Propane-1,2-diyl diacetate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

7-17 April 1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to test guidelines and in accordance with GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Principles of method if other than guideline:

Groups of 5 male and 5 female rats were exposed to 0, 20, 100 or 200 ppm (0, 0.13, 0.65 or 1.31 mg/L, respectively) for 6 hours/day, 5 days/week for a total of 9 exposures during an 11-day interval. In-life body weights, urinalyses, hematology, clinical chemistry, organ and organ/body weights, gross pathology or histopathology were examined.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propane-1,2-diyl diacetate

EC Number:

210-817-6

EC Name:

Propane-1,2-diyl diacetate

Cas Number:

623-84-7

Molecular formula:

C7H12O4

IUPAC Name:

propane-1,2-diyl diacetate

Details on test material:

The test substance (I. D. No. XZ87265) was obtained with analysis from Dow Chemical Europe. The identity was confirmed and the purity was determined to be 100% + 0.5% by nuclear magnetic resonance (Hasha, 1986) and gas chromatography (Warriner, 1986).

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female Fischer 344 rats (7 weeks of age) were purchased from Charles River Breeding Laboratories, Inc., Kingston, New York. Selection of this species and strain was based on a variety of considerations including hardiness, low incidence of respiratory disease and historical control data. Upon arrival in the laboratory, the rats were examined for health status by the laboratory animal veterinarian and acclimated to the laboratory for approximately 5 weeks prior to exposure. Animals were fed Purina Certified Rodent Chow #5002 (Ralston Purina Company, St. Louis., Missouri) and water ad libitum except during exposure. Water and feed analyses were performed according to the Standard Operating Procedures of the Mammalian and Environmental Toxicology Research Laboratory.

Rats were weighed and randomized by weight into respective groups. Animals were individually identified with a metal ear tag, and housed one per cage in rooms designed to maintain adequate environmental conditions concerning temperature and relative humidity and which are regulated for the specific species under test.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Not applicable.

Details on inhalation exposure:

Chambers.
Exposures were conducted using 1 m3 stainless steel and glass Rochester-type chambers. The airflow through the chambers was calibrated and maintained at approximately 150 liters/min. The air supplied to the chambers was controlled by a system designed to maintain temperature at approximately 22°C and relative humidity at approximately 50%. The temperature and relative humidity in each chamber were recorded at the end of each exposure period.

Vapor Generation.
The animals were exposed to target concentrations of 0 (control), 20, 100 or 200 ppm (0, 0.13, 0.65 or 1.31 mg/L, respectively) PGDA vapors 6 hours per day, 5 days per week, for a total of 9 days during a 2-week interval. The highest concentration was near to the maximum practically attainable concentration for PGDA. The liquid test substance was vaporized according to methods described by Miller et. al., (1980a). The nominal concentration (ratio of the amount of test material vaporized to the total amount of air through the chambers) was calculated for each chamber on a daily basis.

Reference
Miller, R. R., Letts, R. L., Potts, W. J. and McKenna, M. J. (1980a). Improved methodology for generating controlled test atmospheres. Am. Ind. Hyg. Assoc. J. 41:844-846.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The actual concentration in each chamber was measured 1-2 times/hr using a MIRAN 1A infrared gas analyzer. The analytical equipment was standardized by vaporizing measured voiumes of the test substance in Teflon bags filled with a measured volume (50 L) of air. The concentration of PGDA in each chamber was then.determined by interpolation from a standard curve via a microprocessor unit as described in Dow Chemical Company report, (1980b). Standardization of the analytical system was evaluated each day prior to exposure with at least one standard of known concentration.

Reference
Dow Chemical Company report (1980b). Automated data acquisition system for monitoring controlled test atmospheres in inhalation studies. Unpublished report, Toxicology Research Laboratory, Dow Chemical U.S.A.

Duration of treatment / exposure:

6 hours/day

Frequency of treatment:

5 days/week for 9 exposures in 11 days (Monday through Friday exposures followed by Monday through Thursday exposures)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 100 or 200 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

5 males and 5 females per exposure group

Control animals:

yes, sham-exposed

Details on study design:

Male and female Fischer 344 rats were exposed 6 hours/day, 5 days/week, for two weeks (nine exposures interrupted by one weekend) to vapors of propylene glycol diacetate (PGDA). The study was performed from 7 April 1986 to 17 April 1986. There were 5 rats/sex in a control group and each of three exposure groups. On the day following the last exposure, all animals were examined for gross pathologic lesions. Urine and blood were obtained for selected clinical evaluations. Major organs were weighed, and tissues saved in buffered formalin for subsequent examination. Vapor inhalation was selected as the means of administration because this is a relevant potential route of human .exposure.

Positive control:

Not applicable.

Examinations

Observations and examinations performed and frequency:

All animals were observed after each day of exposure for overt signs of toxicity. The observations included an evaluation of the fur, eyes, mucous membranes, and respiration. Behavior pattern and nervous system activity were also assessed by specific observations for tremors, convulsions, salivation, lacrimation and diarrhea, as well as lethargy and other signs of central nervous system depression. An additional daily observation and observations on holidays and weekends were made to ensure the availability of food and water. All animals were weighed prior to the first day of exposure and again prior to, the 3rd, 5th, and 11th days of exposure.

Sacrifice and pathology:

Hematology.
Blood samples were collected. by orbital sinus puncture from rats anesthetized with methoxyflurane immediately prior to necropsy. The following hematologic parameters were evaluated for each animal with an Ortho ELT-8 (Ortho Instruments; Boston, MA): hematocrit (PCV), hemoglobin (HGB), erythrocyte count (RBC), total leukocyte count (WBC), and platelet count (PLAT). Slides for differential leukocyte counts were prepared for all animals. Differential white counts were performed only for animals in the control and high exposure groups.

