D-Glucitol, propoxylated

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993

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other: GLP-compliant well-conducted and documented study, available as unpublished report, no restrictions, fully adequate for assessment.

Justification for type of information:

Read across to an analogue based on structural similarity. An analogue justification is attached to setion 13 of the dataset.

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

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propane-1,2-diol

EC Number:

200-338-0

EC Name:

Propane-1,2-diol

Cas Number:

57-55-6

Molecular formula:

C3H8O2

IUPAC Name:

1,2-Propanediol

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 or test system 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 / concentrations

Remarks:

Doses / Concentrations:
0, 0.5, 5.0 and 10.0 ml/kg bw/day (0, 52, 520 and 10400 mg/kg bw/day)
Basis:
actual ingested

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

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
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.
No treatment-related clinical signs, effects on maternal body weights and body weight gains, food consumption were observed at any dose level. 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.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

10 400 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

52 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of treatment on the number of ovarian corpora lutea, on the number of total, viable or nonviable (early or late resorptions, and dead fetuses) implantations/litter or on sex ratio. There were no effects on fetal body weights/litter which were attributed to treatment. There were no differences in individual external, visceral or skeletal malformations by category, or in total malformations among all grouops. There were no treatment related increases in the incidences of individual fetal external or visceral variations. 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:

NOAEL

Effect level:

10 400 mg/kg bw/day (actual dose received)

Basis for effect level:

other: Developmental toxicity: No adverse effects on development at the highest dose tested.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In the present study, propylene glycol administered by gavage to pregnant CD-1" mice during organogenesis at dosages up to 10.0 ml/kg/day was not associated with any treatment-related effects on endpoints such as clinical signs, body weight, body weight gain, food consumption, or pregnancy outcome. Increases in water consumption were observed in dams from the 5.0 and 10.0 ml/kg/day groups and were probably a physiologic response to the high dosages given by gavage. There was no evidence of treatment-related effects on developmental parameters. Therefore, in this study, the "no-observed-effect level" (NOEL) for maternal effects was 0.5 ml/kg/day. The NOEL for develapmental toxicity was at least 10.0 ml/kg/day.

Executive summary:

Timed-pregnant CD-1® mice were administered propylene glycol [CAS No. 57-55-6] by gavage on gestation days (gd) 6 through 15. Thirty copulation plug-positive females/group were dosed with undiluted propylene glycol at dosage volumes of 0.5, 5.0, or 10.0 ml/kg/day. An additional 30 females, assigned to the control group, received Milli-Q® water (CAS No. 7732-18-5) at a dosage volume equivalent to that used in the high dose group. Clinical observations were made daily (twice daily during dosing), and maternal body weights were measured on gd 0, 6, 9, 121 15, and 18. Maternal food and water consumption were measured over 3-day intervals throughout gestation, gd 0-18. At scheduled sacrifice on gd 18, the dams were evaluated for body weight, liver and kidney weight, gravid uterine weight, number of corpora lutea, and number and status of implantation sites (including early and late resorptions, dead fetuses, and live fetuses). All live and dead fetuses were dissected from the uterus, weighed, and examined externally for malformations, variations, and gender determinations. All live fetuses in each litter were examined for visceral malformations and variations. Approximately one-half of the live fetuses in each litter were examined for craniofacial malformations and variations. All live fetuses

(50% intact, 50% decapitated) in each litter were stained with alizarin red S and examined for skeletal malformations and variations. The pregnancy rate was equivalent among groups and ranged from 93.3 to 100%. No females died prior to scheduled sacrifice. At scheduled sacrifice, one female each from the 0.5 and 10.0 ml/kg/day groups had a litter of non-viable implants (early resorptions) only. Twenty-eight to 29 live litters were available for evaluation from each group. There were no treatment-related clinical signs or effects on body weight, body weight gain, or food consumption at any dose level. Water consumption was increased in the 10.0 ml/kg/day group during gd 6 to 9, 9 to 12, 12 to 15, for the combined treatment interval of gd 6 to 15, and subsequent to treatment from gd 15 to 18. In the 5.0 ml/kg/day group, water consumption was increased during treatment from gd 9 to 12, 12 to 15, 6 to 15 (the combined treatment interval) and subsequent to treatment from gd 15 to 18. There were no treatment-related necropsy findings on gd 18. There were no effects of treatment on terminal body weight, gravid uterine weight, corrected body weight (terminal body weight minus gravid uterine weight), corrected body weight change, or absolute and relative liver and kidney weights. No treatment-related differences were observed in the total number of implantations, the number of viable and nonviable implants, or in sex ratios. There were no effects on fetal body weights/litter, or on the incidences of external, visceral, and skeletal malformations or variations. Administration of propylene glycol by gavage to pregnant CD-1® mice during organogenesis produced increases in water consumption in the 5.0 and 10.0 ml/kg/day groups. No developmental toxicity was observed at any dose. Therefore, in this study, the "no-observed-effect level" (NOEL) for maternal effects was 0.5 ml/kg/day. The NOEL for developmental toxicity was at least 10.0 ml/kg/day (the maximum dosage tested).