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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:
weight of evidence
Study period:
19 Jun - 12 Sep 1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study. According to the ECHA guidance document "Practical guide 6: How to report read-across and categories (March 2010)"

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1992
Report Date:
1992
Reference Type:
secondary source
Title:
SIDS DIPROPYLENE GLYCOL (MIXED ISOMERS AND DOMINANT ISOMER) CAS N°:25265-71-8 & 110-98-5)
Author:
OECD
Year:
2001
Bibliographic source:
UNEP Publications

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): dipropylene glycol
- Physical state: colourless, odourless, and slightly viscous liquid
- Analytical purity: ≥ 96%

Test animals

Species:
rat
Strain:
other: Crl:CD® (ICR) VAF/Plus™ outbred albino rats (CD® rats)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, USA
- Weight at study initiation: 225.1 - 226.8 g (mean per dose group)
- Housing: sperm-positive females were individually housed in solid-bottom polycarbonate cages with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ) and Ab-Sorb-Dri® cage litter (Laboratory Products, Garfield, NJ).
- Diet: Purina Certified Rodent Chow®, ad libitum
- Water: deionized filtered water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): ca. 22
- Humidity (%): 54
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: distilled deionised 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
- Amount of vehicle: 5 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Pre-dose analysis of dosing solutions demonstrated the dose concentrations to be within a range of 93 - 106% of target concentrations.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: individual breeding pairs were cohabited overnight.
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Day 6 - 15 of gestation
Frequency of treatment:
daily in the morning, 7 days/week
Duration of test:
Day 0 - 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
800, 2000 and 5000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
Control and 800 mg/kg bw/day dose group: 27 P females
2000 and 5000 mg/kg bw/day dose group: 26 P females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on previous studies, the concentrations of the concentrations of the test substance were anticipated to cause some maternal toxicity at the highest dose, while the lowest dose was expected to produce no maternal or developmental toxicity.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were observed daily beginning on GD 6.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: animals were observed daily beginning on GD 6 for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights of time-mated females were determined in the mornings of GD 0, 3, 6, 9, 12, 15, 18 and 20.

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: water consumption was determined 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: liver, uterus
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:
General Linear Models (GLM) procedures were applied for the analyses of variance (ANOVA) of maternal and foetal parameters. Prior to GLM-ANOVA analysis, an arcsine-square root transformation was performed on all litter-derived percentage data to normalise the means and Bartlett's test for homogeneity of variance was performed on all data to be analysed by ANOVA. GLM-ANOVA analysis determined the significance of dose-response relationships and the significance of dose effects, replicate effects and dose x replicate interactions. 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 foetal body weight. Non-significant (p > 0.05) dose x replicate effects on selected foetal parametric measures were considered justification for pooling data across replicates for non-parametric analysis on related measures. When a significant (p < 0.05) dose x replicate interaction occurred, the data for that endpoint and for any related nominal scale data were analysed separately for dose effects within each replicate in the study, as well as for all replicates combined. Nominal scale measures were analysed by a X2 test for independence and by a test for linear trend on proportions. When a X2 test showed significant experimentwise differences, a one-tailed Fisher's exact probability test was used for pair-wise comparisons of treatment and control groups.
Indices:
All litters: no. corpora lutea/dam; no. Implantations/litter; % pre-implantation loss/litter; % resorptions/litter; % lit. with resorptions
Live litters: no. live foetuses/litter; male foetal body weight/Iitter (g); female foetal body weight/Iitter (g); % male fetuses/litter
Malformations: % foetuses malformed/litter; % males malformed/litter; % females malformed/litter; % litters with malformed foetuses
Variations: % foetuses with variations/litter; % litters with variations

