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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:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report date:
1975

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
- Principle of test: subcutaneous injection of test item in oily solution from day 6 to 15 of gestation in female rats, the control group was treated similar only with castor oil and benzylbezoate (4:6). After cesarean section on day 19 the dams and fetuses were investigated for teratogenic and embryolethal effects. The experiments were conducted according to FDA recommendations of January 1966.
- Short description of test conditions: Male and female SPF albino rats of a Sprague Dawley strain were mated in a ratio of 1: 4 in collection cages overnight. 82 inseminated female animals were selected by daily control of the vaginal smear and placed individually in Makrolon cages "Type II" without perforated bottom. 20 or 22 animals were randomly assigned to the individual test groups. The time at which sperm appeared or a vaginal plug was found was determined to be gestation day 0. The substance was applied sc under the shaved dorsal skin as an oily solution in doses of 0.0001, 0.0003 or 0.001 mg per kg kgw per 20 animals from day 6 to 15 of gestation. 22 control animals received during the same period of pregnancy and in the same volume ratios castor oil and benzyl benzoate (4: 6) After the dams were anesthetized with chloroform (DAB 7), all fetuses were removed by caesarean section on the 19th day of pregnancy.
- Parameters analysed / observed:
Examinations of the dams
Body weight measurements on days 0, 6, 15 and 19. p. c. – determination of the number of corpuscles, determination of the number of Implantations Determination of the number of living and dead fetuses and their position in the uterus, determination of the number of resorptions with and without fetal remains and their position in the uterus, examinations for special pathological-anatomical Changes.
Examinations of the fetuses
Determination of body weight "sex determination" macroscopic and / or stereomicroscopic inspection. About 1/3 of the litters were examined for visceral malformations using the Wilson technique. About 2/3 of the litters were examined for skeletal malformations after staining with Alizarin Red S.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Estradiol
EC Number:
200-023-8
EC Name:
Estradiol
Cas Number:
50-28-2
Molecular formula:
C18H24O2
IUPAC Name:
estra-1,3,5(10)-triene-3,17-diol

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: W. Gassner Sulzfeld
- Weight at study initiation: females: 160-255 g and males: 315-435 g
- Housing: kept in collection cages under conventional conditions and separated by sex during acclimation period. After mating females were kept individually in Macrolon cages, type II without perforation.
- Diet (e.g. ad libitum): standard chow (Ssniff) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24
- Humidity (%): 50-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
castor oil
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- M/F ratio per cage: 1/4 ratio
- Proof of pregnancy: vaginal plug and sperm referred to as day 0 of pregnancy
Duration of treatment / exposure:
20 days
Frequency of treatment:
daily from day 6 to day 15 post coitum
Duration of test:
ca. 3 weeks
No. of animals per sex per dose:
20 females/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the reports of the preliminary tests No. 1053 (1973-08-10) and No. 1125 (1973-11-13)

Examinations

Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 15 and 19


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 19


OTHER: determination of the number of corpuscles, determination of the number of Implantations Determination of the number of living and dead fetuses and their position in the uterus, determination of the number of resorptions with and without fetal remains and their position in the uterus, examinations for special pathological-anatomical changes.
Examinations of the fetuses
Determination of body weight "sex determination" macroscopic and / or stereomicroscopic inspection. About 1/3 of the litters were examined for visceral malformations using the Wilson technique. About 2/3 of the litters were examined for skeletal malformations after staining with Alizarin Red S.
Fetal examinations:
- External examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No
- Anogenital distance of all live rodent pups: yes

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):
not examined
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
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
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:
not examined
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
> 0.001 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOEL
Effect level:
> 0.001 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Anogenital distance of all rodent fetuses:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
In 15 (13.9%) of the control fetuses examined for skeletal malformations skeletal variations were observed. The type and frequency of these variations are known from control groups of earlier experiments of the same type. Skeletal variations were also found in the fetuses of the treated dams examined for skeletal malformations after application of 0.0001 mg / kg bw in 5 fetuses (4.2%) after application of 0.0003 mg / kg bw in 21 fetuses (18.4%) and after application of 0.001 mg / kg bw in 6 fetuses (4.3%). These observed variations are considered incidental findings since the variations in the same manner and frequency are known from control groups of earlier experiments of the same type.
Visceral malformations:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
> 0.001 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: not further specified

Overall developmental toxicity

Key result
Developmental effects observed:
no
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
No teratogenicity and maternal toxicity up to the highest dose level observed. No classification required.
Executive summary:

In a study conducted to examine the developmental toxicity/teratogenicity of Estradiol, the test item was administered s.c. to 20 female Sprague Dawley rats each dose, at dose levels of 0, 0.0001, 0.0003, and 0.001 mg/kg bw/day from days 6 through 15 of gestation.


There were no adverse effects observed in the dams. No Mortality occurred, no clinical signs of toxicity were detected, no abnormal body weight changes were reported. The maternal NOEL is > 0.001mg/kg bw/day..


In 15 (13.9%) of the control fetuses skeletal variations were observed. The type and frequency of these variations are known from control groups of earlier experiments of the same type. Skeletal variations were also found in the fetuses of the treated dams after application of 0.0001 mg / kg bw in 5 fetuses (4.2%) after application of 0.0003 mg / kg bw in 21 fetuses (18.4%) and after application of 0.001 mg / kg bw in 6 fetuses (4.3%). These observed variations are considered incidental findings since the variations are known in the same manner and frequency from control groups of earlier experiments of the same type. The developmental NOEL is  0.001 mg/kg bw/day.


 


The present study in the rat for the detection of developmental toxicity/teratogenicity after subcutaneous application from gestation day 6 to 15 is classified acceptable and satisfies at least in parts the requirements for the detection of developmental toxicity and teratogenicity in rats.