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In a study to examine the metabolism 2 -(2 -methoxyethoxy)ethanol, SD rats were given a single oral dose of 1000mg/kg and the urine collected over two 24 hour periods for analysis for a number of expected metabolites. The dominant metabolite was 2 -(2 -(2-methoxyethoxy)ethoxy)acetic acid, which accounted for 80% of the original dose. Unmetabolised 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol and its glucoronide conjugate, triethylene glycol, methoxyethoxyethoxyacetic acid were also found at levels of 1 -5% . In addition, the metabolite methoxyacetic acid (MAA) was found, the amount accounting for 0.5% of the dose of 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol given. This demonstrates that oxidation of the hydroxyl function is the dominant metabolic pathway but small amounts of the substance are metabolised by cleavage of the ether linkage. The study also showed that around 98% of the dose of 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol was eliminated within 24 hours. The trace amounts of MAA formed could explain the testicular effects seen in the repeat dose study at the very high dose of 4g/kg but the level formed is also consistent with no developmental effects being seen at a dose of 1.2g/kg.

Studies on read across substances

In an in vitro study to establish the rate of in vitro metabolism of 2 -(2 -butoxyethoxy)ethyl acetate in the blood of rats to the parent glycol ether 2-(2-butoxyethoxy)ethanol, hydrolysis was found to be very rapid with a half life of approximately 3 minutes. This suggests that data for the latter is likely to be a very good surrogate for the systemic toxicity of the former.

In a study to examine the absorption and elimination of radio-labelled 2 -(2 -butoxyethoxy)ethanol in rats following 24hr dermal occluded exposure, it was established that the main route of elimination is overwhelmingly via the urine and the metabolite 2 -(2 -butoxyethoxy)acetic acid. The glucoronidate conjugate was also found at significant levels (5 -8%). Females appeared to absorb and therefore excrete larger quantities than males and the dermal absorption rate was estimated to be 0.73 and 1.46mg/cm2/hr for males and females respectively. Washing studies showed that 90%+ of externally applied substance could be removed after 5 minutes exposure by skin washing.

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 review of various experimental studies was conducted to assess the absorption, distribution and excretion of 2 -(2 -ethoxyethoxy)ethanol through various routes of administration.The evidence obtained indicated that diethylene glycol monoethyl ether distributes 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 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%).

In a study to examine the metabolism 2 -(2 -methoxyethoxy)ethanol, SD rats were given single oral doses of 500, 1000 and 2000mg/kg and the urine collected over two 24 hour periods for analysis for a number of expected metabolites. The dominant metabolite was 2 -(2 -methoxyethoxy)acetic acid, which accounted for 87 -95% of the original dose. Unmetabolised 2 -(2 -methoxyethoxy)ethanol, the glucoronide conjugate and diethylene glycol were also found in small quantities. In addition, the metabolite methoxyacetic acid was found, the amount accounting for 0.8 -1.4% of the dose of 2 -(2 -methoxyethoxy)ethanol given, with the amount seeming to decline with increasing dose. This demonstrates that oxidation of the hydroxyl function is the dominant metabolic pathway but small amounts of the substance are metabolised by cleavage of the ether linkage. The study also showed that around 98% of the dose of 2 -(2 -methoxyethoxy)ethanol is eliminated within 24 hours and that MAA half life increases significantly at very high dose, which could explain the reproductive effects seen at very high dose with this substance.

Key value for chemical safety assessment

Additional information

The main metabolic pathway for metabolism of ethylene glycol monoalkyl ethers is oxidation via alcohol and aldehyde dehydrogenases (ALD/ADH) that leads to the formation of an alkoxy acid. Alkoxy acids are the only toxicologically significant metabolites of glycol ethers that have been detected in vivo. Methoxy acetic acid, a metabolite of ethylene glycol methyl ether, is a known testicular toxicant in rats, and butoxyacetic acid, a metabolite of ethylene glycol butyl ether, causes hemolysis of rodent red blood cells. The principal metabolite of 2-(2-(2 -methoxyethoxy)ethoxy)ethanol is 2-[2-(2- methoxyethoxy)ethoxy] acetic acid. Although ethylene glycol, a known kidney toxicant, has been identified as an impurity or a minor metabolite of glycol ethers in animal studies, it does not appear to contribute to the toxicity of glycol ethers. Some glycol ethers have been shown to undergo conjugation with sulfate and glucuronic acid, and the alkoxyacetic acid metabolites may conjugate with glycine (rodents) or glutamine (humans). Conjugation is regarded as a pathway of detoxification.

An in vitro study determined that the permeability of 2-(2-(2 -methoxyethoxy)ethoxy)ethanol to human skin is quite low. The permeability co-efficient was determined to be 34 +/-7.7ug/cm2/hr, which is around 1.5% of the skin penetration rate of the shorter chain glycol ether ethylene glycol methyl ether. Exposure to the substance caused slight deterioration of skin barrier properties as quantified by the damage ratio (rate of permeation of tritiated water through the skin before and after exposure).

Discussion on bioaccumulation potential result:

The main metabolic pathway for metabolism of ethylene glycol monoalkyl ethers is oxidation via alcohol and aldehyde dehydrogenases (ALD/ADH) that leads to the formation of an alkoxy acid. Alkoxy acids are the only toxicologically significant metabolites of glycol ethers that have been detected in vivo. Methoxy acetic acid, a metabolite of ethylene glycol methyl ether, is a known testicular toxicant in rats, and butoxyacetic acid, a metabolite of ethylene glycol butyl ether, causes hemolysis of rodent red blood cells. The principal metabolite of 2-(2-(2 -methoxyethoxy)ethoxy)ethanol is 2-[2-(2- methoxyethoxy)ethoxy] acetic acid. Although ethylene glycol, a known kidney toxicant, has been identified as an impurity or a minor metabolite of glycol ethers in animal studies, it does not appear to contribute to the toxicity of glycol ethers. Some glycol ethers have been shown to undergo conjugation with sulfate and glucuronic acid, and the alkoxyacetic acid metabolites may conjugate with glycine (rodents) or glutamine (humans). Conjugation is regarded as a pathway of detoxification.