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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Peer reviewed near guideline study, adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD guideline 451
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Propylene oxide was obtained from Leidy Chemical Corporation (Baltimore, MD).lot no. 6477-22 was used for the 2-year
studies. Purity and identity analyses were conducted at Midwest Research Institute (Kansas City, MO). The identities of both lots of the
chemical were confirmed by elemental and spectroscopic analyses. Elemental analyses for carbon and hydrogen agreed with
theoretical values. Two gas chromatographic systems indicated only a major peak. Data obtained from these studies indicate that the propylene
oxide used in these studies was greater than 99.9% pure.

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Labs,Inc. (Portage, MI)
- Age at study initiation: 7-9 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing:individually
- Diet : ad libitum (except during exposure)
- Water: ad libitum
- Acclimation period: 18-21 days


ENVIRONMENTAL CONDITIONS
20 changes room air/h (during nonexposure, chamber door left open); fluorescent light 12 h/d;
chambertemp:18.3-27.8°C , chamber humidity:32%-84 %
room temp: 21.1° C during exposure; 23.9° C during nonexposure

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
Propylene oxide was vaporized at room temperature, diluted with air, and introduced into the chambers.

The liquid to be vaporized was contained in a 1.6-liter stainless steel reservoir that was housed in a vapor hood within the exposure room. The liquid
was pumped from this reservoir to a vaporizer by a stable micrometering pump with adjustable driftfree pump rates ranging from 0.03 to 20 ml/min. Four pump/vaporizer systems were fed from the single reservoir by incorporating a manifold liquid distribution system. Clear Teflon® tubes of
measured volume, preceded by a three-way valve, were attached just upstream of each pump to facilitate measurements of liquid flow rate to each vapor generator. This was accomplished by momentarily switching the three-way valve from the run to the test position. A small bubble of air
was pulled by the pump from the room through the valve and into the clear tube. The progress of this bubble from one end of the tube to the other (calibrated volume) was timed with a stopwatch. Flow rate was calculated by dividing the volume by the time.
The volume of the tubes was chosen so that the error due to start and stop time ambiguity (introduced by the pulsatile nature of the pumps) was
less than 5%. Measurement of this flow, along with measurement of chamber dilution air flow, was used to calculate expected concentration of
vapor in the chamber. This provided a method, secondary to that of the gas chromatograph, of monitoring concentration. Three-way valves and lines returning from the vaporizer to a beaker in the vapor hood facilitated filling the distribution system.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations in the exposure chambers were monitored 8-12 times
per exposure period by a Hewlett-Packard 5840A Gas Chromatograph. The vapor concentrations were within
10% of the mean values of the concentrations at all positions sampled within the chamber.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/ week for 103 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 200 and 400 ppm (0, 474 and 948 mg/m3)
Basis:
nominal conc.
No. of animals per sex per dose:
50
Control animals:
yes
Details on study design:
- Dose selection rationale: based on the 13-weeks study
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day for morbundity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once per month

BODY WEIGHT: Yes
- Time schedule for examinations: once per week for the firts 13 weeks, then once a month and twice per month for the remaining 3 months.

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
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data


HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Necropsy performed on all animals; the following tissues were examined: gross lesions,
skin, mandibular lymph nodes, tissue masses and regional lymph nodes, thigh muscle, sciatic nerve,
sternebrae, including marrow, costochondral junction (rib), thymus, larynx, pharynx, trachea, lungs and
bronchi, heart, thyroid gland, parathyroids, esophagus, stomach, duodenum, jejunum, salivary gland, ileum,
colon, cecum, rectum, liver,eyes, pancreas, spleen, kidneys, adrenal glands, urinary bladder, seminal vesicles/prostate/testes
or ovaries/uterus, nasal cavity and nasal turbinates(3 sections), brain, pituitary gland, and spinal cord

Histopathologic exam(including blood smear)
pertormed on an above tissues except, thigh muscle, sciatic nerve, costochondral junction (rib), duodenum
jejunum, salivary gland, ileum, cecum, rectum, seminal vesicles, and eyes and pharynx unless grossly abnormal.
Statistics:
Survival: Kaplan and Meier (1958). Statistical analyses for a possible dose-related effect on survival used
the method of Cox (1972) for testing two groups for equality and Tarone's (1975) extensions of
Cox's method for testing for a dose-related trend. All reported P values for the survival analysis are two-sided.

Analysis of Tumor Incidence: Three statistical methods are used to analyze tumor incidence
data. The two that adjust for intercurrent mortality employ the classical method for combining
contingency tables developed by Mantel and Haenszel (1959).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Survival of exposed male and female mice decreased relative to that of the controls (male: control, 42/50; low dose, 34/50; high dose, 29/50; female: 38/50; 29/50; 10/50), but the difference was significant only for animals in the high dose groups. High dose female mice had a mean terminal body weight 10% below that of the controls; high dose male mice had a terminal body weight 22% below that of the controls.

The respiratory epithelium of the nasal turbinates was also one of the primary tissues affected in male and female mice; exposure-related increases
occurred in the incidences of inflammation, and squamous metaplasia was observed in one low dose male and two high dose female mice.
One squamous cell carcinoma and one papilloma occurred in the nasal cavity of different high dose male mice, and two high dose female mice had
adenocarcinomas of the nasal cavity. The endothelial cells of the submucosal vascular plexus in the nasal turbinates also appeared to be a major site affected in high dose male mice. Three high dose male and three high dose female mice had a saccular dilation (classified as angiectasis) of
submucosal turbinate vessels. Further, hemangiomas were seen in the nasal cavity of 5/50 high dose male mice and 3/50 high dose female mice, and
hemangiosarcomas were found in the nasal cavity of 5/50 high dose male mice and 2/50 high dose female mice. The increased incidences of
hemangiomas in males and females and of hemangiosarcomas in males were statistically significant. Vascular tumors were not present in the nasal
turbinates of any low dose or control mice.

Chronic inflammation of the nasal cavity was noted at all exposure levels: 1/50, 13/50, and 38/50 (males); 0/50, 13/50 and 17/50 ( females).

Effect levels

Dose descriptor:
LOAEC
Effect level:
200 ppm
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion