Physicochemical properties of PG
At room temperature, PG has the appearance of a slightly syrupy liquid. It is odourless, tasteless, and colourless. With the molecular formula C3H8O2, PG has a boiling point of 187°C, a melting point of -60°C, and a density of 1.036 kg/L at 20°C.
PG is a polar molecule, its negative and positive charges carried by the atoms are not distributed homogeneously. It is miscible in water and alcohol, but not in oils or very non-polar solvents (hexane, octane, etc.). Its high polarity enables it to solubilise many aromatic compounds (polar molecules such as: vanillin, maltol, etc.), which justifies its use as an aromatic substrate. However, it is an unsuitable substrate for flavours containing a high concentration of non-polar molecules such as terpenes (limonene, pinene, etc.).
Production process of PG
PG is derived from carbon chemistry and very generally from petrochemistry. It is synthesised by the hydration reaction of propylene oxide in an acid medium as shown in the following reaction
Chemical reaction enabling the production of propylene glycol [1]
This reaction takes place at 200°C under a pressure of 12 bar. It then produces a mixture of PG, dipropylene glycol (DiPG), tripropylene glycol (TriPG) and smaller quantities of longer-chain glycols. The mixture obtained is dehydrated by evaporation, then each of the glycols produced is purified by distillation.
It should be noted that research is currently ongoing to achieve organic synthesis. However, “organic” PG is an extrapolation as it does not actually exist in the natural state. It can only be obtained, in some cases, from organic raw materials.
Uses of propylene glycol
Many industrial sectors use PG for its diverse physicochemical properties, some examples of which are given below:
- The tobacco industry and the cosmetic industry use it as an antibacterial moistening agent to prevent premature dehydration of their products. Its hygroscopicity allows it to trap surrounding water molecules. In 2009, a study demonstrated that out of over 30,000 personal care products tested (shower gel, shampoo, cream, makeup, toothpaste, shaving foam, etc.), PG is detected in over 28% of cases (the concentration ranging from 0.0008 to 99%) [2].
- The agri-food industry uses it at low doses, as an emulsifier (E1520) and as a substrate for certain flavours or dyes.
- The aeronautical industry combines it with ethylene glycol to produce antifreeze, for aircraft heating/air conditioning circuits. It is important to note that although PG is a constituent of antifreeze, it should not be confused with Ethylene Glycol (EG). These two molecules are extremely different, and unlike PG, EG is considered toxic for humans. Moreover, there are records of cases of poisoning or even mortality due to the ingestion of EG [34] (voluntary or not), whereas no severe cases have been observed following the intake of high doses of PG.
- The pharmaceutical industry uses it as a substrate for some active substances. For example, PG is found in sprays (nasal, oral) and in some medicinal products injected intravenously [3, 4].
- The entertainment industry uses it as an aerosol to simulate natural smoke.
- Finally, it is used in the vaping industry as a flavour substrate and diluent for e-liquids.
Metabolisation of propylen
The metabolisation of a molecule by a body is defined by the sequence of chemical reactions that the compound undergoes after uptake for its utilisation or elimination.
PG is absorbed by the body via ingestion, inhalation or injection (subcutaneous and intravenous). It is essentially metabolised in the liver and, to a lesser degree, in the kidneys. It is then converted into lactic acid and into pyruvic acid. These elements, naturally present in the body, are required to produce the energy that the body needs (Krebs cycle). In a healthy adult, most PG is metabolised or excreted by the body 2 to 4 hours after uptake. 12 to 45% of non-metabolised PG is excreted in urine [5-7].
N.B.:
PG is mostly derived from petrochemistry. It is used in many industrial fields due to its diverse chemical properties and particularly its relative safety. It has become an inescapable part of your everyday life: from toothpaste to paint, and including food and medicinal products, we consume it on a daily basis without realising it.
Toxicology
In the scientific literature, no deaths involving overexposure to PG have been reported. As a food additive, it is considered low-toxicity, as demonstrated by its FDA classification as a “GRAS substance” (Generally Recognised As Safe). The authority specifies that there is no reason to suspect a hazard for the population in the case of PG intake in view of the quantities consumed [8].
Based on a precautionary principle, the World Health Organization (WHO) has set the recommended maximum daily intake dose at 25 mg/kg. For an individual weighing 70 kg, this represents approximately 1.7 g of PG/day. However, studies using much higher doses have not shown any irreversible adverse side-effects.
Nevertheless, repeated daily exposure to a high quantity of PG over a period of several months can result in kidney failure or lactic acidosis [5, 7,10]. The latter is actually triggered by excess lactic acid (metabolisation product) in the body, inducing an acid-base balance disorder. The symptoms associated with lactic acidosis are not specific and are essentially characterised by diffuse chest or abdominal pain, nausea, or respiratory problems. Similarly, some subjects appear to be prone to side-effects. Liver diseases or specific treatments (medicinal product on PG substrate) appear to accentuate the accumulation of PG and hence of lactic and pyruvic acid [11]. However, in most cases, the patients tested returned to normal once the intake of PG was discontinued [12]. Repeated overexposure could also have an effect on the central nervous system [34].
