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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the Principles of GLP and the report contains sufficient information to permit a meaningful evaluation of study results

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Objective of study:
other: in vitro hydrolysis and kinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The aim of this study were to determine the in vitro rates of hydrolysis of PGMEA to PGME in whole blood from rats and humans as well as the half-life for hydrolysis in liver homogenate from rats and humans. Another aim was to determine the blood kinetics of PGMEA and PGME following intravenous administration to Fischer 344 rats.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Propylene Glycol Monomethyl Ether Acetate (PGMEA) and Propylene Glycol Monomethyl Ether (PGME)
- Physical state: liquid
- Analytical purity: PGMEA: 99.32% and PGME: 99.63%
- Composition of test material, percentage of components: not specified in the report
- Isomers composition: not specified in the report
- Lot/batch No.: PGMEA: The Dow Chemical Company, Midland, Michigan (OA17019G04), PGME: Aldrich, Milwaukee, Wisconsin (OB1001B101)
- 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:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories for non-cannulated animals and Hilltop Lab Animals, Inc. for jugular vein cannulated animals
- Age at study initiation: approximately 10 weeks old
- Weight at study initiation: 191-210 g
- Fasting period before study: not specified in the report
- Housing: Non-cannulated animals were housed two per cage in stainless steel cages and jugular vein cannulated animals were housed individually
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): LabDiet Certified Rodent Diet #5002 in pelleted form provided ad libitum
- Water (e.g. ad libitum): Municipal water provided ad libitum
- Acclimation period: Non-cannulated animals were acclimated to the laboratory environment for at least one-week prior to use. Jugular vein cannulated rats were acclimated in metabolism cages for one day prior to use.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25 °C
- Humidity (%): 38-48%
- Air changes (per hr): 12-15 times/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark photocycle

Administration / exposure

Route of administration:
intravenous
Vehicle:
physiological saline
Details on exposure:
PREPARATION OF INTRAVENOUS DOSING SOLUTIONS: For dose solutions administered intravenously, PGME or PGMEA was weighed directly in a tared vial and physiological saline was added to reach final concentrations of 5 mg PGME/ml or 7.35 mg PGMEA/ml. Similarly for the higher concentrations, PGME or PGMEA was weighed directly in a tared vial and physiological saline was added to reach final concentrations of 50 mg PGME/ml or 73.5 mg PGMEA/ml.

All dose solutions were within 90-101% of their targeted concentrations. For targeted PGME doses of 10 or 100 mg/kg, the actual mean values were
10.72 or 99.57 mg/kg, respectively. For targeted PGMEA doses of 14.7 or 147 mg/kg, the actual mean values were 16.83 or 142.42 mg/kg, respectively.
Duration and frequency of treatment / exposure:
12 hour(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 10 and 100 mg PGME/kg body weight
Males: 14.7 and 147 mg PGMEA/kg body weight
No. of animals per sex per dose:
Males: four cannulated rats/group
Control animals:
not specified
Positive control:
not applicable
Details on study design:
- Dose selection rationale: Based on previously conducted studies
- Rationale for animal assignment: randomly assigned to treatment groups using a computer-driven randomization procedure
Details on dosing and sampling:
Blood samples of about 0.1 ml each were drawn from the jugular cannula 5, 10, 15, 30, 45 minutes, and 1, 2, 4, 6, 8, 12 hours post dosing using a heparinized syringe.
Statistics:
All data based calculations were conducted using Microsoft Excel with full precision (Microsoft Corporation, 1998). Descriptive statistics were calculated mean +/- standard deviation (SD) for all sets of data collected during the study. The in vivo concentration time course of PGME and PGMEA in plasma was described by a noncompartmental model using the method of residuals and linear regression to estimate the half-life (PK Solutions, Summit Research Services, Ashland, Ohio). PK Solutions was also used to estimate rates of hydrolysis for PGMEA in the in vitro studies.

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
not measured

Any other information on results incl. tables

Plasma time courses of PGME in rats following intravenous administration of a low-dose of PGME or PGMEA were indistinguishable, within experimental error of the measurements. For the high-dose of PGME or PGMEA, time courses of PGME were also identical. Half-lives for PGME following administration of a low-dose of PGME or PGMEA were 8.1 and 10.4 minutes, respectively. These data are in agreement with a probe study conducted by Stott et al., 1982 where the half-life was determined to be 5.72 minutes following IV administration of 10 mg PGMEA/kg bw.

Plasma time courses of PGMEA in rats following intravenous administration of 14.7 or 147 mg PGMEA/kg bw were determined. Half-lives were 1.55 and 3.37 minutes following intravenous administration of the low- and high-dose, respectively. These data are in agreement with a probe study conducted by Stott et al., 1982 where the half-life was determined to be 2.2 minutes following IV administration of 50 mg PGMEA/kg bw.

In summary, data from this study support rapid hydrolysis of PGMEA in vivo and once hydrolyzed, the kinetics of PGME derived from the ester PGMEA are identical to the kinetics for PGME. The findings also support the existing toxicology database on PGMEA. Since PGMEA was not detected in the plasma or urine of rats exposed to PGMEA via inhalation indicates that the parent chemical is very rapidly and extensively hydrolyzed, presumably via tissue and plasma carboxylesterases. In studies by Stott and McKenna, 1984 and 1985, and Miller 1984, PGME and PGMEA vapors were extensively absorbed by the upper respiratory tract and PGMEA was shown to be a substrate for nasal carboxylesterase in an in vitro study.

Applicant's summary and conclusion

Conclusions:
PGME was injected intravenously to rats at dose of 10 and 100 mg/kg . Blood samples were collected up to 12 hours post exposure to determine kinetic parameters. PGMA was also tested with the same experimental procedures in order to determine kinetic differences between the two substances. Half lives of blood PGME were 10.36 and 38.62 min for the low and high dose respectively
Executive summary:

For investigation of the kinetics of PGME or PGMEA following intravenous administration via the jugular vein cannula, equimolar doses of 10 mg PGME/kg or 14.7 mg PGMEA/kg and 100 mg PGME or 147 mg PGMEA/kg were used. Blood samples were drawn from the jugular vein cannula at 5, 10, 15, 30, 45 minutes and 1, 2, 4, 6, 8, and 12 hours post-dosing. The samples were analyzed via PCI+EI-GC/MS for determination of PGMEA and PGME.

Plasma time course of PGME in rats following intravenous administration of 10 mg PGME/kg bw or 14.7 mg PGMEA/kg bw were

identical. For the high-dose of 100 mg PGME/kg or 147 mg PGMEA/kg, time courses of PGME were also identical.

Plasma time courses of PGMEA in rats following intravenous administration of 14.7 or 147 mg PGMEA/kg bw were determined. Half lives were 1.55 and 3.37 minutes following intravenous administration of the low- and high-dose, respectively.

In summary results from these studies as well as from earlier studies indicate that propylene glycol monomethyl ether acetate is rapidly hydrolyzed in the body to its parent glycol ether, propylene glycol monomethyl ether. Once hydrolyzed the kinetics for PGME derived from PGMEA is identical to that for PGME.