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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
September 27, 1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to GLP and the report contains sufficient information to permit a meaningful evaluation of study results.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983
Reference Type:
publication
Title:
Metabolism and Disposition of Dipropylene Glycol Monomethyl Ether (DPGME) in male rats
Author:
R.R.Miller, E.A.Hermann, L.L.Calhoun, P.E.Kastl and D.Zakett
Year:
1985
Bibliographic source:
Fundamentals of Applied Toxicology; 1985; 5: 721-726

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Male Fischer 344 rats were given a single oral dose of approximately 8.7 mmole/kg of 14C DPGME. After dosing, expired air, excreta and tissues were analysed for 14C activity and metabolites in urine were isolated and identified.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dipropylene Glycol Monomethyl Ether (DPGME)
- Analytical purity: >98% (unlabelled)
- Isomers composition: 4 isomers (87.4:11.2:1.3:0.1) - unlabelled (sourced from Organic Chemicals)
- Purity test date: not specified in the report
- Lot/batch No.: DPC-132-5
- Expiration date of the lot/batch: not specified in the report
- Radiochemical purity (if radiolabelling): 93.2% (sourced from Wizard Laboratories)
- Specific activity (if radiolabelling): 5 µCi/mole
- Locations of the label (if radiolabelling): not specified in the report
- Expiration date of radiochemical substance (if radiolabelling): 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:
yes
Remarks:
14C DPGME

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: 175-200 grams
- Fasting period before study:
- Housing: individual
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days (laboratory conditions) + 2 days (glass Roth-type metabolism cage)


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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: (DPGME) 2.3:1 (water)
Details on exposure:
ORAL

PREPARATION OF DOSING SOLUTIONS: DPGME was diluted in 2.3:1 ratio in water
Duration and frequency of treatment / exposure:
Oral - single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
Oral - 1289 mg/kg
No. of animals per sex per dose:
Oral - 3 male animals
Control animals:
not specified
Details on study design:
- Rationale for animal assignment (if not random): animals assigned to dosage groups using a computer assisted randomization procedure
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, expired air, blood, liver, kidney, fat, brain, skin, carcass and cage-wash
- Time and frequency of sampling: 4, 8, 12, 24, 36 and 48 hours (three animals - oral)

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: same as above
- From how many animals: samples pooled from 3 animals
- Method type(s) for identification: Radioactivity in tissues was analysed using a biological oxidizer in order to determine the total post exposure body burden. Radiolabeled metabolites of 14C DPGME in urine were isolated via an ion-exclusion chromatography system quantitated by use of an in-line radioactivity detector. The fractions from the ion-exclusion chromatography system were analysed using one or more of the following techniques - chemical ionization-gas chromatography-mass spectrometry interfaced with a Panax radiogas detector or Fast atom bombardment (FAB) mass spectrometry and MS/MS. The mass spectrometry was performed with either a Finnigan Model 3200 chemical ionization mass spectrometer equipped with a Model 6110 data system or a Finnigan TSQ MS/MS spectrometer equipped with FAB capabilities.
- Limits of detection and quantification: not specified in the report

Statistics:
standard statistics (mean and standard deviation)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The liver and skin had the greatest amounts of radiolabeled DPGME per gram of the various tissues which were evaluated 48 hours after dosing with 14C DPGME. The 14C activity in the liver was approximately 1.93 fold greater than for blood and the 14C in skin was 2.21 fold greater than in blood. Fat, kidney and body had appreciably less radiolabeled DPGME per gram than blood. Refer to table 1-2 for further details
Details on distribution in tissues:
The liver and skin had the greatest amounts of radiolabeled DPGME per gram of the various tissues which were evaluated 48 hours after dosing with 14C DPGME. The 14C activity in the liver was approximately 1.93 fold greater than for blood and the 14C in skin was 2.21 fold greater than in blood. Fat, kidney and body had appreciably less radiolabeled DPGME per gram than blood. Refer to table 1-2 for further details
Details on excretion:
Urine and expired CO2 were the major routes of elimination of radioactivity after dosing with 14C DPGME. Approximately 60% of the 14C DPGME was excreted in urine, while 27% was eliminated as 14CO2 within 48 hours after an oral dose of 14C DPGME. Less than 3% of the dose was recovered in feces, indicating that the test material was effectively absorbed.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Four major radiolabeled peaks and one minor radiolabeled peak were identified in urine from rats during the 0-12 hour interval after dosing with 8.7 mmole/kg 14C DPGME.
The first peak had a retention time of 11 minutes and represented 15% of the 14C in urine which was conclusively identified as the sulfate conjugate of DPGME.
The second peak had a retention time of 22 min and 16% of the 14C which indicated the peak to be a glucuronide conjugate of DPGME.
The third peak had a retention time of 26 minutes and 16% of the 14C and this was identified as propylene glycol (the GC and LC retention times of this peak was same as that of propylene glycol, however, this peak had insufficient ion intensity to obtain a total positive ion mass spectrum.
The LC retention times of the fourth peak were consistent with those obtained for PGME and dipropylene glycol (DPG).
The LC and GC retention times of the fifth peak were the same as DPGME.

Applicant's summary and conclusion

Conclusions:
Based on the results, there were no major differences in the toxicologic properties of DPGME and PGME and DPGME was biotransformed via the same routes to the same general types of metabolites as identified for PGME.
Executive summary:

Male Fischer 344 rats were given a single oral dose of approximately 8.7 mmole/kg of 14C DPGME. After dosing expired air, excreta and tissues were analysed for 14C activity and metabolites in urine were isolated and identified.

Approximately 60% of the 14C DPGME was excreted in urine, while 27% was eliminated as 14CO2 within 48 hours after an oral dose of 14C DPGME. Less than 3% of the dose was recovered in feces, indicating that the test material was effectively absorbed. DPGME was not completely hydrolysed to PGME and a higher percentage of the radiolabeled DPGME was eliminated in the urine after dosing with DPGME than occurred with PGME or PGMEA. DPGME, PGME, dipropylene glycol, propylene glycol as well as sulfate and glucuronide conjugates of DPGME were identifed in urine of animals. Therefore, DPGME is apparently metabolized via the same routes to the same general types of metabolites as those for PGME.