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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other: GLP-compliant well-conducted and documented study, available as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): propylene glycol
- Molecular formula (if other than submission substance): C3H8O2
- Molecular weight (if other than submission substance): 76.0942
- Smiles notation (if other than submission substance): C([C@@H](C)O)O
- InChl (if other than submission substance): InChI=1/C3H8O2/c1-3(5)2-4/h3-5H,2H2,1H3
- Substance type: organic
- Physical state: slightly viscous colorless liquid
- Analytical purity: 99.9%
- Batch number: 02907TT
- Storage: at room temperature in an environmentally controlled area

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (St. Constant, Canada)
- Age at study initiation: males 49 days old upon arrival, females 46 days old upon arrival
- Weight at study initiation: males 26-28 g, females 25-28 g upon arrival
- Housing: males were housed singly in stainless steel, wire mesh cages (23.5 x 40.0 x 18.0 cm); females were housed 2 to a gage in a stainless steel, wire mesh cages (23.5 x 20.0 x 18.0 cm) during acclimation.
- Diet (e.g. ad libitum): Ground, certified Rodent Chow #5002 (Purina Mills, Inc.) was available ad libitum during most of the acclimation period, and then powedered, certified AGWAY PROLAB animal Diet Rat, Mouse, Hamster 3200 (Agway Inc.) was available ad libitum for the duration of the study.
- Water: tap water (Municipal Authority of Westmoreland County, Greensburg, PA), ad libitum
- Acclimation period: ca. 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-77
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Propylene glycol was administered undiluted.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: January 30 - February 3, 1991
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal and dropped copulation plug, referred to as day 0 of pregnancy
Duration of treatment / exposure:
On gestation days 6 through 15
Frequency of treatment:
Daily
Duration of test:
18 days
Doses / concentrationsopen allclose all
Dose / conc.:
520 mg/kg bw/day (actual dose received)
Remarks:
administerd as 0.5 ml/kgb w/day.
Dose / conc.:
5 200 mg/kg bw/day (actual dose received)
Remarks:
administerd as 5 ml/kgb w/day.
Dose / conc.:
10 400 mg/kg bw/day (actual dose received)
Remarks:
administerd as 10 ml/kgb w/day.
No. of animals per sex per dose:
30 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a range-finding gavage study with propylene glycol in CD-1 mice (BRRC project 91-22-23801)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for morbidity and mortality. Prior to the treatment period, animals were observed for clinical signs once daily. During treatment, animals were observed for clinical signs immediately before and during dosing, and approximately 1 hour following each daily dosing period. Subsequent to the treatmnet period, animals were observed for clinical signs once daily (a.m.)

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, 18


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


WATER CONSUMPTION: Yes
- Time schedule for examinations: gestation days 0, 3, 6, 9, 12, 15

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 18
- Organs examined: uterus, ovaries (including corpora lutea), cervix, vagina, peritoneal and thoracic cavities were examined grossly; maternal liver and kidneys were weighed and kidneys preserved for possible subsequent microscopic evaluation.

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:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, all per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Statistics:
Levene's test for equality of variances, analysis of variance (ANOVA) and t-tests. The latter were used when the F value from the ANOVA was significant. When Levene's test indicated equal variances, and the ANOVA was significant, a pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by a separate variance t-test for pairwise comparisons. Nonparametric data were statistically evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney U test when appropriate. Incidence data were compared using the Fisher's Exact test.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption was increased in the 10.0 ml/kg bw/day groups during gestation days 6 to 9, 9 to 12, 12 to 15, for the combined treatment interval, gestation day 6 to 15, and subsequent to treatment from gestation days 15 to 18. In the 5.0 ml/kg bw/day group, water consumption was increased during treatment from 12 to 15 and sebsequent to treatment from gestation days 15 to 18. In addition, though not statistically significant, water consumption values were increased in the middle dose group from gestation days 9 to 12 of treatment and for the combined treatment interval (gestation days 6 to 15) by 6-7% of control values.
Organ weight findings including organ / body weight ratios:
no effects observed

Maternal developmental toxicity

Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Details on maternal toxic effects:
There were no treatment-related necropsy findings of the dams at the scheduled sacrifice on gestation day 18. There were no effects of treatment on terminal body weight, gravid uterine weight, corrected body weight, corrected weight change, or relative and absolute liver and kidney weight. There were no effects of treatment on the number of ovarian corpora lutea, on the number of implantations/litter.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
520 mg/kg bw/day (actual dose received)
Basis for effect level:
water consumption and compound intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no effects on fetal body weights/litter which were attributed to treatment.
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no treatment related increases in the incidences of individual fetal external or visceral variations.
Details on embryotoxic / teratogenic effects:
Statistically significant increases in the incidences of fetal atelectasis and poorly ossified supraoccipital bone and an decrease in the incidence of extra ossification site in the nasal fontanel in the 0.5 ml/kg/day group were not considered to be treatment-related due to the lack of a dose-response relationship.

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
1 040 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion