Safety Data on Heated Vegetable Glycerin

MONQ uses USP (United States Pharmacopeia) grade vegetable-derived glycerin. Glycerin, also known as glycerol, is derived from plant or animal fats and is phosphorylated by glycerol-3-kinase to become glycerol-3-phosphate for entry into fatty acid metabolism.

Metabolism of glycerin occurs primarily in the liver (80%), but can occur in any cell as glycerol is a principle component of normal cell metabolism. The elimination of glycerin in humans follows zero order kinetics¹, and the plasma t_1/2 of glycerin is approximately 30 minutes (10min-50min)¹ in humans. Between 40-79% of glycerin is converted to glucose², with the remainder presumably transesterified into fat. The toxicity of glycerin is remarkably low across a broad range of animal models and in humans. Healthy humans tolerate doses of 2.2g/kg for 50 days with no observable adverse effects (NOEL)². The total amount of glycerin consumed in a typical consumer vaporization device is <1mg per puff^3–5. This represents a 1650-fold lesser amount than has been shown to be safe as the oral dose in humans, calculated from the following formula (2.2g/kg*75kg/person)/(100 puffs/day *.001g/puff). Because of the relatively low systemic exposure from vaporization devices, only the respiratory glycerin exposure will be considered for purposes of risk assessment.

Glycerin Vapor Inhalation:

Mechanics of Electronic Glycerin Vaporization Devices

In consumer vaporization devices, an 80% glycerin mixture is heated to a minimum of 132C⁶ at which point a combination of heat, negative pressure from inhalation, and turbulent airflow over the large surface area of wick filaments causes aerosolization and vaporization of the liquid. Exposure to glycerin vapor occurs primarily during inhalation and exhalation, which is called the “puff”, lasting between 1-3 seconds ^3,4. Between each puff, there is an inter-puff interval, that lasts between 15s-60s (mean=23s)^4,7 during which ambient air is inhaled that contains very little glycerin vapor relative to the concentration of the puff. This is due to simple gas diffusion mechanics and the relatively small volume of gas from the lung expanding into the vastly larger volume of the consumer’s environment. For the purposes of exposure calculations, only the concentration of glycerin vapor during the puff phase will be considered.

Animal Studies

Long term inhalation studies showed no evidence of toxicity 0.033mg/L and 0.165mg/L glycerol in rats⁸. Irritation was seen at 0.662mg/L of continuous glycerol vapor exposure for 6 hours per day⁸, which does not represent a feasible usage situation for humans^3,7.

Human Studies

The National Institute for Occupational Safety and Health (NIOSH) and the Occupational Health Safety and Health Administration (OSHA) have established a permissible exposure limit (PEL) for aerosolized glycerin (mist) of 10mg/m³ and 5mg/m³ for total exposure and respiratory exposure, respectively^6,7,9,10,11. For the purposes of assessing the relative risk of inhaled glycerin mist, the lower dose of 5mg/m³ will be considered. Importantly, the PEL of 5mg/m³ is a time weighted average (TWA) of exposure over an 8-hour workday. Researchers have shown that a recreational inhalant vaporization device can yield an acute glycerol concentration of 300-500mg/m³ from a single puff⁵ which superficially seems well above the NIOSH guidelines of 5mg/m³ . However, the exposure in a consumer vaporization device is mostly limited to the 1-3 seconds duration of each puff⁵ followed by a 15-60 sec (mean=23 sec) interval³, in which the glycerin concentration decreases immediately upon respiration. Because of the puff/inter-puff interval, 1 hour of continuous use of a typical vaporization device would result in less than 180 seconds of cumulative exposure. As a comparison , the workday used for NIOSH calculations^10,11 is 28,800s (8hr) which is 160X the total exposure time (180s) in hour of continuous use. The time component of exposure is critical in accurately assessing exposure risk from inhaled glycerol.

