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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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Toxicity to reproduction:
Waiver as the study dose not to be conducted because a pre-natal developmental toxicity study is avaliable.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
- Quality of whole database:
- Waiver
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Effects on developmental toxicity
Description of key information
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. based on the above studies on Norchlorcyclizine(303 -26 -4) and its structurally similar read across substance chlorcyclizine hydrochloride (14362-31-3),It was considered that it had teratogenic potential on the bases of skeleton malformation observed in both the rodent species i.e rats and mice when exposed 11-14 days through gestation by oral gavage and also supported by study done using Intrauterine application .
Thus, comparing this value with the criteria of CLP regulation Norchlorcyclizine(303 -26 -4) can be classified as “Category 2”for reproductive toxicity.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting 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
- 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 in rats.
- GLP compliance:
- not specified
- Limit test:
- no
- 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 - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- No data available
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test material diluted with water
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0,20,40,60,80 and 100 mg/kg
- Amount of vehicle (if gavage): 1.0ml
- Lot/batch no. (if required):
- Purity: - 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 day of finding sperm is now called day 1 of pregnancy rather than day 0.
- Any other deviations from standard protocol:No data available - Duration of treatment / exposure:
- 3 days (Through gestation day 13-16)
- Frequency of treatment:
- Drug was administered, in general, on days 13-16 rather than on previously designated days 12-15.
- Duration of test:
- 19 days
- Remarks:
- 0,20,40,60,80 and 100 mg/kg
- No. of animals per sex per dose:
- No data available
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No data available
- Maternal examinations:
- No data available
- Ovaries and uterine content:
- No data available
- Fetal examinations:
- - External examinations: Yes:
- Soft tissue examinations: No data
- Skeletal examinations: Yes: (At day 21 of gestation the palate was observed for the presence of a cleft by simply opening the mouth. At days 17,18, and 19, frozen fetal heads were first sectioned with a razor blade so as to remove the mandible; the tongue was then removed. The palate
could then be observed with the aid of low magnification, either directly or after brief staining with mildly alkaline 0.5 % aqueous alizarin red S.)
- Head examinations: Yes: - Statistics:
- Yes statistics was observed.
- Indices:
- No data available
- Historical control data:
- No data available
- 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
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- 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
- Dose descriptor:
- other: not specified
- Based on:
- test mat.
- Basis for effect level:
- other: not specified
- Remarks on result:
- other: not specified
- Abnormalities:
- not specified
- Localisation:
- not specified
- 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 sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significant Cleft palate was observed at 30 mg/kg/day dose level.
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Dose descriptor:
- LOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- skeletal malformations
- Remarks on result:
- other: Cleft palate was observed.
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: Cleft palate was observed.
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
- Conclusions:
- Developmental toxicity study, LOAEL was considered to be 30 mg/kg/day for Norchlorcyclizine (303-26-4) in male and female Sprague Dawley rats fetuses when there dams where exposed for 13-16 days through gestation by oral gavage.
- Executive summary:
Developmental toxicity study was observed in male and female Sprague Dawley rats fetuses when there dams were exposed for 13-16 days through gestation by oral gavage for Norchlorcyclizine .The test material diluted with water .The day of finding sperm is now called day 1 of pregnancy rather than day 0and the pregnant female Sprague Dawley rats were exposed through the 13-16 days of gestation at concentration of 0, 20,40,60,80 and 100 mg/kg. At day 21 of gestation the palate was observed for the presence of a cleft by simply opening the mouth. At days 17,18, and 19, frozen fetal heads were first sectioned with a razor blade so as to remove the mandible; the tongue was then removed. The palate could then be observed with the aid of low magnification, either directly or after brief staining with mildly alkaline 0.5 % aqueous alizarin red S. Statistically significant Cleft palate was observed at 30 mg/kg/day in fetuses’ .Therefore LOAEL was considered to be 30 mg/kg/day for Norchlorcyclizine (303-26-4) in male and female Sprague Dawley rats fetuses when there dams were exposed for 13-16 days through gestation by oral gavage.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 25 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Data is Klimicsh 2 and from peer reviewed journal
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Developmental toxicity
In different studies, Norchlorcyclizine(303 -26 -4) has been investigated for developmental toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for Norchlorcyclizine(303 -26 -4) also been compared with the experimental studies performed on structurally similar read across substance Tartrazine(1934-21-0).
