In e-liquids containing acetyl propionyl, butanedione forms via oxidation. Diacetyl is among the most common prohibited substances in Vape regulations; enhanced oversight of pentanedione and acetyl propionyl is essential.
Pulegone is a major component in mint plant volatile oils, present in high amounts in natural mint essential oils. Classified by the World Health Organization as a Group 2B possible carcinogen, oral exposure may cause liver cancer, lung tissue deformation, and neoplasms in mice. The U.S. FDA removed pulegone from its food additive list in 2018. Duke University Medical Center researchers tested six pulegone-containing e-liquids and smokeless cigarettes, finding exposure limits of 325 to 6012 for e-liquids and 549 to 1646 for smokeless cigarettes, all posing carcinogenic risks. FDA stipulates that carcinogenic "exposure limits" (maximum non-carcinogenic dose divided by expected daily use) must not fall below 10,000; lower values indicate higher health risks. Pulegone is a high-risk component in mint-flavored Vapes, necessitating control of menthol flavors and finished product pulegone levels.
Tobacco-specific nitrosamines (TSNAs) are potent carcinogens, with eight reported types; N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanatabine (NAT), and N-nitrosoanabasine (NAB) are most studied. NNN and NNK are IARC Group 1 carcinogens, strong animal carcinogens, and included in the U.S. PMTA HPHCs list. Nicotine, typically extracted from tobacco plants, is the primary risk source for nitrosamine impurities in Vapes; tobacco extracts in tobacco flavors also introduce risks. Extensive studies report nitrosamines in e-liquids and aerosols; controlling them enhances product safety.
Carbonyl compounds are key regulated substances in EU TPD, U.S. PMTA, and China's Vape standard. Low-molecular-weight carbonyls irritate sensory and respiratory systems, particularly formaldehyde, acetaldehyde, acetone, acrolein, propionaldehyde, crotonaldehyde, 2-butanone, and butyraldehyde. Formaldehyde, acetaldehyde, and crotonaldehyde are IARC Groups 1, 2B, and 3 carcinogens, respectively; acrolein is on the U.S. EPA's hazardous air pollutants list. In Vapes, carbonyls originate from inferior flavors and relate to atomization temperature. Fan et al. found formaldehyde mainly from glycerol cracking, acetaldehyde from propylene glycol, and acrolein from glycerol dehydration at higher temperatures; release increases with device power. France's XP D90-300-2, UK's PAS 54115, and AEMSA standards prohibit adding formaldehyde, acetaldehyde, or acrolein to e-liquids.
Volatile organic compounds (VOCs) are volatile, harmful organics, with over 100 types; in Vapes, mainly benzene series like benzene, toluene, ethylbenzene, and xylenes. Long-term exposure causes headaches, dizziness, insomnia, memory loss, and blood disorders. Benzene, ethylbenzene, and xylenes have been detected in Vapes. VOCs easily enter as residual solvents, common in tobacco extracts; manufacturers must monitor benzene in nicotine raw materials.
Phenolic compounds include phenol, hydroquinone, cresol, and bisphenol A, with irritating odors and strong stimulation to skin and respiratory mucosa. Phenol is on FDA's 93 HPHCs list; hydroquinone irritates skin and respiratory systems; cresol mimics phenol's toxicity; bisphenol A, an endocrine disruptor, moderately irritates respiratory and digestive tracts. Cigarette smoke phenolics are well-studied; Luo et al. developed a UPLC-MS/MS method for eight phenolics in e-liquids and aerosols, finding low safety risks but guiding method development.
Eugenol methyl ether, or methyleugenol, extracted from plants like asarum, cinnamon, and clove, is in citronella oil and used in food flavors and tobacco. Its metabolites are reactive, with central inhibitory effects and anesthesia in animals, leading to strong toxicity. In 2018, FDA banned it from food additives; Germany's Tobacco Products Ordinance prohibits it.
