2-(2-ethoxyethoxy)ethanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From July 2001 to November 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted with guideline equivalent protocol

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

2-(2-ethoxyethoxy)ethanol

EC Number:

203-919-7

EC Name:

2-(2-ethoxyethoxy)ethanol

Cas Number:

111-90-0

Molecular formula:

C6H14O3

IUPAC Name:

2-(2-ethoxyethoxy)ethan-1-ol

Details on test material:

- Name of test material (as cited in study report): Transcutol HP (source sponsor); 4- 14C-Diethylene glycol monoethyleter (source Moraveck Biochemicals Inc.)
- Physical state: non coloured clear liquid
- Analytical purity: 99.98%
- Impurities (identity and concentrations): 2-methoxyethanol <20ppm; 2-ethoxyethanol <20ppm; ethylene glycol <20ppm; diethylene glycol <20ppm; ethylene oxyde <1ppm
- Lot/batch No.: Transcuto #l: 0025005 ; radiolabelled #: 104-272-053
- Expiration date of the lot/batch:
- Radiochemical purity (if radiolabelling): 98.2%
- Specific activity (if radiolabelling): 53mCi/mmol
- Locations of the label (if radiolabelling): 4- C
- Storage condition of test material: 0-5C

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

other: Sprague-Dawley; BDIX

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA CREDO, L'Arbresle, France
- Age at study initiation: 7-8 weeks
- Weight at study initiation:

IV Route:
Sprague-Dawley: Male: 252+/-13g; Female: 228+/-8g
BDIX: Male: 253+/-4g

Oral Route:
Sprague-Dawley: Male 247+/-6g; Female 221+/-7g
BDIX: Male 233+/-10g; Female 180+/-7g

- Fasting period before study: overnight before administration and 4 hours following administration
- Housing: in makrolon cages furnished with stainless steel wire lids with catches
- Individual metabolism cages: yes, animals of the last group (168hr) ('techniplast', U.A.R. epinay sur Orge, France).
- Diet (e.g. ad libitum): ad libitum except during fasting period. Pellets (AO4C) supplied by U.A.R. (Epinay sur Orge, France).
- Water (e.g. ad libitum): ad libitum. Tap water.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21C+/-2 (extreme temperature observed as 18-25C for short period of time)
- Humidity (%): 55+/-10% (extreme temperature observed as 25-90% for short period of time)
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2001, June 27 To: 2001, November 6

Administration / exposure

Route of administration:

other: i.v. and oral

Vehicle:

other: saline for i.v. and water for oral

Details on exposure:

Syringe binding test: A syringe was filled up with the dosing solution and after agitation for 10 min, the dosing solution was transferred in another syringe and shaken again for 10 min. The radioactivity was measured before and after the 2 sequences of agitation in order to show any binding. This test was performed in triplicate. The difference between the two measurements did not exceed 10% which demonstrates the absence of significant binding.
PREPARATION OF DOSING SOLUTIONS:
For IV route: 20 mg of diethylene glycol monoethylether including 50 uCi (1.85MBq) of 14C-Diethylene glycol monoethylether was added in 1g of saline. Then the volume was completed to 2ml with saline.
For oral route: 20 mg of diethylene glycol monoethylether including 50 uCi (1.85MBq) of 14C-Diethylene glycol monoethylether was added in 1g of water. Then the volume was completed to 5ml with water.

In both cases the dosing solutions were not kept in contact with air for a long time to prevent any oxidation of the solutions.
Each day of administration the radioactivity content of the dosing solution was checked by HPLC.

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
20mg/kg (50uCi/kg) for both, i.v. (2ml/kg) and oral (5ml/kg) administrations

No. of animals per sex per dose / concentration:

See details under 'Any other information on materials and methods incl. tables'.

Control animals:

yes, concurrent no treatment

Details on study design:

See details under 'Any other information on materials and methods incl. tables'.

Details on dosing and sampling:

See details under 'Any other information on materials and methods incl. tables'.

Statistics:

Mean and standard variation.
Calculations were performed using Excel software directly from the raw data.

