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Several studies have been identified that examine the basic toxicokinetics of Diethylene glycol dimethyl ether. Due to the high structural similarity of Triethylene glycol dimethyl ether and Diethylene glycol dimethyl ether (difference: one ethyl group; but same functional groups) it is very likely that both compounds will be metabolised by the same enzymes/metabolic path. Therefore, a read across from Triethylene glycol dimethyl ether to the metabolism data generated with Diethylene glycol dimethyl ether (Diglyme) is jusitfied to clarify the toxicokinetic behaviour of this substance (for further clarification please refer to the attached document "Proposed metabolism of Triethylene glycol dimethyl ether.doc" attached to the referring basic toxicokinetics files).

 

- Human and rat hepatic microsomes were incubated with Diethylene glycol dimethyl ether (Diglyme). The rat microsomes catalysed the NADPH-dependent cleavage of the central ether linkage of Diglyme yielding 2-Methoxyethanol and 2-(2-Methoxyethoxy)ethanol. Microsomes isolated from phenobarbital- or ethanol-pretreated rats exhibited an increased capacity to cleave diglyme to 2 -Methoxyethanol. This ethanol-induced increase in 2-Methoxyethanol formation was not observed if incubations contained the cytochrome P450 IIEI inhibitor Isoniazid. Pretreatment of rats with Diglyme significantly increased microsomal P-450 levels, P-450 associated enzyme activities and the conversion of Diglyme to 2-Methoxyethanol. Human hepatic microsomes also catalysed the NADPH-dependent cleavage of Diglyme to 2-Methoxyethanol. The formation of 2-Methoxyethanol from Diglyme correlated with the aniline hydroxylase activity (P450 IIEI) levels measured in human hepatic microsomes. These results suggest that the ether linkages of Triglyme are cleaved by rat and human P-450 and 2-Methoxyethanol is formed.

 

- An embryotoxic oral dose of Diethylene glycol dimethyl ether, 3.73 mmol/kg bw (500 mg/kg bw), administered on gestation day 11 to pregnant CD-1 mice was metabolised predominatly by O-demethylation to 2-(2-Methoxyethoxy)ethanol with subsequent oxidation to (2-Methoxyethoxy)acetic acid. Urinary excretion of this metabolite over 48 hours amnounted to 63 +/-2% of the dose. A smaller percentage of the administered dose was metabolised at the (central) ether linkage to produce 2-Methoxyethanol, which was further metabolised by alcohol dehydrogenase to Methoxyacetic acid. Urinary excretion of Methoxyacetic acid, a potent developmental toxicant, amounted to 28 +/-1% of the administered dose by 48 hours and was the second most prominent urinary metabolite. Unchanged Diglyme and Methoxyacetic acid were detected in the embryonic tissues from these animals and embryos harvested after the initial 6 -hour period showed detectable amounts of only Methoxyacetic acid. The average amount of Methoxyacetic acid per embryo was calculated to be 1.5 +/-1.0 µmol (5.9 mmol/kg bw) at the 6 -hour termination time. A similar result (but with formation of a smaller amount of Methoxyacetic acid) is expected to occur in case of Triethylene glycol dimethyl ether.

 

- The metabolism of (2 -Methoxyethyl)ether (Diglyme) was studied in isolated rat hepatocytes and in intact rat. Male Sprague-Dawley rats were used in both studies. Primary hepatocytes were cultured as monolayers and incubated with [14C]-Diglyme at 1, 10, 30 and 50 µM for up to 48 hours. For the in vivo study, rats were given single oral doses of [14C]-Diglyme at 5.1 mmol/kg bw and urine was collected for up to 96 hours. The principal metabolite from primary rat hepatocytes and in the urine was (2-Methoxyethoxy)acetic acid (approx. 67% of the administered dose after 48 hours). Other prominant metabolites common to both systems included 2-(2.Methoxyethoxy)ethanol, Methoxyacetic acid, 2-Methoxyethanol and diglycolic acid. Diglyme was demonstrated to be not cytotoxic to rat hepatocytes. Because of the high structural similarity between Triethylene glycol dimethyl ether and Diethylene glycol dimethyl ether an analog pathway can be assumed for both glycol ethers. Since there are ether linkages within Triethylene glycol dimethyl ether 2 -Methoxyethanol and Methoxyacetic acid are the most likely metabolites to occur.

 

Taking into account the results of all above mentioned ADME-studies performed with Diethylene glycol dimethyl ether, the structural analogon, one possible metabolic pathway of Triethylene glycol dimethyl ether is considered to form 2-Methoxy acetic acid, which is excreted rapidly via urine. The generation of this reproduction and teratogenic toxicant is assumed to be responsible for the reprotoxic properties of Triethylene glycol dimethyl ether. There is no tendency for bioaccumulation.

 

Due to the high structural similarity of Triethylene glycol dimethyl ether and Diethylene glycol dimethyl ether (difference: one ethyl group; but same functional groups) it is very likely that both compounds will show a similar skin penetration behaviour. Therefore, a read across from Triethylene glycol dimethyl ether to the data generated with Diethylene glycol dimethyl ether is justified to give a rough indication for the dimension of skin penetration properties. Furthermore, since the molecular weight of Triglyme (178.23 g/mol) is higher than that of Diglyme (134.18 g/mol), the substance is expected to be absorbed by the skin in a smaller amount than Diglyme.

Anin vitroskin absorption study was performed applying Diethylene glycol dimethyl ether (read across) to dermatomed human skin. The lag time was reported to be 36 +/- 3 min, the flux at steady state permeation was 0.952 +/- 0.340 mg/cm2/h.