It should be noted that these effects are only observable in the context of scientific studies where the subjects were exposed to very high concentrations of PG, which are therefore well above the recommended amounts. These doses are in no way comparable to those found in agri-food or vaping type products. By way of comparison, a vaper inhaling 5 ml of an e-liquid containing 50% PG is exposed to 2.5 g of PG/day. As Paracelsus said in 1537, “the dose makes the poison”.
All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison – Sieben defensiones (1537) by Paracelsus
Oral administration
No studies mention a lethal oral dose of PG in humans [16]. In rare cases of non-lethal overexposure, the toxicity of PG has not been clinically demonstrated. Studies relating to effects of PG administered by gavage on different types of animals note few side-effects (a decrease in activity can be detected) [13-15].
The intake of extreme quantities of PG would cause nervous system disturbances (intake of 228 mg/kg/day for 13 months) [38]. Similarly, excess lactic acid, due to the effects of metabolising an excessively high repeated dose of PG, would induce lactic acidosis.
An overdose can also result in osmotic deregulation (cell dehydration) and induce cardiac toxicity [17, 18].
Administration by inhalation
The scientific literature includes studies on the toxicological effects of inhaling PG conducted on animals and humans.
On animals, mention can be made of two studies in which PG vapours were inhaled by primates and rats daily, for several months [19,20]. Some non-serious side-effects were observed such as: weight loss or gain, nose bleeds, slight drop in white blood cell count, etc. The post-mortem examination of the animals showed no organ damage. A similar but more recent experiment showed similar findings [39].
Human trials are rarer. Mention can nonetheless be made of one study [21] relating to 93 patients suffering from chronic respiratory disorders. For 15 minutes and using a breathing mask, the subjects inhaled an aerosol obtained from a 40% PG solution. The authors of this study report that the patients tolerated the inhalation of the aerosol, without any side-effects being reported during the test and in the following days. These researchers even recommend the use of PG as a “vehicle” for administering bronchodilator aerosol drugs.
It is therefore clear that, when inhaled, PG does not exhibit any toxicity for any organs, including the lungs. The only adverse effect observed is irritation of the respiratory tract following repeated exposures. This phenomenon would only apply to some of the population, demonstrating its subjectivity.
Administration through skin contact
PG is used in the composition of numerous pharmaceutical and cosmetic products intended to be applied on the skin. There are currently a large number of studies available on these effects due to skin contact.
In the majority, the authors find that PG can trigger a reaction on the treated area in some subjects. Several skin sensitisation or irritation tests have been conducted using deodorant containing high doses of PG (up to 86%). In these different studies, only a few cases experienced a visible irritation reaction [22-24].
Similarly, a study conducted on 886 subjects placed in contact with pure PG in patch form (no data on exposure frequency) shows that 16% of the subjects displayed signs of irritation [25]. Of these 16%, 65% of subjects report having regular skin problems, reducing the causal relationship between the irritant reaction and PG exposure. Irritation phenomena induced by PG exposure therefore appear to be linked with the individual’s physiology and do not appear to follow a pattern applicable to the entire population.
Moreover, a review based on studying over 45,000 subjects liable to be allergic to PG (eczema reaction caused by the application of a patch containing 20% PG) finds that merely a tiny proportion of the population may have PG-related side-effects [26].
In 1991, Catanzaro J.M and Smith J.G [27] prepared a summary of the research relating to the impact of PG on the skin. In the studies listed, up to 12.5% of the subjects sensitive to PG were reported to have displayed an allergic reaction. Similarly, the higher the proportion of PG to which the study population is exposed, the greater the increase in the percentage of individuals sensitive to irritation from PG. This demonstrates the concept of a “threshold” below which no irritant response would occur. This threshold appears to be specific to the individual, underlining the subjective nature of the response to PG exposure.
On balance, the literature is contradictory on the irritant or allergenic nature of this sensitisation. The question is still open, but a majority of studies would classify PG as a moderate skin irritant.
Intravenous administration
Cases of intravenous (IV) overexposure to PG. In some cases, researchers have observed kidney dysfunction following IV injection of more than 90 g of PG [28] per day. The patients’ condition improved after treatment was discontinued. Studies on the administration of large IV doses of PG show that the side-effects (metabolic disorders) are temporary (return to normal after 24 to 72 hours after discontinuing treatment) [4, 5, 29].
