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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From Jan. 25, 1982 to Jul. 7, 1982
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1982

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethylenebis(oxyethylene) bis[3-(5-tert-butyl-4-hydroxy-m-tolyl)propionate]
EC Number:
253-039-2
EC Name:
Ethylenebis(oxyethylene) bis[3-(5-tert-butyl-4-hydroxy-m-tolyl)propionate]
Cas Number:
36443-68-2
Molecular formula:
C34H50O8
IUPAC Name:
ethane-1,2-diylbis(oxyethane-2,1-diyl) bis[3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propanoate]

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: From a closed breeding colony (CIBA GEIGY, WST)
- Age at study initiation: 2 months old
- Weight at study initiation: 190 g
- Fasting period before study: Not reported
- Housing: Makrolon cages equipped with a wire mesh top and water bottles, and saw dust (granular form) serving as bedding material. The cages were placed in movable racks kept in a air-conditioned room.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2-5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21ºC ± 2ºC
- Humidity (%): 55% ± 10%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: Not applicable
Vehicle:
peanut oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The suspension of the test material was freshly prepared daily by means of a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Batches of diet were assayed for composition and contaminant level by the manufacturer. No other details were provided.
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1 Male/3 Females
- Length of cohabitation: Overnight
- Proof of pregnancy: Sperm in vaginal smear referred to as Day 0 of pregnancy
Duration of treatment / exposure:
Day 6 until Day 15 of pregnancy, inclusive.
Frequency of treatment:
Once/day
Duration of test:
Females were killed on Day 21 of pregnancy.
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
900 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 rats/group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
In order to determine the dose levels for the main study, a preliminary experiment was carried out on 10 fertilized rats each for the vehicle control and the dose group (1,000 mg/kg). The test material was suspended in a mixture of distilled water and polyethylene glycol 400 (1:1) and administered orally by intubation from Day 6 until Day 15 of pregnancy, inclusive. Treatment at this 1,000 mg/kg dose level caused a reduction in bodyweight gain and food consumption in the mother animals. Apart from a reduced body weight no adverse effects were recorded for the progeny at sacrifice shortly before term in comparison with the vehicle control. On the basis of the foregoing results the doses for the main study were selected at 0, 100, 300 and 900 mg/kg of body weight.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the period of treatment, general body condition, weight gain and symptoms were checked daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: During the period of treatment, general body condition, weight gain and symptoms were checked daily.

BODY WEIGHT: Yes
- Time schedule for examinations: The average body weight gain of the females was determined on the basis of the actual body weight as well as that on the first day of treatment and at the time of necropsy, corrected by subtracting the weight of the gravid uterus.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No applicable

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: Ovaries and uterus (mucosa and contents, including amniotic fluid and placentae as well as abortions and resorption sites)
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
- Skeletal examinations: Yes: two-thirds of the litter
- Head examinations: Yes
Statistics:
Chi-square test, Yates' correction, Student's t-test (one-tailed)
Indices:
None reported.
Historical control data:
Spontaneous data characteristic of the breed of rats used in the present study refer to a series of untreated controls ("historical" or cumulative control) observed over a period of about 5 years.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Females No. 1, 4 (vehicle control) and 50 (100 mg/kg) died spontaneously on days 12, 11 and 8 p.c. (i.e. days 7, 6 and 3 of treatment).
respectively.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The dams of the intermediate and high-dose groups reacted to the treatment by a reduction in body-weight gain.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The dams of the intermediate and high-dose groups reacted to the treatment by a reduction food consumption
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:
not examined
Gross pathological findings:
not examined
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
Description (incidence and severity):
The numbers of embryonic and/or fetal deaths (resorptions) were not increased at either dose
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:
100 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
The progeny of the intermediate and high-dose groups displayed diminished body-weight shortly before term.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The male to female ratios of the foetuses were also comparable for all groups.
Changes in litter size and weights:
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):
Skeletal maturation showed some delay in these groups: phalangeal nuclei, calcanei and sternebrae were affected in this respect; in the 900 mg/kg group the number of still incompletely ossified thoracic vertebral centres was found to be enhanced, in addition. The occurrence of sternebral anomalies in all groups was not assumed to be of an experimental significance, the overall incidence of sternebral anomalies being 0.26% in the historical control.
Visceral malformations:
no effects observed
Description (incidence and severity):
One occasional malformation found in the high-dose group (generalized oedema) was considered to be of a spontaneous origin and not related to the treatment. Generalized oedema occurred at a rate of 0.02% in the historical control population of the breed of rats used for the present experiment.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
other: some delay in skeletal maturation

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The substance was devoid of embryotoxic activity and did not reveal teratogenic potency in the rat under the present experimental conditions. Some delay of physiological growth was noted for the foetuses of a 300 mg/kg and, in particular, the foetuses of the 900 mg/kg group but considered to be non-specific and related to maternal toxicity; the low-dose (100 mg/kg) was unaffected in this respect.

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