Bis(2-ethoxyethyl) ether

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study run to a reliable method but not to GLP and no guideline followed. However it is a peer-reviewed publication.The restriction is also due to the use of the category read accross approach. study was performed not with DEGDEE but with DEGDME, a substance which like DEGDEE is part of the diethylene glycol monoalkyl and dialkyl ethers category. These substances have been demonstrated to be similar in structure, physical/chemical properties and toxicological profile.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1993

Report date:

1993

Materials and methods

Objective of study:

absorption

excretion

metabolism

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bis(2-methoxyethyl) ether

EC Number:

203-924-4

EC Name:

Bis(2-methoxyethyl) ether

Cas Number:

111-96-6

Molecular formula:

C6H14O3

IUPAC Name:

1-methoxy-2-(2-methoxyethoxy)ethane

Constituent 2

Reference substance name:

Diethylene glycol dimethyl ether

IUPAC Name:

Diethylene glycol dimethyl ether

Constituent 3

Reference substance name:

Diglyme

IUPAC Name:

Diglyme

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): Diglyme
- Molecular formula (if other than submission substance): C6H14O3
- Molecular weight (if other than submission substance): 134
- Smiles notation (if other than submission substance): COCCOCCOC
- InChl (if other than submission substance): 1S/C6H14O3/c1-7-3-5-9-6-4-8-2/h3-6H2,1-2H3
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type: organic
- Physical state: liquid
- Analytical purity: >99%
- Radiochemical purity (if radiolabelling): Not known
- Specific activity (if radiolabelling): 0.88 and 29.8 mCi/mmol
- Locations of the label (if radiolabelling): carbon atoms 3 and 4
- Expiration date of radiochemical substance (if radiolabelling): no data

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: weanlings
- Weight at study initiation: 190 - 220 g
- Fasting period before study:
- Housing: 3 per cage during 7 daty quarantine then individually
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Formulab Chow No. 5008 ad libitum except none for 18 hours immediately before treatment
- Water (e.g. ad libitum): ad libitum (rats used in induction study given ethanol (15% v/v) in drinking water for 5 days immediately before hepatocyte isolation
- Acclimation period: Quarantine 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

water

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
Dose 5.1 mol (148 uCi)/kg body weight

No. of animals per sex per dose / concentration:

5 male rats were dosed singly

Control animals:

no

Results and discussion

Preliminary studies:

In vitro metabolism: Isolated rat hepatocytes in monolayer culture metabolized [14C]diglyme and released radioactive metabolites into the incubation in a time-dependent manner. Initially, >97% of the administered radioactivity was recovered from the culture medium after each incubation period, and medium from control incubations of [14C]diglyme without cells showed no detectable radioactive metabolites.

Any other information on results incl. tables

In Vivo metabolism:

The predominant metabolite MEAA ((2 -methoxyethoxy)acetic acid) was excreted rapidly during the first 24 hours to account for 65.3% of the administered dose and then plateaued at 67 -68% of the dose between 48 and 96 h. The next metabolite (MAA) (methoxyacetic acid) was excreted more slowly, representing only 2.5% of the dose after 24 h. However the cumulative level of MAA more than doubled to 5.1% during the 24 to 48 h period before reaching 6.2% at the end of the 96-h metabolism period. Unchanged diglyme (1.8% of the administered dose) was excreted within 24 h.

In Vitro metabolism:

Routinely 5 metabolites and unmetabolized diglyme were found in medium recovered from 48 h cultures. During the first 12 h metabolism period, however, only MEAA and MEE (2 -(2 -methoxyethoxy)ethanol) were detected in the incubation medium with each of these representing <2.5% of the total radioactivity added to the cultures. In addition to MEAA and MEE, 2ME

(2 -methoxyethanol) and MAA in 18 h medium were similar. After a 48 h incubation period, the formation of all in vitro metabolites was linear with the initial diglyme concentration over the 1 to 50 uM range.

Applicant's summary and conclusion

Conclusions:

The results of the in vitro/in vivo comparative metabolism study demonstrate that isolated rat hepatocytes in monolayer culture can be used to predict the urinary meatabolites of diglyme. In addition, the urinary metabolite MEAA would best serve as a short-term indicator of exposure to diglyme. The in vitro metabolism of diglyme with rats pretreated with ethanol was increased over that in hepatocytes from untreated rats. The induction of hepatic enzymes by ethanol resulted in the concersion of increased amounts of diglyme to MAA, the metabolite associated with the reproductive and developmental toxicity of diglyme.

Executive summary:

DEGDEE and DEGDME, which is in the above study tested for its metabolism in rats, are both part of the diethylene glycol monoalkyl and dialkyl ethers category described and evaluated in the document titled "Category Approach-Read across Bis(2 -ethoxyethyl)ether" (2013).

These substances have been demonstrated to be very similar in structure, physical/chemical properties and toxicological profile . Therefore, a read-across from DEGDEE to data obtained with DEGDME is scientifically justified.