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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
Description of key information
Skin Sensitization:
The skin sensitization potential of1-[(4-chlorophenyl)(phenyl)methyl]piperazinewas estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor.1-[(4-chlorophenyl)(phenyl)methyl]piperazine was predicted to be sensitizing to the skin of male Hartley guinea pigs.
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- (Q)SAR
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
- Justification for type of information:
- data is from OECD QSAR toolbox v3.4 and the QMRF report has been attached
- Qualifier:
- according to guideline
- Guideline:
- other: Estimated data
- Principles of method if other than guideline:
- Prediction was done using OECD QSAR toolbox v3.4
- GLP compliance:
- not specified
- Type of study:
- other: Estimated data
- Justification for non-LLNA method:
- not specified
- Specific details on test material used for the study:
- - 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 - Species:
- guinea pig
- Strain:
- Hartley
- Sex:
- male
- Details on test animals and environmental conditions:
- no data available
- Route:
- epicutaneous, open
- Vehicle:
- not specified
- Concentration / amount:
- no data available
- Day(s)/duration:
- no data available
- Adequacy of induction:
- not specified
- No.:
- #1
- Route:
- intradermal
- Vehicle:
- not specified
- Concentration / amount:
- no data available
- Day(s)/duration:
- no data available
- Adequacy of challenge:
- not specified
- No. of animals per dose:
- 10
- Details on study design:
- no data available
- Challenge controls:
- no data available
- Positive control substance(s):
- not specified
- Vehicle:
- not specified
- Concentration:
- no data available
- No. of animals per dose:
- no data available
- Details on study design:
- no data available
- Positive control substance(s):
- not specified
- Statistics:
- no data available
- Positive control results:
- no data available
- Other effects / acceptance of results:
- no data available
- Reading:
- 1st reading
- Group:
- test chemical
- Clinical observations:
- signs of sensitization observed
- Remarks on result:
- positive indication of skin sensitisation
- Interpretation of results:
- other: Sensitizing
- Conclusions:
- 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was predicted to be sensitizing to the skin of male Hartley guinea pigs
- Executive summary:
The skin sensitization potential of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor.1-[(4-chlorophenyl)(phenyl)methyl]piperazine was predicted to be sensitizing to the skin of male Hartley guinea pigs.
Reference
The
prediction was based on dataset comprised from the following
descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 7 nearest neighbours
Domain logical expression:Result: In Domain
(((((((((((((("a"
or "b" or "c" or "d" )
and ("e"
and (
not "f")
)
)
and ("g"
and (
not "h")
)
)
and ("i"
and (
not "j")
)
)
and ("k"
and (
not "l")
)
)
and ("m"
and (
not "n")
)
)
and ("o"
and (
not "p")
)
)
and ("q"
and (
not "r")
)
)
and ("s"
and (
not "t")
)
)
and "u" )
and ("v"
and (
not "w")
)
)
and ("x"
and (
not "y")
)
)
and ("z"
and (
not "aa")
)
)
and ("ab"
and "ac" )
)
Domain
logical expression index: "a"
Referential
boundary: The
target chemical should be classified as Secondary amines by OECD HPV
Chemical Categories
Domain
logical expression index: "b"
Referential
boundary: The
target chemical should be classified as Aliphatic Amines by US-EPA New
Chemical Categories
Domain
logical expression index: "c"
Referential
boundary: The
target chemical should be classified as Michael addition AND Michael
addition >> P450 Mediated Activation to Quinones and Quinone-type
Chemicals AND Michael addition >> P450 Mediated Activation to Quinones
and Quinone-type Chemicals >> Arenes AND SN1 AND SN1 >> Iminium Ion
Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines
by DNA binding by OECD
Domain
logical expression index: "d"
Referential
boundary: The
