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Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted as per compliance to Good Laboratory Practices TSCA Standards; Federal Register 48(230): 5397-53944, November 29, 1983.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Objective of study:
other: pharmacokinetics
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.8320 (Oral/dermal pharmacokinetics)
Principles of method if other than guideline:
not applicable
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hexyloxyethanol
EC Number:
203-951-1
EC Name:
2-hexyloxyethanol
Cas Number:
112-25-4
Molecular formula:
C6H13OCH2CH2OH
IUPAC Name:
2-hexyloxyethanol
Details on test material:
- Name of test material (as cited in study report): Ethylene Glycol Monohexyl Ether (EGHE)
- Physical state: clear liquid
- Analytical purity: 98.5% by gas chromatography
- Impurities (identity and concentrations): not specified
- Composition of test material, percentage of components: not specified
- Isomers composition: not specified
- Purity test date: not specified
- Lot/batch No.: S-020773/BRRC No. 50-383
- Expiration date of the lot/batch: not specified
- Radiochemical purity (if radiolabelling): 97.2% by thin layer chromatography and 99% by gas chromatography
- Specific activity (if radiolabelling): 2.1 mCi/mmole, which is equivalent to 31.88 x 10(6) DPM/mg.
- Locations of the label (if radiolabelling): 14C-labelled EGHE was synthesized by DuPont/New England Nuclear Products, Boston, MA
- Expiration date of radiochemical substance (if radiolabelling): not specified
- Stability under test conditions: stated to be stable in the Material Safety Data Sheet; stability studies at BRRC showed EGHE to be stable in physiological saline solution
- Storage condition of test material: The chemical was stored at ambient temperatures throughout the course of the study
Radiolabelling:
yes

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland
- Age at study initiation: 9-10 weeks of age
- Weight at study initiation: 2-3 kg
- Fasting period before study: not specified
- Housing: individually housed in Roth-type metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): standard conditions
- Humidity (%): standard conditions
- Air changes (per hr): standard conditions
- Photoperiod (hrs dark / hrs light): 12-hour light/darkcycle

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
In the intravenous studies, EGHE and 14C-EGHE were diluted in 0.9% (w/v) NaCl in water. The dose solution was delivered gravimetrically to each animal in a study. In intravenous studies, the dose solution was delivered using a syringe with a sawed-off needle into an indwelling cannula over a period of 2 minutes. The dose volume was followed by the same volume of 0.9% NaCl to clear the cannula, then the cannula was plugged.
Duration and frequency of treatment / exposure:
single
Doses / concentrations
Remarks:
Doses / Concentrations:
10 and 1 mg/kg
No. of animals per sex per dose / concentration:
6 animals
Control animals:
not specified
Positive control reference chemical:
not applicable
Details on study design:
- Dose selection rationale: based on acute and probe study
- Rationale for animal assignment: random
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, plasma, blood, cage washes
- Time and frequency of sampling: Urine was collected on dry ice in 6- to 12-hr intervals and feces in 24-hr intervals. Urine samples were assayed immediately for 14c and the remaining volumes were stored at approximately -80°C until chemical analysis was conducted by HPLC. Feces were frozen at approximately -20°C until analyzed. Expired 14CO2, was collected at 12-hour intervals and stored at approximately -20°C until analyzed for 14C

Statistics:
The pharmacokinetic description of the fate of absorbed l4C-EGHE w as derived using best-fit parameter estimates for the plasma. The parameters
estimated included: rate constant of absorption, ka; rate constant of elimination, ke; volume of distribution, Vd; half-lives (t1/2) of absorption and elimination and area under the plasma concentration (AUC) versus time.

