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EC number: 206-137-4 | CAS number: 303-26-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
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:
- 1 965
- 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
- 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)
Constituent 1
- 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.
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