Areca nut is the fourth most common psychoactive substance after caffeine, alcohol, and nicotine; arecoline is its key component. A parasympathomimetic alkaloid, it promotes saliva and sweat secretion, stimulates adrenal hormones, causing excitement and hallucinations during betel chewing. Adding arecoline to e-liquids heightens health risks. IARC classified areca nut as Group 1 carcinogen in 2003; many Western countries strictly control it, even as a drug, posing legal risks for e-liquid addition.
Diethylene glycol and ethylene glycol are required tests in TPD and PMTA; diethylene, ethylene, and triethylene glycols are mildly toxic solvents banned in cosmetics, drugs, and food, easily contaminating e-liquids. UK's PAS 54115 limits diethylene glycol to 0.1%. Methanol, a toxic residual solvent in flavors, harms nervous and blood systems. Ethanol, in "cola" flavors as a solvent, is volatile and flammable; high levels lower flash points, posing safety hazards in production/storage. Ethyl acetoacetate, for fruit flavors, decomposes to ethanol during storage, accelerated by nicotine; light avoidance and acidic flavors stabilize it. Islamic countries like Saudi Arabia prohibit alcohol due to religious beliefs, requiring ethanol-free e-liquids for Middle East exports to avoid risks.
Heavy metals like lead, arsenic, chromium, mercury, nickel, cadmium, and antimony are focal in Vape regulations; inhalation accumulates in organs, inactivating enzymes and causing chronic poisoning. E-liquids have low detection risks, but aerosols higher, linked to heating coils, ceramic cores, pod materials, and temperatures. Han et al.noted heating coils as nickel-chromium alloys, welds as copper-zinc, and connectors as nickel alloys. Fan et al.found nickel migration to aerosols (0.02-0.93 μg/200 puffs) and lead from copper-zinc impurities (0.01-1.30 mg/kg). France's standard references ICH inhalation limits for heavy metals.
EU TPD explicitly bans vitamins, caffeine, taurine, and colorants. Caffeine, addictive, was added in "energy" e-liquids like "electronic coffee," causing poisoning risks and regulatory bans. Vitamins and taurine imply "health" benefits, mimicking functional drinks but posing risks. Colorants, popular in big-cloud vaping for colorful smoke, create health hazards.
EU TPD prohibits CMR (carcinogenic, mutagenic, reprotoxic) substances per EU Regulation (EC) 1272/2008 (Categories 1A, 1B, 2) and STOT (specific target organ toxicity) Category 1 for respiratory effects. These pose significant health harms and should be banned. Notably, benzoic acid is STOT RE 1 (repeated exposure lung toxicity) per EU CLP, yet nicotine benzoate, a common salt, is allowed in many regulations despite controversy.
In 2012, FDA listed 93 HPHCs in tobacco and smoke, covering carcinogens, respiratory/cardiovascular/reproductive toxins, and addictives. PMTA requires HPHC reports for Vapes, including aldehydes, heavy metals, nitrosamines, benzenes, and ~30 others like benzo pyrene, increasing lung cancer risk. Controlling HPHCs reduces safety risks, considering tobacco and Vape traits.
Sweeteners boost fruit flavors in Vapes, including sucralose, neotame, acesulfame K, saccharin sodium, neohesperidin dihydrochalcone, stevioside, and advantame. China's standard allows only neotame at 10 mg/g. Many countries ban diabetes-risk sweeteners (glucose, fructose, lactose, sucrose); France prohibits acesulfame potassium, aspartame, saccharin sodium, sucralose; CEN's EN 17648:2022 bans sucralose.
Phthalates, common plasticizers, are viscous, low-volatility liquids with odors, insoluble in water but soluble in organics; environmental hormones disrupting endocrine and reproductive functions. As extractables/leachables in packaging they risk migrating from Vape mouthpieces, airways, and reservoirs.
PBBs and PBDEs, brominated flame retardants in electronics, cause acute/chronic toxicity to brain, liver, kidneys, nervous/endocrine/reproductive systems, with carcinogenic, teratogenic, mutagenic effects. Reports detected them in e-liquids; direct contact with components, especially under heat/storage, poses risks. Liu et al.analyzed 20 PBBs/PBDEs in e-liquids/aerosols via GC-MS, finding low risks, possibly due to materials, short heating, and low temperatures.