Glycerin Exposure in MONQ

We adapted a simplified AUC model for total exposure (mg*s/l) to be more appropriate for aerosolized exposure and compensated for continuous (PEL) vs intermittent exposure (vaporizer use) assuming an immediate clearance upon exhalation.

Each puff of a MONQ yields an estimated 3-4mg glycerin based on: 800mg/device/200-300 puffs/device. The time of exposure is approximated at 1 sec exposure, with a 23 sec inter-puff interval, based on published models^3,4. The volume of the sinuses, pharynx and upper trachea are estimated at 50 mL and will be used for exposure calculations.

	dose (mg)	exposure time (min)	volume (m3)	mg*s/m3	fold exposure vs MONQ usage	Adverse event
MONQ recommended (10 puffs/day)	4	0.16667	0.0002	3333.4	1	none
MONQ high usage (50 puffs/day)	4	0.83335	0.0002	166670	5	none
Kienhaus et al	400	60	1	24000	7.199856	NA
NIOSH REL	10	28800	1	288000	86.39827	Cough
Renne et al low dose	0.033	21600	0.001	712800	213.8357	NOEL*
Renne et al. highest dose	0.66	21600	0.001	14256000	4276.714	Inflammation

 

Propylene Glycol vs Glycerin:

Due to its lower boiling point and viscosity, and different solvent properties, propylene glycol is often mixed with glycerin in liquid blends intended for inhalation. However, in relation to glycerin, the safety profile of propylene glycol is less well established. Propylene glycol is known to cause irritation at high doses, but has not been shown to cause damage at low doses. It has also been noted that heating of propylene glycol can result in the production of formaldehyde and acetaldehyde.

Thermal Considerations and Carbonyls

The heating of glycerol has been shown to generate a wide range of carbonyl compounds, including formaldehyde, acrolein, and acetaldehyde. This process seems to be limited to temperatures in excess of 250C and high wattage in the context of ecig devices, where most of the current research has been done. MONQ uses a similar technology to aerosolize an 80% glycerin solution, with a 3.7V battery and a 2.5-3 ohm coil. Using Voltage²/resistance, the power output of the MONQ device is estimated at 4.5-5.4 watts.

Multiple studies have shown that no detectable amounts of carbonyls are produced from glycerin aerosolization at low power (5w) settings^3,6. Using experimental values from Kienhuis⁵ which showed a time of exposure calculations from Fig 1, we estimated the total carbonyl exposure (mg*s/m³).

Based on the routine safe use of glycerin in food and pharmaceuticals and on the published literature of inhalation of vaporized polyol carriers, the routine use of MONQ represents a risk that is 86-fold lower than NIOSH recommended exposure limits⁷ for irritation, and 200 fold lower than the NOEL in rodent experiments.

 Sources:

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4. Behar, R. R. Z. et al. Puffing topography and nicotine intake of electronic cigarette users. PLoS One 10, e0117222 (2015).

5. Kienhuis, A. S. et al. Potential harmful health effects of inhaling nicotine-free shisha-pen vapor: a chemical risk assessment of the main components propylene glycol and glycerol. Tob. Induc. Dis. 13, 15 (2015).

6. 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. Int. J. Hyg. Environ. Health (2016). doi:10.1016/j.ijheh.2016.01.004

7. Farsalinos, K. E. & Baeyens, F. Harmful effects from one puff of shisha-pen vapor: methodological and interpretational problems in the risk assessment analysis. Tob. Induc. Dis. 14, 22 (2016).

8. Renne, R. A. et al. 2-Week and 13-Week Inhalation Studies of Aerosolized Glycerol in Rats. Inhal. Toxicol. 4, 95–111 (1992).

9. Hebbinghaus, H. et al. Gefahrstoffe- Reinhaltung der Luft. Gefahrstoffe- Reinhaltung der Luft 7–8, 299–307 (2014).

10. OSHA PEL Airborne Contaminant Calculation.

11. Eller, P. M. NIOSH manual of analytical methods. DIANE Publishing (1994).