target chemical should be classified as Narcotic Amine by Acute aquatic
toxicity MOA by OASIS
Domain
logical expression index: "e"
Referential
boundary: The
target chemical should be classified as No alert found by DNA binding by
OASIS v.1.4
Domain
logical expression index: "f"
Referential
boundary: The
target chemical should be classified as AN2 OR AN2 >> Carbamoylation
after isocyanate formation OR AN2 >> Carbamoylation after isocyanate
formation >> N-Hydroxylamines OR Radical OR Radical >> Radical mechanism
via ROS formation (indirect) OR Radical >> Radical mechanism via ROS
formation (indirect) >> N-Hydroxylamines OR SN1 OR SN1 >> Nucleophilic
attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after
nitrenium ion formation >> N-Hydroxylamines OR SN2 OR SN2 >> Acylation
OR SN2 >> Acylation >> N-Hydroxylamines by DNA binding by OASIS v.1.4
Domain
logical expression index: "g"
Referential
boundary: The
target chemical should be classified as Inclusion rules not met by Skin
irritation/corrosion Inclusion rules by BfR
Domain
logical expression index: "h"
Referential
boundary: The
target chemical should be classified as Alkylalkanol-amines OR Phenols
OR Primary and secondary aliphatic amines OR Tertiary aliphatic amine by
Skin irritation/corrosion Inclusion rules by BfR
Domain
logical expression index: "i"
Referential
boundary: The
target chemical should be classified as (!Undefined)Group All Lipid
Solubility < 0.01 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 4
g/kg AND (!Undefined)Group CNHal Lipid Solubility < 400 g/kg by Skin
irritation/corrosion Exclusion rules by BfR
Domain
logical expression index: "j"
Referential
boundary: The
target chemical should be classified as (!Undefined)Group CNS Surface
Tension > 62 mN/m OR Exclusion rules not met OR Group All log Kow < -3.1
by Skin irritation/corrosion Exclusion rules by BfR
Domain
logical expression index: "k"
Referential
boundary: The
target chemical should be classified as (!Undefined)Group All Lipid
Solubility < 0.01 g/kg AND (!Undefined)Group CNHal Lipid Solubility < 4
g/kg AND (!Undefined)Group CNHal Lipid Solubility < 400 g/kg by Skin
irritation/corrosion Exclusion rules by BfR
Domain
logical expression index: "l"
Referential
boundary: The
target chemical should be classified as Group CN log Kow > 5.5 by Skin
irritation/corrosion Exclusion rules by BfR
Domain
logical expression index: "m"
Referential
boundary: The
target chemical should be classified as Group 14 - Carbon C AND Group 15
- Nitrogen N AND Group 17 - Halogens Cl AND Group 17 - Halogens
F,Cl,Br,I,At by Chemical elements
Domain
logical expression index: "n"
Referential
boundary: The
target chemical should be classified as Group 16 - Sulfur S by Chemical
elements
Domain
logical expression index: "o"
Referential
boundary: The
target chemical should be classified as Amine AND Aromatic compound AND
Aryl chloride AND Aryl halide AND Halogen derivative AND Heterocyclic
compound AND Secondary aliphatic amine AND Secondary amine AND Tertiary
aliphatic amine AND Tertiary amine by Organic functional groups, Norbert
Haider (checkmol)
Domain
logical expression index: "p"
Referential
boundary: The
target chemical should be classified as Secondary alcohol by Organic
functional groups, Norbert Haider (checkmol)
Domain
logical expression index: "q"
Referential
boundary: The
target chemical should be classified as Amine AND Aromatic compound AND
Aryl chloride AND Aryl halide AND Halogen derivative AND Heterocyclic
compound AND Secondary aliphatic amine AND Secondary amine AND Tertiary
aliphatic amine AND Tertiary amine by Organic functional groups, Norbert
Haider (checkmol)
Domain
logical expression index: "r"
Referential
boundary: The
target chemical should be classified as 1,2-aminoalcohol OR Alcohol by
Organic functional groups, Norbert Haider (checkmol)
Domain
logical expression index: "s"
Referential
boundary: The
target chemical should be classified as Amine AND Aromatic compound AND
Aryl chloride AND Aryl halide AND Halogen derivative AND Heterocyclic
compound AND Secondary aliphatic amine AND Secondary amine AND Tertiary
