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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
ANTIHISTAMINES AND TERATOGENICITY IN THE RAT
Author:
C. T. G. KING, S. A. WEAVER AND S. A. NARROD
Year:
1965
Bibliographic source:
Journal of Pharmacology and Experimental Therapeutics. 147,391,1965

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
To evaluate the teratogenic potential of Norchlorcyclizine, a metabolite of antihistamine in female Sprague-Dawley pregnant rats.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-(4-chlorobenzhydryl)piperazine
EC Number:
206-137-4
EC Name:
N-(4-chlorobenzhydryl)piperazine
Cas Number:
303-26-4
Molecular formula:
C17H19ClN2
IUPAC Name:
N-(4-chlorobenzhydryl)piperazine
Test material form:
solid
Details on test material:
- Name of the test material: 1-[(4-chlorophenyl)(phenyl)methyl]piperazine
- Common Name: Norchlorcyclizine
- IUPAC name: 1-[(4-chlorophenyl)(phenyl)methyl]piperazine
- Molecular weight: 286.804 g/mol
- Molecular formula: C17H19ClN2
- Substance type: Organic
- SMILES Notation: c1([C@@H](c2ccccc2)N2CCNCC2)ccc(Cl)cc1
- InChI: 1S/C17H19ClN2/c18-16-8-6-15(7-9-16)17(14-4-2-1-3-5-14)20-12-10-19-11-13-20/h1-9,17,19H,10-13H2
- Physical State: Solid (white to pale yellow)
Specific details on test material used for the study:
- Name of the test material: 1-[(4-chlorophenyl)(phenyl)methyl]piperazine
- IUPAC name: 1-[(4-chlorophenyl)(phenyl)methyl]piperazine
- Molecular weight: 286.804 g/mol
- Molecular formula: C17H19ClN2
- Substance type: Organic
- Smiles: c1([C@@H](c2ccccc2)N2CCNCC2)ccc(Cl)cc1
- Inchi: 1S/C17H19ClN2/c18-16-8-6-15(7-9-16)17(14-4-2-1-3-5-14)20-12-10-19-11-13-20/h1-9,17,19H,10-13H2

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: [artificial insemination / purchased timed pregnant / cohoused]
- If cohoused:
- M/F ratio per cage: No data available.
- Length of cohabitation:No data available.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.No data available.
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available.
- Verification of same strain and source of both sexes: [yes / no (explain)]No data available.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy The onset of gestation was established by the demonstration of spermatozoa in vaginal smears. The day following the appearance of a positive smear was recorded as the first day of pregnancy
- Any other deviations from standard protocol:No data available.
Duration of treatment / exposure:
First 16 days of gestation 16
Frequency of treatment:
12-15 day of gestation
Duration of test:
16 days
Doses / concentrations
Remarks:
12.5,25, 37.5,50 and 125 mg/kg
No. of animals per sex per dose:
Total :17
12.5 mg/kg/day-3 female rats
25 mg/kg/day -4 female rats
37.5 mg/kg/day-3 female rats
50 mg/kg/day- 4 female rats
125 mg/kg/day-3 female rats
Control animals:
other: No data available.
Details on study design:
No data available.

Examinations

Maternal examinations:
No data available.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes:
- Soft tissue examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
- Skeletal examinations: Yes:
- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Statistics:
No data available.
Indices:
No data available.
Historical control data:
No data available.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No significant change were observed at the resorption rate and the number of mean nidation sites at 125 mg/kg /day.
Total litter losses by resorption:
not specified
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
The significant increase in fetal death at a dose level of 125 mg/kg /day was observed.
Changes in pregnancy duration:
not specified
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 specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: No significant change were observed at the resorption rate and the number of mean nidation sites at 125 mg/kg /day
Remarks on result:
other: No effects on reproductive performance

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
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 specified
Reduction in number of live offspring:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, treatment-related
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
The test material induces malformations, i.e., cleft palate with glossopalatine fusion, brachygnathia, micromelia, microstomia and inhibition of calcification, at dose level 25 mg/kg body weight /day.
Visceral malformations:
not specified
Other effects:
not specified

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
external malformations
skeletal malformations
Remarks on result:
other: No developmental effects observed
Dose descriptor:
LOAEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
external malformations
skeletal malformations
Remarks on result:
other: developmental effects observed

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: induces malformations, i.e., cleft palate with glossopalatine fusion, brachygnathia, micromelia, microstomia and inhibition of calcification at dose level 25 mg/kg body weight /day.

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
25 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
not specified
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

 

Influence of norchlorcyclizine on the gestation of the rat

Dose (mg/kg)

Days treated

No. of pregant rats

No. Of grossly normal young

No. Of young resorbed

% young resorbed

Avg nidation site per pregnant rats

No. of young malformed

% young malformed

grossly

Shown by clearing

125

12-15

3

0

7

21.2

11.0±2

6

26

100

50

10-15

4

15

3

7.5

10.0±2

24

39

61.5

37.5

12-15

3

2

0

0

9.6±2

26

28

92.9

25

12-15

4

21

3

10.0

8.2±2

9

20

30

25

10-15

3

8

0

0

9.3±2

20

20

71.4

12.5

12-15

3

28

1

3

9.6±2

0

0

0

Applicant's summary and conclusion

Conclusions:
Devlopmental toxicity study, NOAEL was considered to be 12.5 mg/kg/day as no developmental effects was observed and LOAEL was considered to be 25 mg/ kg/bw on the bases of malformations, i.e., cleft palate with glossopalatine fusion, brachygnathia, micromelia, microstomia and inhibition of calcification was observed at given dose level. When female Sprague-Dawley rats were exposed with Norchlorcyclizine (303-26-4) through the 12-15 day of gestation by oral gavage.
Executive summary:

Developmental toxicity study for Norchlorcyclizine(303 -26 -4) in male and female Sprague-Dawley rats when there dams were exposed through the 12-15 day of gestation by oral gavage as a metabolite of antihistamines was observed .They were exposed at different concentration  12.5,25, 37.5,50 and 125 mg/kg/day. No significant change was observed at the resorption rate and the number of mean nidation sites at any dose level in dams. Fetal death at a dose level of 125 mg/kg /day was observed. Norchlorcyclizine induces malformations, i.e., cleft palate with glossopalatine fusion, brachygnathia, micromelia, microstomia and inhibition of calcification at dose level 25 mg/kg body weight /day. Therefore NOAEL was considered to be 12.5 mg/kg/day as no developmental effects was observed and LOAEL was considered to be 25 mg/ kg/bw on the bases of Norchlorcyclizine induces malformations, i.e., cleft palate with glossopalatine fusion, brachygnathia, micromelia, microstomia and inhibition of calcification at given dose level. When female Sprague-Dawley rats were exposed with Norchlorcyclizine (303-26-4) through the 12-15 day of gestation by oral gavage.