An experimental study conducted by C. T. G. KING, S. A. WEAVER AND S. A. NARROD (Journal of Pharmacology and Experimental Therapeutics. 147,391, 1965) 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.
It is supported by experimental study conducted by HERBERT S. POSNER AND ALZENA DARR (TOXICOLOGY AND APPLIED PHARMACOLOGY 17,67-75(1970)) Developmental toxicity study was observed in male and female Sprague Dawley rats fetuses when there dams were exposed for 13-16 days through gestation by oral gavage for Norchlorcyclizine .The test material diluted with water .The day of finding sperm is now called day 1 of pregnancy rather than day 0and the pregnant female Sprague Dawley rats were exposed through the 13-16 days of gestation at concentration of 0, 20,40,60,80 and 100 mg/kg. At day 21 of gestation the palate was observed for the presence of a cleft by simply opening the mouth. At days 17,18, and 19, frozen fetal heads were first sectioned with a razor blade so as to remove the mandible; the tongue was then removed. The palate could then be observed with the aid of low magnification, either directly or after brief staining with mildly alkaline 0.5 % aqueous alizarin red S. Statistically significant Cleft palate was observed at 30 mg/kg/day in fetuses’ .Therefore LOAEL was considered to be 30 mg/kg/day for Norchlorcyclizine (303-26-4) in male and female Sprague Dawley rats fetuses when there dams were exposed for 13-16 days through gestation by oral gavage.
It is further supported by experimental study conducted by C. T. G. KING JOYCE HOWELL (American J of Obst. & Gynec, 1996 Vol 95 Is 1 PP 109-111) on structurally similar read across substance chlorcyclizine hydrochloride (14362-31-3). Developmental toxicity study of chlorcyclizine hydrochloride (14362-31-3) was performed on Forty-one mature female NIH albino mice weighing 20 ±3 grams. The compound was intubated in water solution (not to exceed 0.5 ml.) from the eleventh to the fourteenth day of gestation in dose concentration150, 200,250,350mg/kg. Onset of gestation was established by the presence of a vaginal plug and the day following recorded as the first of pregnancy. 325 fetuses examined for malformations namely, cleft palate, fusion of the tongue to the palatine shelves, micrognathia, microstomia, micromelia, and incomplete calcification of the axial skeleton. Treatment with chlorcyclizine hydrochloride (350 mg. per kilogram) yielded malformations in 100 per cent of the young. At 250 mg. per kilogram the incidence was 72 per cent and at 200 mg. per kilogram 68.5 per cent. Administration of this compound at 150 mg. per kilogram did not induce malformations in this strain of mice. Furthermore, it is suggested that their teratogenic action is mediated by the formation of the demethylated metabolite, norchlorcyclizine, Hence NOAEL was considered to be 150 mg/kg/ as no malformation observed and LOAEL was considered to be 250mg/kg on the bases of malformation observed in 68% fetuses .When female mice were exposed with chlorcyclizine hydrochloride (14362-31-3) for 11-14 days through gestation by oral gavage.
Thus, based on the above studies on Norchlorcyclizine(303 -26 -4) and its structurally similar read across substance chlorcyclizine hydrochloride (14362-31-3),It was considered that it had teratogenic potential on the bases of skeleton malformation observed in both the rodent species i.e rats and mice when exposed 11-14 days through gestation by oral gavage and also supported by study done using Intrauterine application .Thus, comparing this value with the criteria of CLP regulation Norchlorcyclizine(303 -26 -4) can be classified for developmental toxicity.
