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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1987
Reference Type:
publication
Title:
Inhalation developmental toxicity study of propylene oxide in Fischer 344 rats
Author:
Harris SB, Schardein JL, Ulrich CE, Ridlon SA
Year:
1989
Bibliographic source:
Fundam. Appl. Toxicol. 13:323-331.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: EPA/TSCA Health Effects Test Guidelines published in the Federal Register 50(188), 39397-39471, 1985 an with EPA test rule "propylene oxide; testing requirements (40 CFR part 799) published in the Federal register 50 (229), 48762-48770, 1985.
Principles of method if other than guideline:
Four groups of 25 mated female rats were exposed to 0, 100, 300 and 500 ppm of PO (by inhalation) for 6 hr per day on Gestation Day (GD) 6 through 15, inclusive. Cesarean sections were performed on all females on GD 20 and the fetuses removed for morphological evaluation.
GLP compliance:
yes (incl. certificate)
Remarks:
International research and development corporation
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: >99%
- Supplier: ARCO Chemical Company

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, NY
- Age at study initiation: 70 days
- Weight at GD 0: about 172 g
- Housing: Individually (except during mating).
- Diet : ad libitum, except during exposure periods
- Water :ad libitum): ad libitum
-Quarantine: over 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 36-70
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m3 exposure chamber of glass and stainless-steel construction
- Source of air: HVAC system, particulate filtered with temperature and humidity control
- System of generating particulates/aerosols: Generation by pumping liquid PO through a glass column and vaporizing it in nitrogen. Vapor concentrations were then diluted to the desired level by the addition of chamber ventilation air

- Method of holding animals in test chamber: in wire mesh cages individualy
- Source and rate of air:0.1, 0.25 and 0.40 ml/min
- Method of conditioning air:
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber: 23.1 C. 54.3 %, no data
- Air flow rate: 150 - 250 L/min
- Air change rate: no date
- Method of particle size determination: no data


TEST ATMOSPHERE
- Brief description of analytical method used: infrared spectrophotometry


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Actual concentrations were measured by infrared spectrophotometry using a Wilks-MIRAN Model 1A-CVF spectrophotometer at a wavelength of 12 µm, calibrated by the closed-loop technique. Each chamber was sampled approximately once each hour during each day of exposure. The nominal concentration of each chamber was calculated on a daily basis.
- Homogeneity of the atmosphere was measured by sampling from 5 different locations. Range: +3.3% to -6.7% of the reference location.
Details on mating procedure:
Impregnation procedure: cohoused

- M/F ratio per cage: 1:1
- Length of cohabitation: until presence of vaginal copulatory plug
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal copulatory plug (assigned as Gestation Day 0)
Duration of treatment / exposure:
from GD 6 continued to and including gestation day 15
Frequency of treatment:
6 hours/day
Duration of test:
Until day 20 of gestation (Day of Cesarean section)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Exposure levels were selected based on a pilot study that demonstrated excessive maternal toxicity at an exposure to 750 ppm.

Examinations

Maternal examinations:
OBSERVATIONS: Yes.
Mortality check and overt changes in appearance and behaviour was performed twice daily. Presence and duration of clinical signs of toxicity were recorded once daily on GD 6-15 and GD 20.

BODY WEIGHT: Yes, on GD 0, 6, 8, 10, 12, 14, 16 and 20


FOOD CONSUMPTION: Yes, daily throughout the treatment period, expressed as g/animal/day and g/kg bw/day .

WATER CONSUMPTION: Yes, daily throughout the treatment period

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Examinations: number and location of viable and nonviable fetuses and early and late resorptions and the number of total implantations and corpora lutea were recorded. Organs weighed: uterus, liver, kidneys. Abdominal and thoracic cavities and organs were examined for gross morphological changes. Maternal tissues were preserved for histopathological examination as deemed necessary. Uteri from females that appeared nongravid were analyzed for implantations.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
Fetuses were individually weighed, sexed, tagged and examined for external malformations and variations. Soft tissue examination was performed in one-half of the fetuses. Skeletal examinations were performed in the remaining fetuses. All gross, visceral, and skeletal alterations were defined as either malformations or developmental variations.
Statistics:
- Male-to-female fetal sex ratios and proportions of litters with malformations: chi-square with Yates' correction for 2x2 contingency tables
- Proportions of resorbed and dead fetuses and postimplantation losses: Mann-Whitney U test
- Numbers of corpora lutea, total implantations and live fetuses, mean fetal bodyweights, maternal body weights, maternal body weight changes, maternal organ weights, food and water consumption: one-way ANOVA, Bartlett's test for homogeneity of variance, and appropriate t-test.
Indices:
Not reported
Historical control data:
Hackett et al, 1982

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The body weight gain in the high exposure group during the entire exposure period (GD 6 through 15) and from GD 0 to 20 (adjusted) were significantly less (p < 0.01) than the control values. A significant loss (p < 0.01 or 0.05) in body weight was noted for all groups exposed to propylene oxide during the first treatment subinterval (GD 6 to 8). Thereafter, statistically significant, but biologically irrelevant effects on body weight in the low-exposure (100 ppm) and midexposure (300 ppm) grouips were observed in the last two subintervals (GD 12 to 14 and GD 14 to 16) of the exposure period and in the Gestation day 0 to 20 (adjusted) interval (midexposure level only). Maternal food consuption values calculated as g/animal/day and g/kg bw/day were generally significantly less (p < 0.01 or 0.05) than the corresponding control values in the high exposure group. Increased water consumption calculated as g/animal/day and g/kg bw/day in the mid and high exposure group were significantly greater (p < 0.01 or 0.05) than the corresponding control values; however, they were not considered related to test material exposure as no consistent trends were apparent.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
300 ppm
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: Decreased maternal food consumption and body weight gain.

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Cesarean section parameter values for the groups exposed to propylene oxide did not indicate the presence of any fetotoxic effects. Mean numbers of viable fetuses, postimplantation losses, total implantations, and corpora lutea for the exposed groups were comparable with the corresponding control values. Increased frequency of fetuses (and litters) with a rib of variable length on the seventh cervical vertebra was noted in the high exposure group when compared to the controls.

Effect levels (fetuses)

Dose descriptor:
NOEC
Effect level:
300 ppm
Basis for effect level:
other: Developmental toxicity
Remarks on result:
other: Increased incidence of fetuses and litters with a rib of variable length on the seventh cervivcal vertebra at 500 ppm associated with maternal toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Survival was 100% for all groups throughout the study. None of the clinical signs or necropsy observations were considered induced by exposure to propylene oxide. All findings occurred either in low incidence or at a rate comparable with that of the control group.

The reduction in food consuption at 500 ppm was likely the reason for the concomitant decrease in body weight gain during gestation. The increased incidence of seventh cervical ribs was considered to be associated with maternal toxicity at the high-exposure level.

Applicant's summary and conclusion