Although few studies are available on PG inhalation in humans, a large number of studies have been conducted on these effects with other modes of administration. In this research, the doses received through ingestion, skin contact, or intravenously are very high, and none caused irreversible effects. The side-effects observed are due to exposure to very high doses of PG. It should be noted that, with a personal vaping device, it is impossible to reach such an exposure level.
Propylene glycol in vaping (e-cigarettes)
Role in e-liquid
PG is a constituent of the diluent matrix used in the majority of commercial e-liquids. Historically, it is also the main ingredient of e-liquids. Tested and approved by the pharmaceutical industry as a vehicle for bronchodilator active substances (e.g. Ventolin), it would appear to be the ideal base for e-liquids due to its physicochemical properties:
It evaporates at a relatively low temperature. In the gaseous state, it is condensed into fine droplets (generally in the presence of an air flow), trapping some of the adjacent molecules (i.e. nicotine, aromatic compounds, water, etc.). This rapid effect produces an aerosol which visually imitates smoke.
The liquid particles or “droplets” of PG forming the aerosol serve to diffuse the other molecules trapped inside. Owing to their size, these PG particles (from 0.1 μm to 2 μm [30]) penetrate deep within the respiratory tract [31], thus ensuring almost optimal delivery and absorption of the nicotine contained inside.
Its low viscosity is beneficial when using a personal vaping device (PV). Indeed, when the e-liquid is vaporised, the wick found at the core of the resistance coils can dry out locally (at the PV heating element). If rehydration is too slow, an overheating phenomenon can occur, inducing an unpleasant olfactory and taste sensation known as a “dry hit”. With a low viscosity (and therefore good capillarity), PG limits local drying of the wick and therefore reduces the dry hit risk.
Its chemical properties enable it to solubilise nicotine perfectly as well as numerous aromatic compounds contained in the flavours used for manufacturing e-liquids. Its thermal stability means that it is not subject to significant degradation when the e-liquid is vaporised (under normal conditions of use). The few toxic compounds generated by its degradation (essentially from the aldehyde family) are present at much lower levels than in tobacco smoke (table 1) [40].
Comparison of VOCs (Volatile Organic Compounds) and carbonyls (including aldehydes) detected in e-liquid vapour (50 x 4-s puffs) versus in tobacco smoke (1 cigarette, 2-s puff) [40]
The role of PG in the “throat hit” phenomenon is more hypothetical. Smokers seek this laryngeal contraction which is caused by the response of the trigeminal nerve [32, 33] to an irritant or painful sensation. Nicotine causes this phenomenon. A number of suppositions can be made on the role of PG: as it is slightly irritant, it could promote the contraction sensation. In addition, due to its physicochemical properties, PG is more fluid and evaporates more readily (at lower temperature) than vegetable glycerin (VG) which is another substrate commonly used by the vaping industry. As such, for the same set-up (same equipment, same vaping behaviour), the intake of an e-liquid containing 100% PG will be approximately two times greater than an e-liquid containing 100% VG (figure 1, tests conducted at LFEL [41]). As such, higher e-liquid intake naturally induces higher nicotine intake, which increases throat irritation and therefore the throat hit.
Figure 2: Variation of e-liquid intake according to proportion of PG (in volume) in e-liquid (The procedures are conducted on CUBIS at 1 Ohm, 15 W, 1.1L/min, on 100 x 3-second puffs).
Limitations and recommendations for use of PG
One of the main limitations in respect of the use of PG as a constituent of the diluent substrate of an e-liquid pertains to its irritant nature. Indeed, it can be difficult to inhale for highly sensitive or intolerant subjects: feeling of discomfort at the back of the throat, potentially strong irritation in the respiratory tract, violent and recurrent coughing. In this specific case, the only solution appears to be that of doing away with PG consumption completely by removing it from the e-liquid composition.
PG-sensitive users, without being intolerant, need to find a balance in the composition of the diluent matrix of the e-liquid. PG can be irritant from a certain threshold – therefore, vapers are advised to test several concentration levels until they find the dosage that suits them.
There is no “ideal” chemical diluent matrix composition. The vaper’s physiology and the subjectivity of the sensations perceived require case-by-case adaptation based on criteria that they see as important: enjoyment, risks of toxic species production, perception of flavours, sensitivity/insensitivity to PG irritation, nicotine delivery, etc. It is key that each user finds the dosage that suits them to help them quit tobacco use.
It should be noted that, in the case of heavy vaping associated with high PG intake, the hygroscopicity of PG can cause dehydration problems such as mucosal dryness or a dry mouth sensation. For this reason, it is recommended to stay well hydrated not only while vaping, but also afterwards.
Similarly, as PG is metabolised in the body into lactic acid (as seen above), excessive intake can promote the onset of more intense cramps or muscle aches than usual following a high level of physical exertion.
