1-(1-methyl-2-propoxyethoxy)propan-2-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

May 22, 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to GLP and the report contains sufficient data to permit a meaningful evaluation of study results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The purpose of this study was to quantify the levels of 2-methoxypropionic acid (MPA) metabolite of DPM (dipropylene glycol methyl ether) in rats and rabbits. The relative formation of MPA was determined between the two test species, two dose levels, and two lots of test material containing various percentages of MPA-forming isomers (1,1- and 1,2-isomers).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(2-methoxymethylethoxy)propanol

EC Number:

252-104-2

EC Name:

(2-methoxymethylethoxy)propanol

Cas Number:

34590-94-8

Molecular formula:

C7H16O3

IUPAC Name:

(2-methoxymethylethoxy)propanol

Details on test material:

- Name of test material (as cited in study report): DPM
- Chemical name: Dipropylene glycol methyl ether
- Substance type: solvent
- Physical state: clear, colourless liquid
- Analytical purity: Lot 1 &2 - 99.3%
- Impurities (identity and concentrations): not specified in the report
- Composition of test material, percentage of components:
Lot 1: (1,2 isomer) - 48.73%, (2,2 isomer) - 46.29%, (1,1 isomer) - 2.44% and (2,1 isomer) - 2.54%
Lot 2: (1,2 isomer) - 81.43%, (2,2 isomer) - 12.30%, (1,1 isomer) - 5.38% and (2,1 isomer) - 0.89%
- Isomers composition: same as sbove
- Purity test date: not specified in the report
- Lot/batch No.: Lot 1 - #RD251920A2, Lot 2 - #393003
- Expiration date of the lot/batch: not specified in the report
- Stability under test conditions: not specified in the report
- Storage condition of test material: not specified in the report

Radiolabelling:

no

Test animals

Species:

other: Crl:CD(SD) rats and New Zealand White rabbits

Strain:

other: Crl:CD(SD) rats and New Zealand White rabbits

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Rats - Charles River Laboratories Inc., Rabbits - Covance Research Products
- Age at study initiation: Rats - 10 weeks, rabbits - 14 weeks
- Weight at study initiation: Rats - 0.21-0.24 kg, rabbits - 2.4-2.6 kg
- Fasting period before study: 16 hours prior to administration
- Housing: Rats - two per cage and individually in metabolism cages, rabbits - housed individually
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum, except during fasting period
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Rats - 2 weeks, rabbits - 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1°C (Rats), 20 ± 1°C (Rabbits)
- Humidity (%): 40-70% (Rats), 40-60% (Rabbits)
- Air changes (per hr): 12-15 times/hour (Rats and rabbits)
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (Rats and rabbits)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The oral dose solutions were prepared in water. Appropriate amounts of non-radiolabeled DPM were added to obtain the target doses doses of 25 or 1000 mg DPM/kg body weight. The amount of dose solution administered was targeted at ~ 5 g/kg body weight.

HOMOGENEITY AND STABILITY OF TEST MATERIAL: Aliquots of the dosing solutions taken from the various locations in the solution containers were used to confirm homogeneity of the dosing solution via gas chromatography (GC). Stability analysis was not performed.

Duration and frequency of treatment / exposure:

single-dose

Doses / concentrations

Remarks:

Doses / Concentrations:
25 and 1000 mg DPM/kg body weight

No. of animals per sex per dose / concentration:

3 rats + 3 rabbits/dose/lot (treatment groups)
2 rats + 2 rabbits (control group)

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: based on previous studies
- Rationale for animal assignment (if not random): animals were stratified by body weight and randomly assigned to treatment groups using a computer program

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Body fluids sampled : urine and faeces
- Time and frequency of sampling: Rat/rabbit urine (12, 24, 48 and 72 hours post-dosing), rat/rabbit feces (24 hour intervals)

METABOLITE CHARACTERISATION STUDIES
- Body fluids sampled : urine
- Time and frequency of sampling: Rat/rabbit urine (12, 24, 48 and 72 hours post-dosing)
- From how many animals: samples not pooled, individual analysis performed
- Method type(s) for identification (GC-MS)
- Limits of detection and quantification: not specified in the report

Statistics:

Descriptive ststistics (mean, standard deviation) was calculated in Microsoft Excel spreadsheets and databases. Pharmacokinetic parameters were estimated for urine data, including AUC (area-under-the-curve) and elimination rate constants, using PK Functions for Microsoft Excel (J. I. Usansky, A. Desai, and D.Tang-Liu, Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine,California (Pizarro et al., 2004)). Elimination rates were calculated via the Sigma-Minus method of amount of compound remaining to be eliminated (Gibaldi andPerrier, 1982). Statistical differences between pairs of dose groups were evaluated via Bartlett and T-tests.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not evaluated

Details on distribution in tissues:

not evaluated

Details on excretion:

The total amount of methoxypropionic acid (MPA) recovered from the dosed animals ranged from 1.5-2.4% and 5.8-12.2% of the administered dose for rabbits and rats, respectively. The rate of methoxypropionic acid (MPA) excretion was substantially faster in the rat than the rabbit. The urinary excretion half-life was calculated to be 7.5-8.1 hours for the female rats. In contrast, MPA was eliminated at a much slower rate by rabbits, corresponding to the urinary elimination half-life of 17.4-20.9 hours. No apparent dose-dependency was observed in MPA elimination rates in either species.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Methoxypropionic acid (MPA) was found as a measurable metabolite from both species, at both dose levels and from both lots of the test material. The relative formation of MPA was highest in the rat, comprising 5.8-12.2% of the administered dose. In contrast, substantially lower levels of MPA were
found in the urine of the rabbit (1.5-2.4% of administered dose). The rate of MPA formation appeared to be dose proportional in the rabbit, and more than dose proportional in the rat. Excretion of MPA was substantially slower in the rabbit than the rat, with calculated half-lives of 17.4-20.9 hours and 7.5-8.1 hours, respectively. The formation of MPA was 1.2-1.6 fold higher from the lot of test material containing the highest levels of the 1,1- and 1,2-isomers (86.81% [Lot 2] vs. 51.17%[Lot 1]).

Applicant's summary and conclusion

Conclusions:

The metabolic conversion of dipropylene glycol methyl ether (DPM) to 2-methoxypropionic acid (MPA) was examined in the female CD rat and the female New Zealand White rabbit. Following oral administration of either 25 mg/kg or 1000 mg/kg of DPM, the amount of MPA excreted in the 0-72 hour urine was determined for each test species. Two different lots of DPM with differing ratios of the 1,1- and 1,2-isomers were used as test materials in this study to investigate isomer-related differences in MPA formation. MPA was found as a measurable metabolite from both species, at both dose leve ls and from both lots of the test material. The relative formation of MPA was highest in the rat, comprising 5.8-12.2% of the administered dose. In contrast, substantially lower levels of MPA were found in the urine of the rabbit (1.5-2.4% of administered dose). The rate of MPA formation appears to be dose proportional in the rabbit, and more than dose proportional in the rat. Excretion of MPA was substantially slower in the rabbit than the rat, with calculated half-lives of 17.4-20.9 hours and 7.5-8.1 hours, respectively. The formation of MPA was 1.2-1.6 fold higher from the lot of test material containing the highest levels of the 1,1- and 1,2-isomers (86.81%[Lot 2] vs. 51.17%[Lot 1]).

Executive summary:

The metabolic conversion of dipropylene glycol methyl ether (DPM) to 2 -methoxypropionic acid (MPA) was examined in three female CD rats and three female New Zealand White rabbits. Following oral administration of either 25 mg/kg or 1000 mg/kg of DPM, the amount of MPA excreted in the 0-72 hour urine was determined for each test species. Two different lots of DPM with differing ratios of

the 1,1- and 1,2-isomers were used as test materials in this study to investigate isomer-related differences in MPA formation. MPA was found as a measurable metabolite from both species, at both dose leve ls and from both lots of the test material. The relative formation of MPA was highest in the rat, comprising 5.8 -12.2% of the administered dose. In contrast, substantially lower levels of MPA were

found in the urine of the rabbit (1.5-2.4% of administered dose). The rate of MPA formation appears to be dose proportional in the rabbit, and more than dose proportional in the rat. Excretion of MPA was substantially slower in the rabbit than the rat, with calculated half-lives of 17.4-20.9 hours and 7.5-8.1 hours, respectively. The formation of MPA was 1.2-1.6 fold higher from the lot of test material containing the highest levels of the 1,1- and 1,2-isomers (86.81% vs. 51.17%).