[2-(2-methoxymethylethoxy)methylethoxy]propanol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-study equivalent to OECD guideline 417

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Reference 2

Reference Type:

publication

Title:

Metabolism and Disposition of Glycol Ethers

Author:

Miller, R.R., (1987)

Year:

1987

Bibliographic source:

Published in Drug Metab. Reviews 18(1): 1-22

Materials and methods

Objective of study:

other: metabolism and disposition

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

EC Number:

247-045-4

EC Name:

[2-(2-methoxymethylethoxy)methylethoxy]propanol

Cas Number:

25498-49-1

Molecular formula:

C10H22O4

IUPAC Name:

[2-(2-Methoxymethylethoxy)methylethoxy]propanol

Details on test material:

The specific activity of original [14C]-TPM was 10.2 mCi/mmole, with a radiochemical purity of 98.7% (Wizard Laboratories, Davis, CA).
Specific activity of dosing solutions (1 mmole/kg = 41.3 µCi/mmole; 4 mmole/kg = 11.1 µCi/mmole). Location of radiolabel(s) was not reported.

Identity: Tripropylene glycol methyl ether (TPM). CAS # 25498-49-1 or 20324-33-8
Appearance: Clear, colorless liquid.
Batch No.: Not specified.
Source: Louisiana Dow Division (Tank #56).
Expiration Date: None specified.
Purity: 99.4% TPM isomers (non-labeled).
Specific Gravity: 0.961 kg/liter.
Solubility in water: Miscible (from other reports).
Stability: Stable up to 200°C (from other reports).
Boiling point: 242.8°C at 760 mmHg.
Vapor pressure: 0.017 mmHg at 25°C.
Storage: Ambient temperature in dark.

Radiolabelling:

yes

Remarks:

0.1 millimole of radiolabelled TPGME (1-14C, 10.2 mCi/mmole), purchased from Wizard Laboratories (purity: 98.7%)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: 175-200 g
- Fasting period before study: not specified in the report
- Housing: individually in stainless steel cages with wire-mesh bottoms
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 °F
- Humidity (%): 45%
- Air changes (per hr): not specified in the report
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Dosing solutions were prepared by diluting the labeled test material with unlabeled TPGME and water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared by diluting the labeled test material with unlabeled TPGME and water

VEHICLE
- Concentration in vehicle: not specified in the report
- Amount of vehicle (if gavage): Each animal was administered approximately 10 µCi total radioactivity in a dose volume which did not exceed 0.5 ml.
- Lot/batch no. (if required): not specified in the report
- Purity: radiochemical purity - 98.7%, purity of unlabeled material - 99.4% TPGME isomers.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: not specified in the report

Three male rats were administered oral doses via gavage of 1 or 4 mmole of C14-radiolabelled TPM/kg body weight. These doses corresponded to approximately 206 or 825 mg TPM/kg body weight. Rats were housed in metabolism cages where urine, feces, and expired air were collected in varying time increments over a total period of 48 hours and monitored for radioactivity. Urine was collected in 12 hour increments, feces in 24 hour increments, and expired air was collected at 4 hour intervals for the first 12 hours and at 12 hour intervals thereafter. In addition, at the end of 48 hours, brain, muscle,peri- renal fat, skin, kidneys, liver and the remaining carcass were analyzed for total radioactivity. Urine samples were fractionated using liquid chromatography and fractions containing radioactivity were analyzed using GC/MS to identify the structures of the metabolites.

Duration and frequency of treatment / exposure:

single exposure

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: 1 or 4 mmol TPM/kg body weight (approximately 206 or 825 mg/kg) of radiolabeled TPGME.

No. of animals per sex per dose / concentration:

Males: 3 Females: 0

Control animals:

no

Details on study design:

- Dose selection rationale: Based on the results of the subchronic dermal study in rabbits
- Rationale for animal assignment (if not random): not specified in the report

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, exhaled CO2, cage washes, tissues (liver, kidney, brain, testes, blood, fat) carcass and skin
- Time and frequency of sampling: 4, 8, 12, 24, 36 and 48 hours
- From how many animals: (samples pooled), 3 animals
- Method type(s) for identification: Biological Material Oxidizer, Liquid scintillation counting and liquid chromatography (urine samples)
- Limits of detection and quantification: not specified in the report

Statistics:

Descriptive statistics (mean and standard deviation)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

The distribution of C14-activity in tissues was similar between dose groups with liver, kidneys, and skin containing the highest percentage after 48 hours (all less than 0.5% of the total dose). Metabolite profiles of urinary C14-activity were qualitatively and, to some extent, quantitatively similar between dose levels. After 48 hours, radioactivity in all measured tissues was less than 1% of the original dose (for either the low or high dose). These tissues included blood, bone carcass, skin, liver, kidney, brain, testes, blood, and fat. An exception was the carcass, which contained 1.18% of the dose after 48 hours in the 1 m mmole/kg dose group.

Details on excretion:

After 48 hrs, 75% of the dose was excreted in urine and 16% as C14-CO2 at 1 mmol/kg BW; while the high dose rats excreted 69% in urine and 16% as C14-CO2. Fecal excretion accounted for approximately 5% of the dose at both dose levels. Less than 1% of the dose was eliminated as expired volatile organics at both dose levels. The carcass retained between 1 and 2% of either dose.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The following urinary metabolites were tentatively identified within Liquid Chromatography (LC) peaks using GC/MS techniques:

LC Peak A (11-18%) - sulfate conjugate of TPM
LC Peak B (12-25%) - 4 isomers of dipropylene glycol methyl ether and 6 isomers of TPM
LC Peak C (1.3-3.8%) - propylene glycol
LC Peak D (54-56%) - 3 isomers (50%) of dipropylene glycol and 2 isomers (50%) of 2-(1-hydroxy-2-propoxy) propanoic acid, described as "isomers of a cyclic dehydration product".
LC Peak E (6 -12%) - Isomers of tripropylene glycol

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
TPGME was rapidly distributed and quickly metabolized and eliminated from the test animals. Approxmately 69-75per cent of the 14C was excreted in urine while only 16 per cent was eliminated as 14CO2 within 48 hours after dosing, overall, greater than 94 per cent of the dose was eliminated within 48 hours. Tripropylene glycol, dipropylene glycol and propylene glycol as well as an oxidation product of dipropylene glycol, dipropylene glycol monomethyl ether (DPGME), TPGME and the sulfate conjugate of TPGME were identified in the urine, less than 5 per cent of the high dose was recovered as unchanged TPGME. These results indicate that TPGME is metabolozed extensively and is comparable to DPGME in disposition and types of metabolites.

Executive summary:

Male Fischer 344 rats were given a single oral dose of approximately 1 or 4 mmole/kg of radiolabeled tripropylene glycol monomethyl ether (TPGME). After dosing, expired air, excreta and tissues were analysed for 14C activity and metabolites in urine were isolated and identified. Approximately 69 (1 mmole/kg) to 75 per cent (4 mmole/kg) of the 14C was excreted in urine while only 16 per cent (both 1 and 4 mmole/kg) was eliminated as 14CO2 within 48 hours after dosing; greater than 94 per cent of the dose was eliminated within 48 hours. Tripropylene glycol, dipropylene glycol and propylene glycol as well as an oxidation product of dipropylene glycol, dipropylene glycol monomethyl ether (DPGME), TPGME and the sulfate conjugate of TPGME were identified in the urine, less than 5 per cent of the high dose was recovered as unchanged TPGME. These results indicate that TPGME is metabolozed extensively and is comparable to DPGME in disposition and types of metabolites.