Clinical Chemistry.
Blood samples for serum analysis were collected at the terminal sacrifice from severed cervical blood vessels. The samples were chilled with crushed ice until analyzed. The following parameters were measured: urea nitrogen (UN), alanine aminotransferase activity (ALT) , aspartate aminotransferase activity (AST) , alkaline phosphatase activity (AP), glucose (GLUC), total protein (TP), albumin (ALB), and globulins (GLOB).

Urinalysis.
Urine was collected from rats prior to the 9th exposure. The following parameters were measured : bilirubin, glucose, ketones, blood, pH, protein and urobilinogen, and specific gravity.

Pathology.
All animals were sacrificed the day following the last exposure. The rats were fasted overnight prior to the scheduled sacrifice. Each animal was weighed, anesthetized with methoxyflurane, and sacrificed. Weights of the brain, liver, kidneys, adrenals and testes were recorded from animals at the scheduled sacrifice. All animals were examined for gross pathologic alterations by a veterinary pathologist. The necropsy included in situ examination of the eyes by a glass-slide technique with fluorescent illumination. A complete set of tissues was collected from each animal and preserved in neutral, phosphate-buffered 10% formalin. The lungs were infused with buffered formalin to their approximate normal inspiratory volume and the nasal cavity was flushed with formalin via the pharyngeal duct to insure rapid fixation of the tissue. Histopathologic examinations were performed on complete sets of tissues for rats in control and high exposure groups (except auditory sebaceous glands). Respiratory tract tissues were examined histopathologically for animals in the middle and low exposure groups. Tissues to be examined histopathologically were processed by conventional techniques, stained with hematoxylin and eosin and evaluated by light microscopy.

Other examinations:

No additional information available.

Statistics:

Descriptive statistics (mean and standard deviation) were reported for white blood cell differential counts. Body weights, absolute and relative organ weights, clinical chemistry data, appropriate hematology data and urinary specific gravity were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, exploratory data analysis was performed by a parametric or non-parametric analysis of variance {ANOVA), followed by Dunnett's test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons. Statistical outliers were identified by a sequential test but were nevertheless included in calculations.

The nominal alpha levels to be used and test references are as follows:
Bartlett's test (Winer, 1971) a = 0.01
Parametric ANOVA (Steel, 1960) a = 0.10
Non-parametric ANOVA (Hollander and Wolfe, 1973) a = 0.10
Dunnett's test (Winer, 1971) a. = 0.05, two-sided
Wilcoxon Rank-Sum test (Hollander and Wolfe, 1973) a = 0..05, two-sided
Bonferroni correction (Miller, 1966)
Outlier test (Grubbs, 1969) a = 0.02, two-sided

Since multiple, interrelated parameters are statistically compared in the same group of animals, the frequency of false positive errors may be much greater than the nominal alpha level. Thus, in addition to statistical analyses, the final toxicologic interpretation of the data also considered factors such as dose-response relationships and whether or not the findings appeared to be plausible and consistent in the light of other biologic findings.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

Exposure Chamber Conditions. The mean-daily time-weighted average (TWA) exposure concentrations were very close to the targeted concentrations. In addition, there was close agreement between the mean daily TWA analytical concentration and the mean daily nominal concentration for each chamber, indicating minimal test material losses in the vapor generation and exposure systems. The relative humidity in the exposure chambers was somewhat low as a result of the winter conditions at the time of the study.

Antemortern Observations.
All rats survived to the scheduled sacrifice date. No differences in body weights of treated animals were seen in either sex throughout the
study. No clinical signs of toxicity were seen at any dose level.

Pathology Observations.
There were no changes of toxicologic significance in urinalysis, hematologic or clinical chemistry examinations or organ and organ/body
weights. The few gross and histopathologic changes seen were considered spontaneous changes typical of rats of this age and strain and were not
considered effects of treatment with PGDA.

Effect levels

Dose descriptor:

NOEC

Effect level:

> 200 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: The highest exposure concentration was near the maximum practically attainable concentration for PGDA. Even at this exposure concentration there were no discernible effects of treatment with PGDA.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No additional information available.

Applicant's summary and conclusion

Conclusions:

The highest exposure concentration was near the maximum practically attainable concentration for PGDA. Even at this exposure concentration there were no discernible effects of treatment with PGDA. Considering the low vapor pressure of PGDA it is unlikely that PGDA would pose a human vapor inhalation hazard at room temperature and normal atmospheric pressure.

Executive summary:

A two week inhalation study in Fischer 344 rats was conducted to assess possible toxicity of propylene glycol diacetate (PGDA). Male and female rats (5 rats/sex/dose) were exposed to target concentrations of 0 (control), 20, 100 or 200 ppm (0, 0.13, 0.65

or 1.31 mg/L, respectively) of PGDA vapors 6 hours per day for a total of 9 days during an 11 -day interval. No changes of toxicologic significance were seen in body weights, urinalyses, hematology, clinical chemistry, organ and organ/body weights, gross pathology or histopathology.

The highest exposure concentration was near the maximum practically attainable concentration for PGDA. Even at this exposure concentration there were no discernible effects of treatment with PGDA. Considering the low vapor pressure of PGDA it is unlikely that PGDA would pose a human vapor inhalation hazard at room temperature and normal atmospheric pressure.