Octanoic acid, 1,1'-(1,3-propanediyl) ester

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

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

Adequacy of study:

supporting study

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well-documented

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Principles of method if other than guideline:

Similar to OECD 412, although only males were used (4 or 5 days per week dosing, for a total of 9 exposures).

GLP compliance:

yes

Remarks:

With the following exceptions: 1) The test substance was charaterized by the Sponsor prior to the initiation of the study in a non-GLP compliant laboratory, and 2) Expired hematology analytical control material was used during clinical laboratory analysis

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propane-1,3-diol

EC Number:

207-997-3

EC Name:

Propane-1,3-diol

Cas Number:

504-63-2

Molecular formula:

C3H8O2

IUPAC Name:

propane-1,3-diol

Constituent 2

Reference substance name:

Propanediol-1,3

IUPAC Name:

Propanediol-1,3

Details on test material:

- Name of test material (as cited in study report): H-23131.
- Physical state: Colorless liquid.
- Analytical purity: 99.891%
- Impurities (identity): 2-(2-hydroxyethyl)-1,3-dioxane, 2-(3-dihydropyranyl)-1,3-dioxane, di(3-hydroxypropyl)ether, 3-hydroxymethyl)tetrahydropyran, water.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA.
- Age at study initiation: approximately 7 weeks (on day of arrival).
- Weight at study initiation: approximately 255g (before exposure on day 1).
- Fasting period before study: None.
- Housing: Singly or in pairs in suspended, stainless steel, wire-mesh cages.
- Diet: Ad libitum, except during exposure.
- Water: Ad libitum, except during exposure.
- Acclimation period: 6 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-1
- Humidity (%): 50+/-10
- Air changes (per hr): Not stated in report.
- Photoperiod (hrs dark / hrs light): 12/12.


IN-LIFE DATES: From: 02-Jun-1998 To: 06-Jul.1998.

Administration / exposure

Route of administration:

other: Inhalation: vapor only, or vapor/aerosol mixture.

Type of inhalation exposure:

nose only

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: MMAD (intermediate and high-level chambers) 2.2 to 2.4um and >99% of the particles were <10um. There was insignificant aerosol in low-level chamber.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposure chambers were contructed of glass (cylindrical) with polymethylmethacrylate face plates and had a nominal internal volume of 38L. A polycarbonate baffle approximately 4 inches from the chamber inlet promoted uniform chamber distribution of the test atmosphere.
- Method of holding animals in test chamber: Individually restrained in polycarbonate cylinders with conical nose pieces. The restrainers were inserted into the polymethylmethacrylate face plate of the exposure chamber so that only the nose of each rat extended into the chamber.
- Source and rate of air: Preheated houseline air (low-level chamber) or high pressure air (intermediate- and high-level chambers).
- Method of conditioning air: Preheated.
- System of generating particulates/aerosols: Metered liquid test substance into a glass, heated mixing flask where preheated houseline air was introduced and carried into the exposure chamber (low-level chamber). Metered liquid test substance into a Spraying Systems nebulizer where high pressure air was introduced and carried into the exposure chamber (intermediate- and high-level chambers).
- Temperature, humidity, pressure in air chamber: 25-28°C, 36-53%, pressure not stated.
- Air change rate: 12 air changes/hour.
- Method of particle size determination: Sierra Series 210 Cyclone Preseparator/Cascade Impactor and Sierra Series 110 Constant Flow Sampler (only for intermediate- and high-level chambers, no appreciable aerosol component in low-level chamber)..
- Treatment of exhaust air: Discharged through a water-filled scrubber followed by an MSA charcoal/HEPA filter cartridge prior to discharge into the fume hood.


TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric and/or gas chromatography analysis for the aerosol and vapour components, respectively.
- Samples taken from breathing zone: yes.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Mean concentrations +/- SEM were 41+/- 1.7, 650 +/- 8.6 and 1800 +/- 27 mg/m3 (targeted were 60, 600 and 1800 mg/m3).