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Treatment with 2000 mg/kg/day produced maternal lethality in 1 out of 25 pregnant animals, while administration of 5000 mg/kg/day caused the death of 2 out of 22 pregnant animals. Since necropsy of these animals failed to determine the exact cause of death (i.e. no evidence was found for gavage error, accidental injury or disease), mortalities were deemed to be related to test substance exposure. Further clinical signs observed in confirmed-pregnant animals during and after exposure to 2000 and 5000 mg/kg/day included ataxia, weight loss, lethargy, unstable gait, piloerection and morbidity. Maternal body weights were significantly decreased at 5000 mg/kg/day from GD 9 through GD 20. In addition, maternal body weight gain of the animals exposed to 5000 mg/kg/day was significantly reduced during the period of treatment and gestation compared to controls. The corrected maternal weight gain (gestation gain minus gravid uterine weight) was also significantly reduced in animals receiving 5000 mg/kg bw/day. The reduction in body weight was accompanied by a significant decrease in absolute (g/day) and relative (g/kg body weight/day) food consumption in the 5000 mg/kg bw/day group for the intervals from GD 6 to 9 and GD 9 to 12 when compared to controls. Food consumption was also decreased during treatment (GD 6 to 15) and across gestation (GD 0 to 20). In the 2000 mg/kg bw/day group, absolute food consumption was decreased from GD 6 to 9. Relative water consumption by the animals in the 5000 mg/kg/day group was increased for all measurement periods between GD 9 and GD 18. Relative liver weight of the maternal animals was significantly increased in the animals exposed to 2000 and 5000 mg/kg/day. At necropsy on GD 20, 74% (20/27) of the mated animals in the controls and 74% (20/27), 96% (24/26), and 83.0% (20/26) of animals treated with 800, 2000 and 5000 mg/kg bw/day, respectively, were confirmed to be pregnant after uterine examination, and thus did not reveal any treatment-related changes.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
>= 2 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 5 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment-related effects on pre- or post-implantation loss were observed. The mean male and female body weights per litter of treated animals were associated with a significant decreasing linear trend, but did not significantly different from control. However, the male and female body weights in treated groups were not significantly different from control. External, visceral and skeletal examinations of the foetuses did not reveal any significant incidences of malformations and variations. The percentage of malformed foetuses per litter was somewhat higher in the exposed groups than in the control (10.49, 9.01, and 11.61% in the 800, 2000 and 5000 mg/kg bw/day group compared to 6.61 % in the control group). This effect was due to the visceral finding of enlarged lateral ventricles of the brain in approximately 8, 15, 14, and 16% of the foetuses examined in the control, 800, 2000 and 5000 mg/kg bw/day group, respectively.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table1. Maternal toxicity in rats treated from GD 6 to 15

Parameter

Control

800 mg/kg bw/day

2000 mg/kg bw/day

5000 mg/kg bw/day

Dose response +/-

Maternal body weight changes (g)a,b

 

Gestation weight gain (GD 0-20)

172.7 ± 4.7

164.0 ± 4.0

167.8 ± 3.8

147.9 ± 4.4*

+

Treatment weight gain (GD 6-15)

86.1 ± 2.8

77.7 ± 2.5

82.3 ± 2.9

71.3 ± 3.7*

+

Corrected weight gainc

86.1 ± 2.8

77.7 ± 2.5

82.3 ± 2.9

71.3 ± 3.7*

+

Gravid uterine weight

86.7 ± 3.7

86.3 ± 2.7

85.5 ± 4.5

76.6 ± 2.7

+

Maternal liver weightsa

 

Absolute (g)

17.73 ± 0.41

18.11 ± 0.41

18.84 ± 0.34

18.28 ± 0.42

-

Relative (% body weight)d

4.45 ± 0.09

4.64 ± 0.09

4.79 ± 0.07*

4.89 ± 0.08*

+

Maternal food consumptiona, e

 

Gestation period (GD 0-20)

Absolute (g/day)

26.6 ± 0.3

26.2 ± 0.5

26.0 ± 0.5

24.0 ± 0.4*

+

Relative (g/kg/day)

87.0 ± 0.7

87.0 ± 1.0

86.7 ± 1.3

83.0 ± 0.9*

+

Treatment period (GD 6-15)

 

Absolute (g/day)

26.5 ± 0.4

25.7 ± 0.6

25.6 ± 0.5

21.8 ± 0.6*

+

Relative (g/kg/day)

88.8 ± 1.2

87.8 ± 1.5

87.8 ± 1.6

77.1 ± 1.6*

+

Maternal water consumptiona, e

 

Gestation period (GD 0-20)

Absolute (g/day)

45.2 ± 1.7

42.4 ± 1.2

47.1 ± 1.4

45.0 ± 1.2

-

Relative (g/kg/day)

147.4 ± 5.9

142.3 ± 4.0

157.1 ± 4.7

156.5 ± 4.5

-

Treatment period (GD 6-15)

 

Absolute (g/day)

45.1 ± 1.8

43.6 ± 1.5

47.3 ± 1.3

47.2 ± 1.7

-

Relative (g/kg/day)

151.1 ± 6.1

149.9 ± 4.9

162.6 ± 5.1

167.9 ± 6.1

+

aincludes all dams pregnant at sacrifice; mean ± S.E.M.; GD =gestational day

b ody weights were recorded in the morning of each designated gestational day.

cweight change during gestation minus gravid uterine weight

dcalculated using body weight at the time of sacrifice on GD 20

eBody weights were recorded in the morning of each designated gestational day. Relative food and water intake (g/kg/day) were calculated using these weights.

+ p < 0.05 - Linear Trend Test

* p < 0.05 - Dunnett's Test

Applicant's summary and conclusion