2-(2-ethoxyethoxy)ethanol

Endpoint summary

Description of key information

Short description of key information on absorption rate:

Humans: 0.125mg/cm2/hr (damage ratio 1.2; control 1-2)

Rat skin: 0.58mg/cm2/hr

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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), 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.  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. Diethylene glycols may be similarly metabolised by the equivalent primary OH group

Diethylene glycols such as 2 -(2 -ethoxyethoxy)ethanol (22EE) may also undergo low level formation of ether cleavage and formation of alkoxyacetic acid such as ethoxyacetic acid (EAA). However, since 22EE shows no evidence of the developmental or testicular toxicity associated with EAA, this is not thought to be a significant route of metabolism.

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).

Some specific studies are available on the toxicokinetics of this substance. In a toxicokinetic study, 20 mg/kg of 14C radiolabelled 2 -(2 -ethoxyethoxy)ethanol was administered in male and female rats by oral and i.v. route. The absolute bioavailability of the radioactivity was 79 -95%. The Cmax corresponded to about 32 -35 mg eq/kg and 23 -27 mg eq/kg for i.v. and oral routes, respectively, at 0.25 and 0.25 -0.50 hrs post dose. With regards to concentrations in plasma, high concentrations were observed in hypophysis, thyroid, adrenals and bone marrow at the same sampling time. The plasmatic t1/2 corresponded to 37 to 84 hours and the radioactivity was rapidly excreted in urine whatever the sex and the route of administration (85% to 90% within 24 hours post dose).  The excretion of glucuronic acid following the oral and subcutaneous administration of 2 -(2 -ethoxyethoxy)ethanol in rabbits was determined. The total percentage increase of glucuronic acid excretion suggests that the test substance is excreted in a conjugate form as a glucuronide but this represents a small percentage of the total amount administered (0.8 -2.3%). The metabolic conversion of 2 -(2 -ethoxyethoxy)ethanol to (2-ethoxyethoxy)-acetic acid was documented in an adult human volunteer (age and sex unspecified) given a single oral dose of 11.2 mmol diethylene glycol monoethyl ether. A summary review is also available of various experimental studies conducted to assess the absorption, distribution and excretion of 2 -(2 -ethoxyethoxy)ethanol through various routes of administration. The evidence obtained indicates that diethylene glycol monoethyl ether distributes rather rapidly from the blood into the tissues where over 80 per cent is metabolized, presumably oxidized, without demonstrable occurrence of such possible degradation products as ethylene glycol or diethylene glycol. The excreted product was found to be pure diethylene glycol monoethyl ether, with some glucuronic acid. The prime metabolites appear to be either 2 -(2 -ethoxyethoxy)acetic acid, conjugates of the original substance or the substance itself unchanged, primarily excreted in urine. The data indicate a low potential for bioaccumulation.

In a well conducted metabolism study, 14C-Diethylene glycol monoethyl ether was administered as a single 1g/kg dose by gavage to four rats for the purpose of identifying the major metabolites. Blood samples were collected at 0.75h and at 24h. Urinary samples were collected before administration and between 0 -8h and 8 -24h. After administration of the test substance, 90% of the administered radioactivity was excreted in urine within the first 24 hours. 14C-Diethylene glycol monoethylether was extensively metabolised; only 3% of the urinary excreted radioactivity corresponded to unchanged parent compound. The two major urinary metabolites were identified as Ethoxyethoxyacetic acid and Diethylene glycol, which represented 83% and 5.4% respectively of the excreted urinary radioactivity respectively. In plasma, only Ethoxyethoxyacetic acid and unchanged 14C-Diethylene glycol monoethylether were found which is consistent with urinary results. A further study was carried out to confirm at low dose the biotransformation of diethylene glycol monoethylether to ethoxyethoxyacetic acid. Two doses were studied: 15 rats received a single dose of 100mg/kg of diethylene glycol monoethylether by oral route and 15 others 20mg/kg. Blood samples were collected at 0.5h, 1h, 3h, 6h and at 24h. Urinary samples were collected before administration and between 0 -8h and 8 -24h. The results obtained confirmed the presence of unchanged diethylene glycol monoethylether and ethoxyethoxyacetic acid as major metabolites for the 0.5hr plasma sampling times. In urine the amount recovered by the analysis of ethoxyethoxyacetic acid is low: about 17% of the administered dose for the rats treated with 20mg/kg of diethyleneglycol monoethylether and about 40% of the administered dose for the rats treated with 100mg/kg of diethyleneglycol monoethylether.

General References

Casarett & Doull’s Toxicology.  Edited by Custis D. Klaassen.  6^th 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 Ther242:222-31.

Discussion on absorption rate:

An in vitro dermal absorption study using human skin showed that 2 -(2 -ethoxyethoxy)ethanol is able to pass through the stratum corneum at a rate of 0.125mg/cm2/hr) but does not cause any damage to the skin in the process. There is a lag time of less than 1 hour for the substance to cross the skin and appear in the receptor fluid. This suggests that adsorption via the skin is likely to be less than 100% for skin deposition rates of >1mg/cm2 over an 8 hour exposure period. Another study using rat skin found the rate of permeation of DEGEE be a relative constant 0.58mg/cm2/hr with he stratum corneum the rate determining layer.