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An in vivo study was carried out to determine the toxicokinetic parameters of propylene glycol ethyl ether acetate following intravenous dosing to male Sprague-Dawley rats and its metabolite propylene glycol ethyl ether. In addition, the toxicokinetic parameters of propylene glycol ethyl ether were determined. The test substance was dosed iv at dose levels of 10 and 100 mg.kg-1 body weight with analysis of the blood samples by GC-MS analysis using a method developed and validated in terms of selectivity, calibration, accuracy/recovery, repeatability and limit of quantification. The PGEEA data in blood showed a rapid decline. The half-life of the resultant metabolite PGEE in blood for the low and high dose group was ~21 and 47 minutes, respectively in the low and high dose animals. This can be compared to the rate of elimination of PGME when injected intravenously to rats at dose of 10 and 100 mg/kg . Blood samples were collected up to 12 hours post exposure to determine kinetic parameters. PGMA was also tested with the same experimental procedures in order to determine kinetic differences between the two substances. Half lives of blood PGME were 10.36 and 38.62 min for the low and high dose respectively.

General considerations related to the metabolism of glycol ethers are well documented (Casarett & Doull’s Toxicology, 2001; ECETOC Technical Report).  Glycol ethers follow two main oxidative pathways of metabolism, either via alcohol dehydrogenase (ADH) or the microsomal CYP mixed function oxidase (MFO) (O‑demethylation or O‑dealkylation). The first pathway gives rise to the formation and excretion of alkoxyacetic acids. The second mainly leads to the production and exhalation of carbon dioxide (CO2) via ethylene glycol (MEG) or propylene glycol, which enter intermediary metabolism via the tricarboxylic acid (TCA) cycle.  Glycol ethers may also be conjugated with glucuronide or sulfate, but this is thought to occur mainly after saturation of the other metabolic pathways.

According to their pathways of metabolism, the glycol ethers may be divided into three groups:

·        ethylene glycol mono- and di-alkyl ethers and their acetates;

·        diethylene glycol mono- and di-alkyl ethers and their acetates;

·        propylene glycol ethers.

Monoethylene glycol ethers bearing a primary OH-group (alkoxyethanols) are primary alcohols that are oxidised via ADH and aldehyde dehydrogenase (ALDH) to their corresponding alkoxyacetic acids. Monopropylene glycol mono-alkyl ethers with a primary OH function (n-alkoxypropanols) follow similar pathways yielding alkoxypropionic acid.  In addition to ADH-mediated oxidation of glycol ethers bearing a primary alcohol function, microsomal oxidation (catalysed by CYP MFO: O-demethylation or O-dealkylation) may also occur, but this pathway has relatively lower capacity.

Monopropylene glycol mono-alkyl ethers etherified at the primary carbon (sec-alkoxypropanols) are secondary alcohols that cannot be metabolised to alkoxypropionic acids. These compounds are either renally excreted after conjugation or, to some extent may form ketones that may enter the intermediary metabolism via the TCA cycle and eventually expired as CO2.  Monopropylene glycol mono-alkyl ethers etherified at the seconday carbon (n‑alkoxypropanols) are primary alcohols, that can be oxidised via ADH to their corresponding alkoxypropionic acids.

The metabolism of glycol ethers is considered a pre-requisite for their systemic toxicity, as the alkoxyacetic acids and perhaps their acetaldehyde precursors are regarded as the ultimate toxicants.  Evidence of this comes from: protection of toxicity afforded by inhibition of alcohol and aldehyde dehydrogenases; similar toxicity profiles of ethylene glycol ethers and their alkoxyacetic acid metabolites; and the differential toxicities of those glycol ethers metabolized via the oxidative and O-dealkylase pathways (Miller et al, 1984; Ghanayem et al, 1987).

The toxicity of the propylene glycol ethers with the alkoxy group at the primary position is quite different from that of the ethylene glycol ethers, presumably because these propylene glycol ethers are not metabolised to their corresponding alkoxypropionic acids.  Miller et al (1984) reported remarkable differences in the toxicological properties of ethylene glycol monomethyl ether (EGME, 2-methoxyethanol, a primary alcohol), and propylene glycol monomethyl ether (PGME, 1-methoxy-2-propanol, a secondary alcohol).  The differences in toxicity were attributed to differences in metabolism, characterized by EGME being primarily oxidized to methoxyacetic acid, and PGME undergoing O-demethylation to form propylene glycol. In the case of propylene glycol methyl ether, developmental effects have been reported when the primary position is occupied by a hydroxyl group.

There is no information available on the metabolism of ethoxypropoxypropanol (DPGEE) but the closely related substance methoxypropoxypropanol (dipropylene glycol methyl ether – DPGME) has been studied and results from this can be extrapolated. In this case, the metabolic routes for the main isomer (secondary/secondary) were followed (equivalent to 85% of the DPGEE composition). Three main metabolic routes were identified for DPGME. Microsomal O-dealkylation is a significant route of biotransformation since dipropylene glycol (DPG) is observed in the urine. This in turn is believed to enter into intermediate metabolism, as does PG. The second major route of biotransformation is hydrolysis of the ether linkage to form s-PGME secondary propylene glycol methyl ether) and propylene glycol (PG). The metabolites seen are consistent with the s-PGME formed metabolising as indicated by the study with s-PGME itself, that is primarily to PG. Rates of elimination of metabolites were consistent between studies. Due to overlapping peaks in the gas chromatogram in the reported study, it was not possible to quantify these two routes. However, the data on s-PGME alone suggests that the major route of metabolism will be to PG and therefore that the unresolved peak is substantially DPG.The third and least important route of elimination is conjugation with sulphate and glucuronic acid followed by urinary excretion. The overlap in the metabolic paths between the mono and dipropylene glycols indicates that data from dipropylene glycol ethyl ether would be suitable for read across to predict the toxicity of propylene glycol ethyl ether.

Casarett & Doull’s Toxicology.  Edited by Custis D. Klaassen.  6th Edition (2001).  Pp 898-899.  McGraw-Hill Companies, Inc.

Miller RR, Hermann EA, Young JT, et al. (1984) Ethylene glycol monomethyl ether and propylene glycol monomethyl ether: Metabolism, disposition, and subchronic inhalation toxicity studies.  Environ Health Perspect 57:233-39.

Ghanayem BI, Burka LT, Matthews HB. (1987) Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: Role of alcohol and aldehyde dehydrogenases. J Pharmacol Exp Ther 242:222-31.

Domoradzki JY, Brzak KA, Thornton CM. (2003) Hydrolysis kinetics of propylene glycol monomethyl ether acetate in rats in vivo and in rat and human tissues in vitro. Toxicol Sci 75:31-39.

Stott WT and McKenna MJ. (1985) Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fundam Appl Toxicol 5:399-404.

Discussion on absorption rate:

Dermal Absorption is an important exposure route for glycol ethers.  Dugard et al (1984) studied the absorption of eight glycol ethers through human skin in vitro.  2-methoxyethanol was most readily absorbed (mean steady rate of 2.82 mg/cm2/hr), followed by 1-methoxypropan-2-ol (1.17 mg/cm2/hr).  There was a trend of reducing absorption rate with increasing molecular weight for monoethylene glycol ethers (2-methoxyethanol, 2.82 mg/cm2/hr; 2-ethoxyethanol, 0.796 mg/cm2/hr; 2-butoxyethanol, 0.198 mg/cm2/hr).  The rate of absorption of 2-ethoxyethanol was similar to that of the parent acetate.

Sumner (1999) studied the blood pharmacokinetics of 1-methoxypropan-2-ol in male rats following a single 6-hour dermal exposure and compared results to those obtained in a similar experiment of the parent acetate.  The efficiency of dermal absorption for the parent acetate was found to be approximately 30% of that for 1-methoxypropan-2-ol.

Dermal uptake studies of 1-methoxypropan-2-ol vapour have also been conducted in human volunteers.  Brooke et al (1998) exposed subjects at rest to 100 ppm 1-methoxypropan-2-ol vapour with and without fresh-air fed half masks to compare skin-only and whole-body exposure, respectively, and measured uptake in blood, breath and urine samples.  Dermal uptake was calculated to be 9.6 ± 6.5% based on breath samples, 8.0 ± 5.7% based on blood samples, and 4.2 ± 1.7% based on urine samples.  In a similar study, Devanthéry et al, 2002 measured total and conjugated 1-methoxypropan-2-ol levels in urine, exhaled air, and blood of human volunteers exposed to 1-methoxypropan-2-ol vapour, with and without respiratory protection, at levels up to 95 ppm for 6 hours.  These investigators reported that 1-methoxypropan-2-ol was not detected in breath, blood or urine following dermal-only exposure.

The rate of dermal penetration of 1 -ethoxypropano-2 -ol liquid was examined in a separate study. The rate of flux of neat substance was quite high through human skin in vitro at ~1400 ±400ug/cm2/hr (similar to the level measured for ethanol) and increased by around 50% to around 2100±100ug/cm2/hr in the presence of water (50% aqueous solution).

Dugard PH, Walker M, Mawdsley SJ, and Scott RC. (1984) Absorption of some glycol ethers through human skin in vitro.  Environ Health Perspect 57:193-7.

Susan C.J. Sumner, Blood Pharmacokinetics of Propylene Glycol Methyl Ether (PGME) and Propylene Glycol Methyether Acetate (PGMEA) in Male F-344 Rats after Dermal Application, Final Report 98003 (1999)

Brooke I, Cocker J, Delic JI, Payne M, Jones K, Gregg NC, Dyne D. 1998. Dermal uptake of solvents from the vapour phase: an experimental study in humans. Ann Occup Hyg 42:531-540. 

Devanthéry A, Berode M, Droz PO. 2002. Propylene glycol monomethyl ether (PGME) occupational exposure 1, biomonitoring by analysis of PGME occupational exposure. Int Arch Environ Health 73:311-315.