Results and discussion

Preliminary studies:

no data

Main ADME results

Main ADME results 1

Type:

excretion

Results:

85-90% within 24 hours post dose

Main ADME results 2

Type:

absorption

Results:

absolute bioavailability 79-95%

Main ADME results 3

Type:

distribution

Results:

Radioactivity in tissues significantly decreased at 48 hours

Toxicokinetic / pharmacokinetic studies

Details on absorption:

For intravenous route, the maximum plasmatic concentration of the radioactivity is observed 0.25 hours post dose and the plasmatic concentrations corresponded to about 32-35mg eq/kg
For oral route, the maximum plasmatic concentration of the radioactivity is observed 0.25- 0.50 hours post dose and the plasmatic concentrations corresponded to about 23-27mg eq/kg

Details on distribution in tissues:

The tissue distribution of the radioactivity was characterised by high concentrations observed in hypophysis, thyroid, adrenals and bone marrow with regardsto the concentrations observed in blood/plasma (100 to 1000 times less ) at the same sampling time.

Details on excretion:

The radioactivity is rapidly excreted in urine whatever the sex and the route of administration (85-90% within 24 hours post dose)

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Cmax: 32.22 and 34.58 mg.eq DIE/kg for male and female, respectively, i.v. route

Toxicokinetic parameters 2

Test no.:

#2

Toxicokinetic parameters:

Cmax: 23.34 and 26.63 mg.eq DIE/kg for male and female, respectively, oral route

Toxicokinetic parameters 3

Test no.:

#1

Toxicokinetic parameters:

half-life 1st: 84 and 48 hours for male and female, respectively, i.v. route

Toxicokinetic parameters 4

Test no.:

#2

Toxicokinetic parameters:

half-life 1st: 37 and 43 hours for male and female, respectively, oral route

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 1. Excretion recovery:

 

SD male rats		i.v. Route	Oral Route
		Mean±SD	Mean±SD
% in urine	0-24hr	89.04±1.26	85.50±3.47
% in urine	0-168hr	92.01±1.43	88.01±2.84
% in faeces	0-24hr	0.34±0.18	1.00±1.12
% in faeces	0-168hr	0.56±0.19	1.59±1.03
% in CO2	0-24hr	0.37	0.42
% in CO2	0-168hr	0.53	0.57
% in cage washing-water	168hr	0.91±0.58	0.98±0.48
% in carcass	168hr	2.78±0.72	1.71±0.41
RECOVERY (%)	0-168hr	96.26±1.80	92.83±1.03
SD female rats		i.v. Route	Oral Route
		Mean±SD	Mean±SD
% in urine	0-24hr	88.22±3.57	90.41±1.88
% in urine	0-168hr	90.78±2.57	93.33±2.17
% in faeces	0-24hr	0.66±0.37	0.35±0.12
% in faeces	0-168hr	0.76±0.33	0.50±0.10
% in CO2	0-24hr	BLQ	BLQ
% in CO2	0-168hr	BLQ	BLQ
% in cage washing-water	168hr	2.03±1.86	1.43±1.28
% in carcass	168hr	1.68±0.27	0.72±0.06
RECOVERY (%)	0-168hr	95.25±2.49	95.97±2.96

 

Table 2. Tissue distribution: Sprague-Dawley

0.5 h mg eq/kg	Male	Female
Thyroid	1.08	1.29
Hypophysis	1.71	9.15
Adrenals	0.34	0.25
Bone marrow	0.22	0.41
Blood	0.02	0.02
Plasma	0.02	0.03
24 h mg eq/kg
Thyroid	0.08	BLQ
Hypophysis	BLQ	BLQ
Adrenals	0.03	0.02
Bone marrow	0.06	0.05
Blood	0.0008	0.0005
Plasma	0.0012	0.0008

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Not bioaccumulative.

Executive summary:

In a toxicokinetic study, 20 mg/kg of 14C radiolabelled 2 -(2 -ethoxyethoxy)ethanol was administered in male and female rats by oral and i.v. route. The absolute bioavailability of the radioactivity was 79 -95%. The Cmax corresponded to about 32 -35 mg eq/kg and 23 -27 mg eq/kg for i.v. and oral routes, respectively, at 0.25 and 0.25 -0.50 hrs post dose. With regards to concentrations in plasma, high concentrations were observed in hypophysis, thyroid, adrenals and bone marrow at the same sampling time. The plasmatic t1/2 corresponded to 37 to 84 hours and the radioactivity was rapidly excreted in urine whatever the sex and the route of administration (85% to 90% within 24 hours post dose). The test substance shows low bioaccumulation potential under the conditions of this study.