Propylene carbonate

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: sub-chronic inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1989-02-20 to 1989-05-25

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented scientifically sound non-guideline study performed under GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1991

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Study pre-dates guideline

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propylene carbonate

EC Number:

203-572-1

EC Name:

Propylene carbonate

Cas Number:

108-32-7

Molecular formula:

C4H6O3

IUPAC Name:

4-methyl-1,3-dioxolan-2-one

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): propylene carbonate (TEXACAR PC)
- Lot/batch No.: 9A-502
- Storage condition of test material: Chemical storage room blanketed with nitrogen
- Other: Source- Texaco Chemical Company, Austin, Texas

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc., Fredrick, MD
- Age at study initiation: 61 days
- Housing: 1-3 per cage, same sex, during non exposure period, individual during exposure, 15 x 22 x 18 cm wire mesh cages
- Diet: Agway Pro Lab powdered food, ad libitum
- Water: Water ad libitum via automatic watering system
- Acclimation period: 2 -3 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): monitored continuously.
- Humidity (%): monitored continuously.
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hour light/dark photoperiod throughout the study.

Administration / exposure

Route of administration:

inhalation: aerosol

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation chamber
- Method of holding animals in test chamber: wire mesh cage
- Source and rate of air: Filtered forced air
- System of generating particulates/aerosols: The test substance was metered from a piston pump into an atomizer fitted withe a liquid nozzle and and air nozzle. The atomizer was inserted into the top of the inhalation turret where the liquid aerosols were dispersed by the filtered chamber supply air.
- Air flow rate: 300 L/min
- Air change rate: 13.5 changes/hr
- Method of particle size determination: Cascade impactor. Measurements made twice a week for each concentration.

TEST ATMOSPHERE
- Brief description of analytical method used: A 25 minute sample was taken from each chamber each day using a vacuum pump dry gas meter or flow meter.
- Samples taken from breathing zone: no

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

6 hours/day, 5 days/week, 13 weeks

Frequency of treatment:

Daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500, 1000 mg/m³
Basis:
nominal conc.

No. of animals per sex per dose:

15 males, 15 females

Control animals:

yes, sham-exposed

Examinations

Observations and clinical examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No


DETAILED CLINICAL OBSERVATIONS: no


BODY WEIGHT: Yes- prior to test initiation for group assignment

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to exposure and on May 17, 1989.
- Dose groups that were examined:All rats


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Week 5 and 14
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: Yes
- How many animals: 10/sex/group
-20 blood chemistry analyses performed


CLINICAL CHEMISTRY: Yes -see above


URINALYSIS: Yes
- Time schedule for collection of urine: 15 hours from 10/sex/group prior to sacrifice
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: 1 and 13 hrs, 6 weeks, 13 weeks
- Dose groups that were examined: Satellite group, 10/sex/dose
- Battery of functions tested: motor activity

Neurobehavioural examinations performed and frequency:

A screen for behavioral functions was performed at 1 and 23 hours after the cessation of the first exposure. No further details on the extent or type of testing performed was provided.

A functional observation battery was performed after 6 weeks, and 13 weeks of exposure.
- The conduct of the FOB involved handling of each animal, evaluating and recording the absence or presence of a predetermined set of behavioral signs and their severity if appropriate. During the examination the animal was placed in a clean plexigalss cage and evaluated for approximately 2 minutes for horizontal and vertical activity, convulsions, tremors, stereotypy, piloerection, respiration,urination, gait, and acoustic startle response. The animal was then held and evaluated for pupil size, pupil response to light, vocalization, salivation, mouth breathing, lacrimation, diarrhea, visual placing, and muscle tone. Catatonia, fore and hindlimb grip strength, surface and air righting reflexes, performance on a rotating treadmill, positive geotropism (inclined screen turn), toe and tail withdrawal reflexes, hind limb splay, and rectal temperature were subsequently evaluated using simple equipment. Body weight measurements were also recorded during the FOB.

Motor activity evaluations were performed performed following 6 weeks and 13 weeks of exposure.
- All animals were tested using an automatic recording apparatus. Ass test sessions were 90 minutes in duration. Data for ambulatory activity, fine motor activity, rearing activity and the sum of these activities (total activity) were collected.

Statistics:

FOB data: The data for continuous, parametric variables were intercompared for the exposed and control groups by use of Levene's test for homogeneiety of variances, by analysis of variance, and by pooled variance t-tests. Comparisons to the control group for frequency data were made using Fisher's exact probablity test. A fiducial limit of 0.05 was used for all comparisons.

Data for Motor Activity Session Cumulative counts (i.e., 0-90 minutes) were analyzed as a continuous parametric FOB variable. Motor activity data presented in 10 minute intrasession intervals were analyzed by repeat measures analysis with exposure level and sex as grouping factors and session time as the within subject factor. The epsilon-adjustment procedure (Greenhouse-Geisser correction) was used in tha analysis of time by exposure level interactions. Significant sex effects (p<0.05) were observed and consequently motor activity data was analyzed separately.
All statistical tests were performed using BMDP statistical software.

Results and discussion

Results of examinations

Behaviour (functional findings):

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

no effects observed

Details on results:

Effects of single exposure - 1 and 23 hour evaluations: There were no exposure related changes in the FOB parameters for males or females.


Effects of repeat exposure 42 and 91 day evaluations: No exposure related changes in the FOB parameters following repeated exposure to the test substance. Statistically significant decreases in mean recatl temperatures in males exposed to 100 mg/m3 on study day 42 and mean treadmill times for theis same dose group on study day 91 were not considered biologically significant based on the lack of dose response, the lack of similar effects in females, the lack of associated FOB findings in males, and the small magnitude of cahnge in the treadmill time.

There were no exposure related changes in the motor activity for males of females following repeated sposure to propylene carbonate.

Effect levels

Dose descriptor:

NOAEL

Basis for effect level:

other: The authors did not identify a NOAEL, however, no neurotoxic effects could be measured in the treated rats.

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Applicant's summary and conclusion

Conclusions:

The test substance had no measured neurotoxic effects in rats.