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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The urinary route is known to account for virtually all of the metabolites of the E series glycol ethers. This study was primarily to look for the presence of methoxyacetic acid as an indicator of the route of metabolism and the relevance of this metabolite when considering potential toxicity. A non radiolabelled analytical approach was developed to look for the expected metabolites in urine following a single dose and single concentration over a 48 hour elimination period.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
Source: INEOS nv, Antwerp, Belgium
Purity: 99.1%.
Batch number TKE107-27/3/17
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Age at study initiation: 9 weeks
- Weight at study initiation: All animals within +/-20% of each other
- Individual metabolism cages: yes
- Diet (ad libitum): Special Diet Services, Witham, UK
- Water (ad libitum): Human grade, Vitens
- Acclimation period: 5 days total including 1 day in metabolism cage. Animals also subject to quarantine period when microbiological status of a random sample of the batch of animals checked.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Photoperiod (hrs dark / hrs light): 12/12
- air changes per hour: 10

IN-LIFE DATES: From: 9/5/17 To: 11/5/17

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Duration and frequency of treatment / exposure:
Single dose. Volume given 10mL.kgbw.
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw (total dose)
Remarks:
Single dose was used based on an earlier study using 2-(2-methoxyethoxy)ethanol at multiple doses which confirmed no significant difference in metabolite patterns with dose
No. of animals per sex per dose:
4
Control animals:
no
Positive control:
no
Details on dosing and sampling:
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: Collection periods 0-24hrs, 24-48hrs
- From how many animals: (samples pooled or not): measurements of individual animals
- Method type(s) for identification: See 'any other information for details of method"
- Limits of detection and quantification: Lower limit of quantification 0.1ug/mL for all metabolites except methoxyethanol and methoxyacetic acid, for which LLOG was 0.5ug/mL.
Statistics:
Mean and standard deviation calculated

Results and discussion

Main ADME resultsopen allclose all
Type:
metabolism
Type:
excretion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Recovery of dose material exceeded 102% leading to conclusion that all the substance is excreted by this route.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Most of the expected metabolites were seen, although the acetic acid derivative of TEGME dominated. DEGME was produced in insignificant amounts. Additionally, the metabolite hydroxyethoxyethoxy acetic acid (HEEAA) and the glucoronide conjugate of TEGME plus trace amounts of two other metabolites (HEAA - hydroxyethoxy acetic acid and the sulphate conjugate of TEGME). A summary of the main metabolite percentages (those expected) is:
- MEEAA: 81.1 % (3.5)
- TEGME: 5.35 % (1.00)
- MEAA: 3.63% (0.34)
- TEG: 2.88% (0.30)
- DEG: 0.81 % (0.06)
- MAA: 0.48 % (0.07)

SD shown in brackets.
Nearly all of the MEEAA was excreted in the first 24 hours, showing it has a relatively short half life.

The following metabolites were also detected:

- HEEAA: 6.75% (.0.47) (only semi-quantified as no standard available for calibration.)
- TEGME-glucoronide: 0.97% (0.17) (only semi-quantified as no standard available for calibration.)
- HEAA: 0.17 (0.02)% (only semi-quantified as no standard available for calibration.)
- TEGME-sulphate 0.18 (0.02) (only semi-quantified as no standard available for calibration.)
-DEGME(MEE) <0.1%

Any other information on results incl. tables

Results for 0 -24 and 24 -48 hour collection periods combined. Note that the figure for DEG also includes the amount detected as glycolic acid, since this is a known metabolite of DEG:

The tables below show the amounts collected over the two different time periods for (average of three animals):

Time period

0 – 24hr

24 – 48hr

MEEAA

80.1%

1.0%

MAA

0.35%

0.13%

DEG

0.80%

0.01%

Glucoronide

0.96%

0.01%

TEGME

5.31%

0.04%

 TEG  2.85%  0.03%
 MEAA  3.60%  0.04%
 DEGME (MEE)  0.04%  0%
 HEEAA  6.67%  0.09%
 HEAA  0.17%  0%
 Sulphate  0.18%  0%

Applicant's summary and conclusion

Conclusions:
TEGME is >95% eliminated within 24 hours in the urine primarily in the form of the acid metabolite 2-(2-(2-methoxyethoxy)ethoxy)acetic acid. About 0.5% of the dose is metabolised to methoxyacetic acid. Triethylene glycol, TEGME itself, 2-(2-methoxyethoxy)acetic acid and hydroxyethoxyethoxyacetic acid are all produced at levels of 1% and above. Trace amounts of other metabolites are also formed. There is no potential for bioaccumulation of this substance.
Executive summary:

In a study to examine the metabolism 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol, SD rats were given a single oral dose of 1000 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 81% 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 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 100% of the dose of 2 -(2 -(2-methoxyethoxy)ethoxy)ethanol was eliminated within 24 hours in the urine.