Note: PG is frequently used as a diluent substrate for certain flavours used in e-liquid design. The use of these flavours introduces a non-negligible quantity of PG into the final e-liquid composition (up to 20% PG in the final e-liquid volume). Its presence as a flavour substrate is not often mentioned on e-liquid brands labels, possibly for trade secrecy reasons. Nevertheless, subjects who react to PG can access this information by consulting the product MSDS or by requesting the information from the manufacturer itself.
Available alternatives to the use of propylene glycol
Glycerol or vegetable glycerin (VG)
The main alternative compound to PG for use as a substrate for an e-liquid diluent matrix is 1,2,3-propanetriol, more commonly known as vegetable glycerin (VG).
During vaping, VG turns into a thick, dense vapour. It has a slightly sweet taste, which masks the perception of the aromatic compounds contained in the e-liquid.
VG has a higher boiling point than that of PG (290°C). As a result, the higher the proportion of VG in an e-liquid, the higher the temperature required for it to evaporate. It is worth noting that raising the temperature of an e-liquid while vaping can promote the production of degradation elements. For this reason, vapour emissions analysis is a key concern for the future of vaping. One of LFEL’s aims is to understand this phenomenon in order to measure its effects.
VG is also around 30 times more viscous than PG. As such, it will have more difficulty impregnating a personal vaping device wick than PG. Therefore, there is a greater risk of local drying. To make up for this, it is necessary to wait for the e-liquid to re-impregnate the device correctly and wait a few seconds between two puffs. Vapers can also choose to adapt their device using resistance coils and wicks suitable for viscous substances. For example, silica wicks are more suitable than cotton wicks for high-viscosity liquids.
1,3-propanediol
1,3-propanediol is the enantiomer of 1,2-propanediol (PG); these two compounds have the same molecular formula (they are formed from the same atoms) but have different molecular structures.
More commonly known as “vegetol” in the vaping world, 1,3-propanediol has intermediate physicochemical properties between those of PG and VG. It has a boiling point of 215°C (PG: 188°C and VG: 290°C).
Furthermore, it is a polar molecule which is therefore capable of solubilising almost all of the components found in e-liquids. It seems to represent a suitable vector both in terms of nicotine delivery and e-liquid flavour perception.
Based on a bibliographic search, there are very few studies available on the toxicity of vegetol due to inhalation. However, a publication dating from 2005 (relating to a study [35] on inhalation) reports that subjects having inhaled 1.8 g of vegetol, 6 hours/day over a 10-day period, showed no irreversible side-effects.
In the light of this single study, vegetol might appear to be suitable for use in inhalation. It is thermally stable (it is used in polyester production) [36,37] and its thermal degradation only occurs above 200°C. When evaporated, it forms an aerosol similar to that obtained with PG.
PG has physicochemical properties which make it the ideal substrate for the diffusion of compounds such as nicotine or aromatic compounds. It helps deliver nicotine by promoting laryngeal contraction (throat hit) while observing the aromatic balance of the e-liquid. However, some subjects can have a reaction to PG or are intolerant. In this case, it should be replaced by VG or vegetol which have similar physicochemical properties to those of PG. Due to the subjective nature of the sensations sought by vapers, there is no perfect or universal diluent matrix composition. It is up to e-liquid consumers to test several substrates and dosages (PG, VG, vegetol) in order to find the mixture that suits them best.
Conclusion
Propylene glycol has been used in many everyday products for a very long time. Although few studies relating to PG inhalation in humans in the context of vaping-related use are available, there are many studies on other modes of administration. In some cases, the injected doses (90 g / day) are considerably higher than those potentially inhaled daily by a PV user. Despite the quantities used in these studies, few side-effects, none of which were irreversible, have been observed. In the context of its use by the vaping industry, PG has a number of qualities that make it an excellent substrate for e-liquids:
- it is non-toxic,
- in the gaseous state, it condenses into fine particles to form an effective aerosol,
- it is a good substrate for nicotine and for flavours,
- in the light of European Chemicals Agency (ECHA) guidelines, PG is not considered as a respiratory irritant, even if intolerances are sometimes observed,
- its low viscosity enables good wick hydration and therefore easier vaporisation.
It is important that the consumer finds the mixture that enables them to quit tobacco use for good. Whether it is based on PG and/or VG and/or vegetol, the composition of an e-liquid will be governed by the vaper’s requirements with regard to their criteria such as tolerance to PG, the density and amount of vapour sought, throat hit intensity, or aromatic flavour perception.
The composition of an e-liquid diluent base can therefore be considered as a subjective parameter to be adapted to each user. It is nonetheless advised to adapt your behaviour and device to the characteristics of the e-liquid used so as to prevent the production of toxic degradation elements in vapour emissions. This topic is one of the key challenges for the future of vaping, and has been studied by the team of scientists at LFEL since 2014.