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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Nov 19 - Dec 10, 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Commission of the European Communities - EEC Directive 79-831, Annex V, Part B, Toxicological Methods of Annex VIII, Teratogenicity Test. Official Journal of the European Communities L 133/24-26, May 30, 1988.
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-phenyl-1H-benzimidazole-5-sulphonic acid
EC Number:
248-502-0
EC Name:
2-phenyl-1H-benzimidazole-5-sulphonic acid
Cas Number:
27503-81-7
Molecular formula:
C13H10N2O3S
IUPAC Name:
2-phenyl-1H-benzimidazole-5-sulphonic acid

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: F. Winkelmann, Versuchstierzucht GmbH in 33178 Borchen
- Age at study initiation: appr. 9 weeks
- Weight at study initiation: 166 (154 - 178) g
- Fasting period before study: no
- Housing: individually under conventional conditions in Makrolon cages (type III) on softwood granulate specially manufactured for housing of animals
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 23 °C
- Humidity (%): 47 - 65 %
- Photoperiod (hrs dark / hrs light): 12 hours /12 hours

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Concentration in vehicle: 20 %
- Amount of vehicle (if gavage): 100 mL
- Lot/batch no. (if required): --
- Purity: distilled
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- M/F ratio per cage: 4 f / 1 m
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of gestation
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
treatment on 10 consecutive days from the 6th to the 15th day post conception
Frequency of treatment:
daily
Duration of test:
20 days
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 3, and 6 p.c., and then daily until the end of the study.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption was determined once a week (on days 6, 10, 15, and 20) by weighing the unconsumed food.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Water consumption was determined on days 3, 6, 9, 12, 15, 18, and 20 by weighing the water not consumed.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
The fetuses were delivered by Cesarean section on the 20th day p.c. and were examined for macroscopic malformations. About 2/3 of them were examined for skeletal and 1/3 for organ malformations.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- 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: 1/3
- Skeletal examinations: Yes: 2/3
Statistics:
Standard statistical methods have been applied for data processing.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
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):
effects observed, treatment-related
Description (incidence and severity):
Water consumption in group 2 was increased during the treatment period and further until day 18 p.c.
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
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
Complete, early, and late resorptions in group 2 were within the spontaneous range.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects: no effects

Details on maternal toxic effects:
All dams were clinically normal and none of the rats died.
Food consumption was normal, but water consumption in group 2 was increased during the treatment period and further until day 18 p.c.
Body weight was not negatively affected by treatment.
23 rats in group 1 (control) and 24 rats in group 2 (treatment) became pregnant.

The numbers of corpora lutea and live fetuses in group 2 corresponded to those in group 1. The number of implantations was reduced. Since implantation had been completed at the beginning of treatment, this finding is not substance related and, thus, irrelevant.

Complete, early, and late resorptions in group 2 were within the spontaneous range. No dead fetuses were found.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

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): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At external examination one fetus with anemia was observed in group 1 (control).
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
Fetal weights were normal.
No runts were seen.
Sex distribution was normal.
At external examination one fetus with anemia was observed in group 1 (control).
No other abnormal findings were seen at external examination, evisceration, skeleton staining and after transverse section.
The skeletal examinations gave no indication of damage.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Apart from the increased water consumption, Phenylbenzimidazole sulfonic acid (Na-salt) did not reveal maternally toxic effects and was neither embryotoxic nor teratogenic at the limit dose of 1000 mg/kg bw/day.
Executive summary:

Study design

The teratogenic potential of Phenylbenzimidazole sulfonic acid (Na-salt) was investigated in Wistar rats after oral administration in a limit test. The test item was administered orally by gavage to 25 mated Wistar rats daily from day 6 through to day 15 post coitum at the limit dose level of 1000 mg/kg bw/day. A control group of 25 animals was dosed with the vehicle alone (water). All females were sacrificed on day 20 post coitum and the fetuses were removed by Caesarean section and examined for macroscopic malformations. About 2/3 of them were examined for skeletal and 1/3 for organ malformations.

Results

All females survived until scheduled necropsy. No signs of discomfort or clinical symptoms were observed. Mean food consumption and mean body weight was not affected by treatment with the test item in the dose group. In the dose group water consumption was increased during the treatment period and further until day 18 post coitum. 23 rat in the control group and 24 rats in the dose group became pregnant. The numbers of corpora lutea and live fetuses in the dose group corresponded to those in the control animals. Complete, early and late resorptions in the dose group were within the spontaneous range. No dead fetuses were recognized.
No effects on fetal body weights were noted. No test-item-related effects on fetal sex ratio were noted in the dose group. During the external examination of the fetuses, no test item-related abnormal findings were noted. No test item-related abnormalities were noted during visceral examination of fetuses. No abnormalities, which were considered to be test item-related, were noted during examination of fetal skeleton.

Conclusion

Apart from the increased water consumption, Phenylbenzimidazole sulfonic acid (Na-salt) did not reveal maternally toxic effects and was neither embryotoxic nor teratogenic at the limit dose of 1000 mg/kg bw/day.