Duration of treatment / exposure:

6 hours per day.

Frequency of treatment:

4 or 5 days per week (total 9 exposures).

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
60 mg/m3
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
600 mg/m3
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1800 mg/m3
Basis:
nominal conc.

No. of animals per sex per dose:

10 males per dose (5 per group killed on day following last exposure, 5 per group killed after an 18-day recovery period).

Control animals:

yes, sham-exposed

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes.
- Time schedule: Before and after exposure (individually), as a group (during exposure), daily during recovery period.

BODY WEIGHT: Yes.
- Time schedule for examinations: Daily (except weekends) during treatment period, twice weekly during recovery period.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No.

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: No.

HAEMATOLOGY: Yes.
- Time schedule for collection of blood: Day following last exposure or end of recovery phase.
- Anaesthetic used for blood collection: Yes (light CO2).
- Animals fasted: Yes.
- How many animals: All.
- Parameters examined were RBC, WBC, PLT, HGB, HCT, MCV, MCH, MCHC, Neut, Band Neut, Lymph, Atyipical Lymph, Mono, Eosin and Baso.


CLINICAL CHEMISTRY: Yes.
- Time schedule for collection of blood: Day following last exposure or end of recovery phase.
- Animals fasted: Yes.
- How many animals: All
- Parameters examined were ALP, ALT, AST, SDH, BILRN, CHOL, TPROT, ALBMN, GLOBN, GLUCO, BUN, CREAT, PHOS, CALC, Na, K, Cl.


URINALYSIS: Yes.
- Time schedule for collection of urine: Overnight (for approximately 16 hours) before bleeding.
- Metabolism cages used for collection of urine: No data.
- Animals fasted: Yes.
- Parameters examined were VOL, OSMOL, UROBL, pH, hemoglobin or occult blood, glucose, protein, bilirubin, ketone (acetoacetic acid).


NEUROBEHAVIOURAL EXAMINATION: No.

Sacrifice and pathology:

5 rats per group killed by CO2 anaethesia followed by exsanguination the day after the 9th exposure. Remaining rats killed by same method after an 18-day recovery period.

Liver, kidneys, lungs, testes and brain weighed at necropsy.

GROSS PATHOLOGY: Yes (all tissues).

HISTOPATHOLOGY: Yes. Full tissue list for control and high-level rats sacrificed after 9th exposure. Nose, pharynx/larynx, lungs, liver, kidneys, testes and any gross lesions from low- and intermediate-level groups killed after 9th exposure and control and high-level groups killed at recovery sacrifice.

Statistics:

Body weight (and gain) and clinical laboratory data: Normal data ANOVA then Dunnetts. If variances heterogenous, robust version of Dunnetts. Data not normal, analyzed by Kruskal-Wallis test, then Dunns.
Organ weights: ANOVA, if F-statistic significant, then Dunnetts. Bartletts used to test homogeniety of variances, and if significant was followed by non-parametric procedures.
Except for Bartletts test (p<0.005), all significance was judged at p<0.05.

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 examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

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:

no effects observed

Effect levels

Dose descriptor:

NOEC

Effect level:

1 800 mg/m³ air

Sex:

male

Basis for effect level:

other: All animals survived the treatment No statistical significant treatment-related differences when compared to the controls

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

There were no test-substance related mortalities or toxicologically important changes in clinical pathology, pathology or in-life measurement parameters in any group. Under the conditions of this study, the NOEL of the test-substance was considered to be 1800 mg/m3.

Executive summary:

Three groups of 10 male rats were exposed by inhalation to the test-substance at targeted air concentrations of 60, 600 or 1800 mg/m3 for 6 hours/day, 4 or 5 days/week for a total of 9 exposures. A control group was similarly treated with air only.

There were no test-substance related mortalities or toxicologically important changes in the monitored clinical pathology, pathology or in-life measurement parameters in any group. Under the conditions of this study, the NOEL of the test-substance was considered to be 1800 mg/m3.