Bis(2-(2-methoxyethoxy)ethyl) ether

Endpoint summary

Description of key information

Based on the read-across consideration, it can be predicted that tetraglyme is readily bioavailable upon oral and dermal exposure and undergoes extensive metabolism, followed by efficient urinary excretion. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic profile of tetraglyme can reasonably be derived based on its physico-chem parameters and on the read-across approach using diglyme as source chemicals.

The underlying scientific rationale is that target chemical belongs to the homologues series of glymes and thus to a “chain length category”, where there is an incremental increase in the number of CH2CH2O units. Based on the basic concept of “chain length category”, the same toxic mode of action can be assigned for each category members and the use of toxicity data of other glyme members (mono-, di-, triglymes) for read-across purpose to tetraglyme is justified (see for more information “Assessment of the validity of the analogue approach”).

 

Three metabolism studies and one dermal penetration study on diglyme are available and summarized below:

- Human and rat hepatic microsomes were incubated with 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.

- An embryotoxic oral dose of diglyme, 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. The total excretion within 48h amounted > 97% 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.

 

- The metabolism of 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 prominent 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.

 

- An in vitro skin absorption study was performed applying Diethylene glycol dimethyl ether to dermatomed human skin. For diglyme, the lag time was reported to be 36 +/- 3 min and the flux at steady state permeation was 0.952 +/- 0.340 mg/cm2/h. For monoglyme, the lag time was reported to be 39 +/- 3 min and the flux at steady state permeation was 3.434 +/- 1.897 mg/cm2/h. Based on the obtained results, it can be concluded that diglyme and monoglyme are dermally readily bioavailable.