Toxicity to reproduction: other studies
Description of key information
Developmental toxicity via other route: Intrauterine application
The teratologenic potential of Norchlorcyclizine (303-26-4) was evaluated by A. L. WILK(Teratology Vol 2, Is 1, PP 55-65, feb 1969) using Intrauterine application technique. The teratognicity of Norchlorcyclizine (303-26-4) was studied in female Sprague-Dawley rats when they were exposed through the 14-15 day of gestation after intrauterine application of test material. In this technique of intrauterine application a compound, which by passes the metabolism of the adult rat and directly subjects the fetus to microgram concentrations of the compound for a known period of time. Pregnant Sprague-Dawley rats were used on days 11-16 of gestation. Vaginal smears were taken to determine pregnancy with the appearance of sperm designated as day 0 of gestation. Semisterile operational procedure was followed. Animals weighing approximately 200 g were anesthetized with an intraperitoneal injection of1ml of a 10% pentobarbital sodium solution supplemented, when necessary, with light ether inhalation. A midline abdominal incision was made and the double horned uterus was exteriorized.Asmall cut was then made through the uterine wall and a Millipore filter square impregnated with norchlorcyclizine HCl, or HCl was inserted either on the yolk sac over the intact amniotic sac (fetal side) or on the placenta .Once inserted, the filters remained in place until after day 16 when fetal movements seemed to dislodge them. In each pregnant rat, fetuses in one uterine horn were usually subjected to experimental filters and the HCl-containing, control filter was placed over fetuses in the other horn. Prior to day 14 of gestation the position of the embryo cannot be seen through the uterus and the filters were always inserted centrally over the fetus. On days 14 and 15 it was possible to insert the filters centrally, over the hindlimb, or over the head area .All fetuses observed on days 14, 15, and 16 appeared to lie with their left side uppermost and the right side toward the placenta. After these uterine manipulations the uterus was returned to the abdominal cavity, the muscle layer sutured, and the skin clamped with stainless steel clips. The animal was then placed on its back in a warm recovery area and when it recovered from the anesthesia it was returned to the animal room and gestation was allowed to continue to day 20.Pregnant rats were weighed and killed on day 20 and the young removed. Gross malformations were noted by observation and the fetuses were weighed and then placed in 80% ethanol. After alcohol fixation the fetuses were cleared of most soft tissue with 1% KOH and stained with 0.5% alizarin redS.The stained specimens were examined for skeletal malformations. The effect of the surgical procedure on the maternal weight gain from days 13-20 and on the fetal weight on day 20. Postoperational survival of pregnant rats was excellent. Pregnant operated rats gained approximately one-third as much weight as did unoperated pregnant animals and operated fetuses had a mean weight of about 3.3g on day 20while that of unoperated fetuses was 3.9 g. Fetal survival after surgery and insertion of HCl-containing filters was over 60% on every day except day 14 when it was approximately 42%. Cleft palate was produced at rates of 29 and 35% after norchlorcyclizine (50ug/filter) was inserted centrally on the fetal side on day 13 or 14 respectively. When the concentration of norchlorcyclizine was increased to 90 or 100 ug/filter and implanted centrally or over the head area of fetuses on day 15, less than 3% cleft palate was observed. Another malformation frequently seen following intrauterine application of norchlorcyclizine, was a limb malformation, which affected either the left forelimb or left hindlimb depending on whether the filter was placed centrally or over the hindlimb area of the fetus. The severity of the malformation ranged from simple fusion of the digits to complete absence of a paw. Left forelimb anomalies occurred at a rate of 24 and 38% after norchlorcyclizine (50 ug/filter) was inserted centrally on day 13 or 14 respectively and at a rate of about 3% after norchlorcyclizine- filter insertion on day 11, 12, 15, or 16Apositive relation between filter position over the fetus and cleft palate production was also found .When norchlorcyclizine (50 ug/filter) was inserted over the head area on the fetal side 42% of the fetuses had cleft palates and 13% had hindlimb malformations. Filters with similar concentration of norchlorcyclizine inserted over the left hind limb, however, resulted in 11% cleft palate and 55% left hind limb malformation. Gross observation of whole and cleared fetuses showed that the heads of some fetuses treated with test material filters were misshapen and the bodies more squat than normal. The control filters produced no malformation when implanted on any of the experimental days. Similarly no abnormalities resulted after norchlorcyclizine-filter insertion over the placenta on day 13.Hence LOAEL was considered to be 0.05mg/kg/day on the bases of teratogenic potential. When female Sprague-Dawley rats were exposed with Norchlorcyclizine (303-26-4) through the 13-14 day of gestation after intrauterine application
Justification for classification or non-classification
Thus, comparing this value with the criteria of CLP regulation Norchlorcyclizine(303 -26 -4) can be classified as “Category 2”for reproductive toxicity.
Additional information
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