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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Review-like publication presenting studies on toxicokinetics as well as on acute toxicity, repeated dose toxicity, teratogenicity, and effects on endocrine organs in different species.

Data source

Reference
Reference Type:
publication
Title:
Absorption, Distribution and Toxicity of Ibuprofen.
Author:
Adams S.S., Bough R.G., Vliffe E.E., Lessel B., Mills R.F.N.
Year:
1969
Bibliographic source:
Toxicol Appl Pharmacol 15: 310-330.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
To evaluate the potential developmental toxicity, Primiparous females and proven males were caged together, the presence of spermatozoa in the vaginal smear being taken as an indication of the first day of pregnancy. From this time, 180, 60,20, or 7.5 mg/kg/day of the test substance, was administered by oral intubation until day 20 of pregnancy. Control females received 10 mL/kg of water daily. The uterine contents were examined on day 21 of pregnancy, and the fetuses were examined for external, visceral, and skeletal abnormalities. Since the young of rats may show certain types of developmental abnormality at weaning which are not visible before birth, additional groups of rats were given 20 or 7.5 mg/kg/day of the test substance throughout pregnancy until parturition, and the young were examined 3 weeks after delivery. Litters were reduced to 9 at birth, and any underweight or neglected young were killed during the suckling period. All were examined in detail for gross abnormalities. From the litter records, the viability index at weaning was estimated.
GLP compliance:
no
Remarks:
pre-GLP study
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Ibuprofen
EC Number:
239-784-6
EC Name:
Ibuprofen
Cas Number:
15687-27-1
Molecular formula:
C13H18O2
IUPAC Name:
2-(4-isobutylphenyl)propanoic acid
Test material form:
solid
Specific details on test material used for the study:
- Name of test material (as cited in study report): Ibuprofen; i.e. 2-(4-isobutylphenyl)propionic acid)

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- male and female Boots Wistar rats (proven males and primiparous females); only females were treated.
- Source: Boots
- Diet: ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was administered as an aqueous solution of the sodium salt; ph of this solution was 8.
Control females received 10 mL/kg of water daily.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: sperm in vaginal smear referred to as day 1 of pregnancy
Duration of treatment / exposure:
Experiment 1: days 1 through 20 of gestation (groups administered 7.5, 20, 60, 180 mg/kg bw/d)
Experiment 2: throughout gestation (two additional groups given 7.5 and 20 mg/kg bw)
Frequency of treatment:
daily
Duration of test:
Experiment 1: until day 21 of gestation (groups administered 7.5, 20, 60, 180 m g/kg bw/d)
Experiment 2: until days 21 post partum (two additional groups given 7.5 and 20 mg/kg bw)
Doses / concentrationsopen allclose all
Dose / conc.:
7.5 mg/kg bw/day (actual dose received)
Remarks:
Experiment 1
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
Experiment 1
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
Experiment 1
Dose / conc.:
180 mg/kg bw/day (actual dose received)
Remarks:
Experiment 1
Dose / conc.:
7.5 mg/kg bw/day (actual dose received)
Remarks:
Experiment 2
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Remarks:
Experiment 2
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
According to the authors, previous results by other investigators [Paget GE and Thorpe E (1964). A teratogenic effect of a sulphonamide in experimental animals. Brit J Pharmacol 23: 305-312.] had shown that the young of rats may show certain types of developmental abnormality at weaning which are not visible before birth. For this reason additional groups of rats were given 20 or 7.5 mg/kg bw/d of the test substance throughout pregnancy until parturition, and die young were examined 3 weeks after delivery (Experiment 2).

Examinations

Maternal examinations:
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21 or on postnatal day # 21
- Organs examined: uterus and uterine contents, ovaries
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
The uterine contents were examined on day 21 of pregnancy.
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data

In the additional groups given 7.5 or 20 or 7.5 mg/kg bw/d, the young were examined 3 weeks after delivery. Litters were reduced to 9 at birth (the normal practice in the investigator's breeding colony), and any underweight or neglected young were killed during the suckling period. All were examined in detail for gross abnormalities. From the litter records, the viability index at weaning was estimated.
Statistics:
no data
Indices:
implantation index, viability index at weaning
Historical control data:
no data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Only females on the highest dose had a diminished rate of growth. These animals had litters of normal size with fetuses of normal weight.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the first experiment females receiving 180, 60, or 20 mg/kg of test substance on days 1 to 20 of pregnancy were found to have gastrointestinal lesions graded in severity according to the dose; no lesions were observed in those an 7.5 mg/kg/day or in the controls.

Maternal developmental toxicity

Other effects:
no effects observed
Description (incidence and severity):
Animals form all groups had litters of normal size with fetuses of normal weight (experiment 1)
In the second experiment, in which dosing was continued throughout pregnancy until parturition, the animals had uneventful pregnancies and delivered their young without difficulty. A similar number of live young per litter was obtained from the test substance treated and control animals.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
General toxicity
Effect level:
7.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic

Results (fetuses)

Description (incidence and severity):
Weaning weight was not significantly affected
External malformations:
no effects observed
Description (incidence and severity):
None of the fetuses obtained from animals given 180 mg/kg/day was malformed.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Different types of skeletal abnormality were found, particularly in the young examined at weaning, but these generally fell within the accepted range of normal variation for the strain used in these investigations. One exception was a fetus with subcutaneous edema, wavy ribs and bilateral curvature of the radius and ulna, obtained from a female with a purulent exudate in the uterus.
Visceral malformations:
no effects observed
Description (incidence and severity):
In both experiments various external and visceral malformations were observed; these were of low incidence and occurred in the treated and control groups
Other effects:
no effects observed
Description (incidence and severity):
Postnatal findings indicate that the viability index at weaning and weaning weight were not significantly affected. Microscopic examination of the organs revealed no histologic abnormalities.
Details on embryotoxic / teratogenic effects:
Postnatal findings indicate that the viability index at weaning and weaning weight were not significantly affected. In both experiments various external and visceral malformations were observed; these were of low incidence and occurred in the treated and control groups. None of the fetuses obtained from animals given 180 mg/kg/day was malformed, and microscopic examination of their organs revealed no histologic abnormalities.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
180 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion