2-methoxy-1-methylethyl acetate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

repeated dose toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented publication, GLP

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2002

Materials and methods

Principles of method if other than guideline:

Combined Chronic Toxicity / Carcinogenicity Study, 24 months in mice. Additional groups of male and female animals used to examine S-phase DNA synthesis and MFO activity were exposed to vapor at 1 or more of the exposure levels used in the toxicity studies/bioassays for 26, 52, or 78 weeks.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-methoxypropan-2-ol

EC Number:

203-539-1

EC Name:

1-methoxypropan-2-ol

Cas Number:

107-98-2

Molecular formula:

C4H10O2

IUPAC Name:

1-methoxypropan-2-ol

Details on test material:

- Name of test material (as cited in study report): PGME
- Analytical purity: >=99.96%

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Portage, MI)
- Age at study initiation: 6-8 weeks
- Housing: singly
- Diet: Purina Certified Rodent Chow #5002 (Purina Mills, Inc, St. Louis, MO), ad libitum
- Water: ad libitum
- Acclimation period: 14 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-2
- Humidity (%):40-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

Animals were whole-body exposed to PGME vapor under dynamic airflow conditions, which provided approximately 12 changes/hour of chamber air, and maintained normal oxygen concentration. Vapor was generated by metering liquid PGME into a glass J-tube assembly, through which was passed a preheated stream of compressed air. The compressed air was heated to the minimum extent necessary to vaporize all of the test material (approximately 65, 105, and 120-160°C for 300, 1000, and 3000 ppm chambers, respectively).
Compressed air and PGME vapor were diluted with room air to achieve a flow rate of 2900 Lpm and the desired PGME vapor concentration.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical concentration of PGME in the breathing zone of the animals was measured, twice per hour, with a infrared spectrophotometer. In addition, the amount of PGME used daily for each chamber was recorded, and the nominal concentrations of PGME vapor were calculated.

The mean time-weighted average chamber concentrations were within 0.5% of the target concentrations for all of the studies. The distribution of PGME at the extremes of the animal breathing zones was measured periodically and generally found to be within 1-2% of the reference sample line.

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 300, 1000 and 3000 ppm, corresponding to ca. 1.11, 3.69 and 11.07 mg/L (calculated with a conversion factor of 3.69 mg/m3 per ppm)
Basis:
analytical conc.

No. of animals per sex per dose:

main study (Group A): 50 (sacrificed after 24 months)
cell proliferation in liver and kidneys/ hepatic and/or renal S-phase DNA synthesis (Group B): 5 (6/ 12 months) or 10 (18 months)
hepatic MFO induction (Group C, only Control and high dose treatment): 5 (6/ 12 months) or 10 (18 months)

Control animals:

yes

Examinations

Observations and examinations performed and frequency:

Animals were observed at least daily and were weighed weekly for the first 13 weeks, and at 4-week intervals, thereafter; except that no in-life body weights were recorded for Group B animals after osmotic minipumps were implanted.

Blood and urine samples were obtained from 10 animals/sex/dose at 6, 12, and 18 months and from 20 animals/sex/dose at 24 months for hematology.

Sacrifice and pathology:

Selected Organs were weighed at the scheduled necropsies and a complete set of tissues from control and high-exposure animals were collected, processed, stained, and examined histopathologically. In addition, the lungs, liver, kidneys and gross lesions of intermediate- and low-exposure group animals were also examined histopathologically.

Statistics:

see "any other information"

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
Animals exposed to 3000 ppm PGME displayed decreased activity, incoordination, and transient sedation during the first week of exposures. Recovery was evident approximately 1 to 2 hours postexposure. During the second week, (where exposures continued), these effects abated and no further sedation was noted.
Cumulative mortality was increased, albeit not statistically significant, in males in the last few months of exposure to 3000 ppm PGME. In male mice cumulative mortality was 18, 20, 18, and 34% for the 0, 300, 1000, and 3000 ppm groups, respectively. The mortality of females was unaffected by treatment, ranging from 15-32%. There was no exposure-related increase in any specific cause of death that were generally typical for the strain and age of animals used in these studies.

BODY WEIGHT AND WEIGHT GAIN
PGME exposure caused a statistically significant decrease in body weights of exposed animals relative to controls during the exposure period (in-life phase of the study). Mice of both sexes exposed to 3000 ppm
PGME had statistically identified decrements in mean in-life body weights (2-7%) over much of the 2-year study. Statistically identified decrements in in-life body weights were also noted, though less frequently, in mice of both sexes exposed to 1000 ppm vapor. Despite these changes during the dosing period, no statistically identified body weight differences of treated animals of either sex were observed at study termination.

HAEMATOLOGY
No hematological effects were attributable to treatment.

CLINICAL CHEMISTRY
There were no other treatment related changes in clinical chemistry parameters.

ORGAN WEIGHTS
Males and females exposed to 3000 ppm had increases in absolute liver weight of approximately 8%, and 6% relative to controls, respectively. No treatment related effects on kidney weight were observed in exposed male or female mice.

GROSS PATHOLOGY
No treatment-related effects observed.

HISTOPATHOLOGY
No treatment-related lesions were observed in mice following 24 months of exposures to PGME vapor.

OTHER FINDINGS: MECHANISTIC STUDIES
Increases in hepatic S-phase DNA synthesis were noted in high-exposure male mice relative to controls. The lack of statistical significance in male mouse data reflected the relatively large variability in these data. The initial response of 3000 ppm exposure group female mice (2-fold increase in LI) was less robust, but generally sustained through the chronic exposure periods. Hepatic S-phase synthesis in high-exposure group male mice remained similar to that found in females.
Hepatic MFO activity in animals exposed to 3000 ppm PGME was increased to the greatest extent relative to controls during the first 13 weeks of the exposure period.
In male mice exposed to 3000 ppm PGME, PROD activity was increased approximately 1.8- to 3-fold higher than control levels for up to 18 months. In high dosed female mice, PROD activity was approximately 2-fold higher than control levels for the whole 18-month period examined. CYP1Al-dependent ethoxyresorufin 0-demethylase (EROD) activity was induced only slightly. The total hepatic Cytochrome P-450 content generally reflected the level of PROD activity over the 18 months of the exposure period examined.

Effect levels

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

ca. 3.69 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: corresponding to 1000 ppm; increased mortality, body weight decrease in the next higher dose

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

PGME induces an adaptive hepatic response characterized by increased S-phase DNA synthesis, likely related to cell proliferation, and induction of MFO enzyme activity. The resultant increased metabolism of PGME leads to an amelioration of PGME-induced sedation observed during the first week of repeated exposure to high concentrations of this chemical.

A NOAEL of 1000 ppm was established in mice, based on slight body weight decreases in both sexes.