Benzaldehyde, with almond/cherry/nut aromas in oils like bitter almond/patchouli/hyacinth, is a top-note flavor in perfumes/food, permitted in GB 2760. High-purity acute exposure irritates eyes/respiratory mucosa; it's genotoxic and may convert to CMR at high temperatures. Cinnamaldehyde, with strong cinnamon aroma, has antibacterial/antiviral/antitumor effects, promoting GI motility; GB 2760/FDA/FEMA GRAS, with residues ≤0.3 mg/kg as preservative. Used in fruit e-liquids, they require PMTA/Australian testing due to respiratory irritation; limits reduce risks.
EU TPD and U.S. PMTA are major regulations specifying prohibited components and HPHCs. UK's post-Brexit TRPR mirrors TPD; Saudi Arabia expands to microbial limits; Australia sets benzaldehyde/cinnamaldehyde ≤10 ppm; New Zealand bans triclosan preservatives, formaldehyde releasers, and aspartame.
For some toxics, regulations ban active addition of diacetyl/diethylene glycol/aldehydes but allow unavoidable traces; limits are reasonable. Diacetyl in cream flavors, aldehydes in tobacco flavors, and pulegone in mint oils require monitoring. Common limited prohibited substances are in Table 1.
| Toxic and Harmful Substance | Limit Requirement | Regulatory Source |
|---|---|---|
| Diacetyl | ≤22 mg/kg | China |
| Diacetyl | ≤22 mg/L | France |
| Aldehydes | Formaldehyde ≤22 mg/L, Acetaldehyde ≤22 mg/L, Acrolein ≤200 mg/L | France |
| Aldehydes | Formaldehyde ≤10 ppm, Acetaldehyde ≤10 ppm, Acrolein ≤10 ppm | Australia |
| Heavy Metals | Pb ≤5 mg/L, As ≤2 mg/L, Cd ≤2 mg/L, Hg ≤1 mg/L, Ni ≤5 mg/L, Cr ≤1 mg/L, Sb ≤5 mg/L | France |
| Heavy Metals | Pb ≤0.5 μg/g, Cd ≤0.2 μg/g, As ≤0.2 μg/g, Hg ≤0.1 μg/g, Cr ≤0.3 μg/g, Ni ≤0.5 μg/g, Sn ≤6 μg/g, Cu ≤3 μg/g | Saudi Arabia |
| Heavy Metals | Pb ≤10 mg/kg, As ≤3 mg/kg | China |
| Diethylene Glycol, Ethylene Glycol | ≤0.1% | UK, Saudi Arabia |
| Nitrosamines | Total of 4 nitrosamines (NNN, NNK, NAB, NAT) ≤0.05 mg/kg | New Zealand |
| Eugenol Methyl Ether | ≤1 mg/kg | European Committee for Standardization |
| Pulegone | <20 mg/kg | European Committee for Standardization |
| Coumarin | ≤5 mg/kg | European Committee for Standardization |
| Benzaldehyde, Cinnamaldehyde | ≤10 mg/kg | Australia |
Vape prohibited substance regulations vary globally; products must comply with destination laws. China's mandatory standard lists 101 permitted additives, reducing risks but limiting flavors; abroad, blacklists of prohibited/restricted substances enhance safety. Vape toxicology research is limited and needs expansion; more studies may uncover additional toxics in e-liquids/aerosols.
(1) Establishing inhalation toxicology evaluation for flavors/additives/e-liquids for scientific safety assessment;
(2) Developing analytical methods for chemical components in e-liquids/aerosols, standardizing puffing regimes for accurate prohibited substance quantification;
(3) Incorporating GHS (Globally Harmonized System) for physical/health/environmental hazards beyond health, reducing risks in production/storage/transport/disposal;
(4) Regulators increasing sampling frequency from markets/warehouses; enterprises maintaining dynamic toxic substance lists, updating with regulations, new technologies/materials/products to minimize Vape hazards.
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