Results and discussion

Preliminary studies:
not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
no data
Details on distribution in tissues:
no data
Details on excretion:
The disposition of radioactivity following 10 and 0.1 mg/kg doses of EGHE/14C-EGHE to male NZW rabbits was that the total recovery of dose in excreta fractions, carcass and the cage wash was approximately 95 to 100% in the two dose groups.
A majority of the dose was eliminated in the urine (approximately 80%) while less than 2% was eliminated in the feces (largely in the first day of exposure).
There were no marked difference in rates or extents of urinary elimination observed between the two dose groups. In general, most of the dose recovered in the urine was eliminated in the first 24 hours after dosing, after which little additional urinary elimination of the dose occurred.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
Cmax: (10 mg/kg): 42.491 µg/g
Test no.:
#1
Toxicokinetic parameters:
Tmax: (10 mg/kg): 0 minutes
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: (10 mg/kg): Half-life of distribution: 40.232 min
Test no.:
#1
Toxicokinetic parameters:
AUC: (10 mg/kg): AUC(48): 3598.5 µg/g.min
Test no.:
#1
Toxicokinetic parameters:
AUC: (10 mg/kg): AUC(∞): 4241.3 µg/g.min
Test no.:
#1
Toxicokinetic parameters:
other: (10 mg/kg): Distribution rate constant k(d): 0.017229 min(-1)
Test no.:
#1
Toxicokinetic parameters:
other: (10 mg/kg): Elimination rate constant k(e): 0.00036001 min (-1)
Test no.:
#1
Toxicokinetic parameters:
other: (10 mg/kg): Apparent volume of distribution Vd: 32610 ml
Test no.:
#1
Toxicokinetic parameters:
other: (10 mg/kg): Systemic clearance Cl(tot): 11.74 ml/min
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: (10 mg/kg): Half-life of elimination: 1925.4 min
Test no.:
#2
Toxicokinetic parameters:
Cmax: (1.0 mg/kg): 5.0998 µg/g
Test no.:
#2
Toxicokinetic parameters:
Tmax: (1.0 mg/kg): 0 minutes
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: (1.0 mg/kg): Half-life of distribution: 16.917 min
Test no.:
#2
Toxicokinetic parameters:
AUC: (1.0 mg/kg): AUC(48): 288.73 µg/g.min
Test no.:
#2
Toxicokinetic parameters:
AUC: (1.0 mg/kg): AUC(∞): 357.38 µg/g.min
Test no.:
#2
Toxicokinetic parameters:
other: (1.0 mg/kg): Distribution rate constant k(d): 0.040973 min(-1)
Test no.:
#2
Toxicokinetic parameters:
other: (1.0 mg/kg): Elimination rate constant k(e): 0.00029278 min (-1)
Test no.:
#2
Toxicokinetic parameters:
other: (1.0 mg/kg): Apparent volume of distribution Vd: 43640 ml
Test no.:
#2
Toxicokinetic parameters:
other: (1.0 mg/kg): Systemic clearance Cl(tot): 12.777 ml/min
Test no.:
#2
Toxicokinetic parameters:
half-life 2nd: (1.0 mg/kg): Half-life of elimination: 2367.5 min

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
3-9 peaks were observed, none of which corresponded to EGHE. These peaks were probably considered metabolites of EGHE, of which at least three of which appear to be major urinary metabolites.

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:
Interpretation of results: low bioaccumulation potential based on study results
Under the conditions of the study, the results in rabbits indicate that while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.
Executive summary:

The absorption, distribution, metabolism and elimination of ethylene glycol monohexyl ether (EGHE) following single intravenous dose was investigated in rabbits. In New Zealand White rabbits, intravenous doses of 10 and 1 mg/kg EGHE given to male rabbits were metabolized rapidly, so that EGHE levels were less than 1% of the total plasma radioactivity by 1 hour post-dosing. About 80% of the radioactivity was recovered in the urine, with less than 2% in the feces. Because the rabbits were housed in open metabolism cages, the recoveries of radioactivity in CO2 and organic volatile fractions could not be assessed; however, over 90% of the dose was recovered in the intravenous studies. The results in rabbits indicate that, while EGHE has a large potential for systemic absorption, it is rapidly and extensively eliminated from the plasma by metabolic conversion to multiple metabolite species.