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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

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

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Remarks:
Testing laboratory: The Dow Chemical Company, 1803 Building, Midland, MI 48674, United States

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1'-iminodipropan-2-ol
EC Number:
203-820-9
EC Name:
1,1'-iminodipropan-2-ol
Cas Number:
110-97-4
Molecular formula:
C6H15NO2
IUPAC Name:
1,1'-iminodipropan-2-ol
Specific details on test material used for the study:
Source: obtained from The Dow Chemical Company (Midland, MI).
Puritie: 98.8% to 99.6%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Time-mated female CRL:CD(SD) rats were obtained from Charles River Laboratories Inc. (Portage, MI).
- Age at study initiation: adults
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: not specified
- Diet: ad libitum LabDiet#5002 Certified Rodent Diet (PMI Nutrition International, St. Louis, MO)
- Water: ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21–25
- Humidity (%): 45–60%
- Air changes (per hr): 12–15 room air changes/h
- Photoperiod (hrs dark / hrs light): 12 h photocycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Groups of 25 time-mated female Sprague–Dawley rats were given 0, 100, 300, or 1000 mg DIPA/kg/day on gestation days 6 through 20 by oral gavage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of DIPA in all dose solutions ranged from 95% to 105% of target.
Details on mating procedure:
time-mated females
Duration of treatment / exposure:
gestation days 6 through 20
Frequency of treatment:
daily
Duration of test:
21 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females
Control animals:
yes
Details on study design:
- Dose selection rationale: dose levels were determined from a probe toxicity study in which 1000 mg/kg/day given to pregnant rats did not cause maternal toxicity or embryotoxicity

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED OBSERVATIONS/EXAMINATIONS: Yes
- Time schedule: weekly, detailed (handheld) clinical examinations, body weight, weight gain, and feed consumption
- On gestation day 21, all rats were euthanized, examined grossly, and the weights of the liver, kidneys and gravid uterus were collected. The number of corpora lutea, uterine implantations, resorptions and live/dead fetuses were determined.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY & CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Ovaries and uterine content:
on day 21 of gestation by CO2 inhalation and gross pathologic examination was conducted.
The weights of the kidneys, liver and gravid uteri were obtained and the kidneys, liver and all gross lesions were preserved in 10%NBF.
A detailed examination of the reproductive tract was conducted which included the number and position of all implants, viable fetuses, dead fetuses, resorptions, and the number of ovarian corpora lutea. Uteri lacking visible implantations were stained with a 10% aqueous solution of sodium sulfide for evidence of early resorptions.
Fetal examinations:
- Sex ratio and body weight
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, one-half of the fetuses from each litter were randomly selected for a visceral examination, conducted by dissection under a low power stereomicroscope
- Skeletal examinations: Yes, Fetuses not selected for visceral examination were skinned, eviscerated, preserved in alcohol, double stained with Alcian Blue and Alizarin Red S, cleared and evaluated for skeletal changes
- Head examinations: Yes, heads of the fetuses used in soft tissue examination were placed in Bouin’s fixative and subsequently serially sectioned for examination of the eyes, brain, nasal passages and tongue
Statistics:
- Maternal body weight, weight gain, feed consumption, organ weights and fetal body weights: Parametric or non-parametric ANOVA, followed by Dunnett’s or Wilcoxon’s test for comparison to controls
- Pre- and post-implantation loss: Censored Wilcoxon’s test Haseman and Hoel
- Corpora lutea, implantations and litter size: Non-parametric ANOVA followed by Wilcoxon’s test
- Pregnancy rates: Fisher exact probability test
- Fetal sex ratios: Binomial distribution test
Indices:
Not specified
Historical control data:
Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
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
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
dermal irritation
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
gross pathology
mortality
necropsy findings
number of abortions
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
A statistically identified shift in sex ratio vs. binomial distribution of the control pups, but this was considered as not toxicologically significant.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
The small number of alterations observed in fetuses from dams given DIPA either occurred at low frequencies and/or not in a dose-related manner.
Visceral malformations:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The present oral development toxicity study with diisopropanolamine in rats resulted in no observed adverse effect levels (NOAEL) >1000 mg/kg/day for both maternal and fetal effects.