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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study, no restrictions, adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1992

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dipropylene glycol
- Molecular formula (if other than submission substance): C6H14O3
- Molecular weight (if other than submission substance): 134.1736
- Smiles notation (if other than submission substance): CCC(O)OC(O)CC
- InChl (if other than submission substance): InChI=1/C6H14O3/c1-3-5(7)9-6(8)4-2/h5-8H,3-4H2,1-2H3
- Analytical purity: > 96%
- Impurities (identity and concentrations): not determined
- Supplier: Aldrich Chemical Co., Inc. Milwaukee, WI

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Weight at study initiation: 204.49-259.42 g on GD 0
- Housing: individually in solid-bottom polycarbonate cages with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ) and Ab-Sort-Dri cage litter (Laboratory Products, Garfield, NJ)
- Diet: Purina Certified Rodent Chow # 5002, ad libitum
- Water: deionized filtered water, ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature: 72 F
- Humidity (%): 54%
- Photoperiod (hrs dark / hrs light): 12 /12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations were stored at room temperature in amber glass bottles and used within the demonstrated period of stability
VEHICLE
- Deionized water
- Concentration in vehicle: 0, 160, 400 and 1000 mg/ml (target concentration)
- Pre-dose analysis of dosing solution demonstrated the dose concentrations to be within a range of 93-106% of target concentrations.
- Amount of vehicle (if gavage): 5 ml/kg bw
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal lavage referred to as day 0 of pregnancy
Duration of treatment / exposure:
Gestation days 6-15
Frequency of treatment:
Once daily
Duration of test:
Till gestation day 20
No. of animals per sex per dose:
20-25 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on previous studies, the concentrations of DPG were anticipated to cause some maternal toxicity at the higher dose while the lowest dose was expected to produce no maternal or developmental toxicity.
- Rationale for animal assignment (if not random): stratified randomization so that mean GD 0 body weights did not differ significantly among dose groups.
- Other: the study was performed in two replicates with one breeding date in the first replicate and three consecutive breeding dates in the second replicate. The breeding date for the first replicate and the first breeding date of the second replicate were 28 days apart.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily from GD 6

BODY WEIGHT: Yes
- Time schedule for examinations: in the mornings of GD 0, 3, 6, 9, 12, 15, 18 and 20


FOOD AND WATER CONSUMPTION: Yes
Food and water weights were reported in the mornings of GD 0, 3, 6, 9, 12, 15, 18 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: the maternal body, liver and intact uterus were weighed.


OTHER:
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:
Maternal and fetal parameters: general linear models ANOVA.
Prior to GLP-ANOVA analysis, an arcsine-square root transformation was performed on all litter-derived percentage data to normalize the means and Bartlett's test for homogeneity of variance was performed on all data to be analyzed by ANOVA. When ANOVA revealed a significant (p < 0.05) dose effect, Dunnett's Multiple Comparison Test was used to compare treated to control groups. One-tailed tests were used for all pair-wise comparisons except maternal body and organ weights and fetal body weight. Nominal scale measures were analyzed by a X-square test for independence and by a test for linear trend on proportions. When a X-2 test showed significant experiment-wise differences, a one-tailed Fisher's exact probability test was used for pair-wise comparisons of treatment and control groups.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One animal in the 2000 mg/kg bw/day and 2 animals in the 5000 mg/kg bw/day died after dosing on GD 14.
Clinical signs observed in confirmed-pregnant animals during and after exposure to 2000 and 5000 mg/kg bw/day of dipropylene glycol included ataxia, weight loss, lethargy, unstable gait, piloerection, morbidity and/or mortality). Significant reduction of body weight after the onset of dosing occurred exclusively in the high dose group from GD 9 through GD 20. Body weight gain of the high dose group animals paralleled control at significantly reduced levels from GD 9 through GD 20. The decreased body weights in the high dose group animals caused a significant decrease in maternal body weight gain throughout gestation (GD 0 -20) and during treatment (GD 6-15). Corrected maternal weight gain was still significantly reduced in the 5000 mg/kg bw/day group even after correction for the weight of the gravid uterus.
Relative (g/kg bw/day) maternal water intake was significantly increased over controls in the 5000 mg/kg/day group from GD 9-12, GC 12-15 and GD 15-18.
Animals exposed to 5000 mg/kg bw/day of dipropylene glycol consumed significantly less food from GD 6 to 9 and GD 9 to 12. As a result, relative food consumption was also decreased in these animals during the same periods, and body absolute and relative food consumption were decreased during treatment and throughout gestation. Absolute food consumption was decreased in the animals from the 2000 mg/kg bw/day group from GD 6 to 9, but relative food consumption was unaffected.
Necropsy of maternal animals on GD 20 showed significantly increased relative liver weights when compared to controls.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day
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 significant differences between the exposed groups and the control in the average number of corpora lutea, implants, live fetuses, early deaths (resorptions), late deaths, or non-live implants per litter. The percent pre- and post-implantation losses per litter were not significantly different from control values.
A significant decreasing linear trend from the control to high dose group was observed for mean fetal weight. The male and female body weights in the DPG exposed groups were not significantly different from control. Although not significant, the mean male and female body weights per litter from the 5000 mg/kg bw/day were decreased to about 95% of control values (males 3.69 vs. 3.90 and females 3.47 vs. 3.67 g/fetus/litter, respectively). There were no other treatment-related effects evident at laparotomy.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion