The urinary metabolic profile of diethylene glycol methyl ether and triethylene glycol methyl ether in Sprague-Dawley rats and the role of the metabolite methoxyacetic acid in their toxicity

• Published in: Regulatory toxicology and pharmacology Vol. 110; p. 104512
• Main Authors: Kelsey, Jeffrey R., Cnubben, Nicole H.P., Bogaards, Jan J.P., Braakman, René B.H., van Stee, Leo L.P., Smet, Karen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2020
• Subjects: 2-(2-(2-methoxyethoxy)ethoxy)ethanol; 2-(2-methoxyethoxy)ethanol; 2-Methoxyacetic acid; DEGME; Glycol ethers; Metabolism; TEGME; DEGME; Glycol ethers; 2-(2-methoxyethoxy)ethanol; 2-Methoxyacetic acid; Metabolism; 2-(2-(2-methoxyethoxy)ethoxy)ethanol; TEGME
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2019.104512

Ethylene glycol ethers are a well-known series of solvents and hydraulic fluids derived from the reaction of ethylene oxide and monoalcohols. Use of methanol as the alcohol results in a series of mono, di and triethylene glycol methyl ethers. The first in the series, monoethylene glycol methyl ether (EGME or 2-methoxyethanol) is well characterised and metabolises in vivo to methoxyacetic acid (MAA), a known reproductive toxicant. Metabolism data is not available for the di and triethylene glycol ethers (DEGME and TEGME respectively). This study evaluated the metabolism of these two substances in male rats following single oral gavage doses of 500, 1000 and 2000 mg/kg for DEGME and 1000 mg/kg for TEGME. As for EGME, the dominant metabolite of each was the acid metabolite derived by oxidation of the terminal hydroxyl group. Elimination of these metabolites was rapid, with half-lives <4 h for each one. Both substances were also found to produce small amounts of MAA (~0.5% for TEGME and ~1.1% for DEGME at doses of 1000 mg/kg) through cleavage of the ether groups in the molecules. These small amounts of MAA produced can explain the effects seen at high doses in reproductive studies using DEGME and TEGME. •The main route of metabolism of orally dosed DEGME and TEGME is via oxidation of the terminal hydroxyl group.•80–90% is metabolized via the above route with a minor amount (~0.5–1.1%) metabolized to MAA via cleavage of the ether group.•Total recovery of substrate and metabolites in urine is 96–103% hence all metabolites are excreted in urine.•Half-lives of all metabolites are in the range of 3–4 h, except MAA which is ~17 h at 1000 mg/kgbw dose.•The small amounts of MAA produced during metabolism explain reprotoxic effects seen at very high doses of DEGME and TEGME.