aliphatic amine AND Tertiary amine by Organic functional groups, Norbert
Haider (checkmol)
Domain
logical expression index: "t"
Referential
boundary: The
target chemical should be classified as Ether by Organic functional
groups, Norbert Haider (checkmol)
Domain
logical expression index: "u"
Referential
boundary: The
target chemical should be classified as Has superfragment AND
R{*}N1CCNCC1 by Superfragments ONLY
Domain
logical expression index: "v"
Referential
boundary: The
target chemical should be classified as Basic [60,70) AND No pKa value
by Ionization at pH = 9
Domain
logical expression index: "w"
Referential
boundary: The
target chemical should be classified as Basic [40,50) by Ionization at
pH = 9
Domain
logical expression index: "x"
Referential
boundary: The
target chemical should be classified as Secondary amines by OECD HPV
Chemical Categories
Domain
logical expression index: "y"
Referential
boundary: The
target chemical should be classified as Not categorized by OECD HPV
Chemical Categories
Domain
logical expression index: "z"
Referential
boundary: The
target chemical should be classified as Developmental & Reproductive
Toxicity (DART) by Database Affiliation
Domain
logical expression index: "aa"
Referential
boundary: The
target chemical should be classified as ECOTOX by Database Affiliation
Domain
logical expression index: "ab"
Parametric
boundary:The
target chemical should have a value of log Kow which is >= -1.67
Domain
logical expression index: "ac"
Parametric
boundary:The
target chemical should have a value of log Kow which is <= 4.44
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
Skin Sensitization:
Several studies were performed to ascertain the extent of dermal sensitization caused by 1-[(4-chlorophenyl)(phenyl)methyl]piperazine in living organisms. These studies include in vivo studies in rabbits as well as predicted data for the target chemical as well its functionally similar read across substances, Piperazine[CAS: 110-85-0] and 1-(2-Aminoethyl) piperazine[CAS: 140-31-8]. Thepredicted data using the OECD QSAR toolbox has also been compared with the experimental data.
The skin sensitization potential of1-[(4-chlorophenyl)(phenyl)methyl]piperazinewas estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor.1-[(4-chlorophenyl)(phenyl)methyl]piperazinewas predicted to be sensitizing to the skin of male Hartley guinea pigs.
Skin sensitization effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 1-[(4-chlorophenyl)(phenyl)methyl]piperazine. Based on estimation, skin sensitization reactions were observed in guinea pigs and humans. Therefore, 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was considered to be sensitizing.
Both the estimated results indicate a possibility of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine being sensitizing to skin.
These results are supported by the Guinea Pig Maximization study performed by HON- WING LEUNG, CAROL S. AULETTA (Journal of Toxicology: Cutaneous and Ocular Toxicology 16, no. 3 (1997): 189-195) to assess the dermal sensitization potential of the functionally similar read across substance, Piperazine [CAS: 110-85-0].The srudy was conducted following the method described by Magnusson and Kligman. 19 male and female Dunkin Hartley Haz:(DH)fBR albino male and female guinea pigs weighing 278-444 grams were used for the study. Range finding studies were conducted to select the appropriate concentration for induction and challenge exposures.
Animals were inspected 24 and 48 h after dosing for signs of necrosis and ulceration. The concentration that produced only local necrosis (i.e., no extensive necrosis or ulceration) was used for the intradermal induction. The highest concentration that produced only mild irritation was appropriate for the epicutaneous induction, and the highest concentration that did not produce irritation was used for the epicutaneous challenge.
The concentrations obtained for piperazine were – 5% intradermal induction, 50% epicutaneous induction,25% epicutaneous challenge. In the main sensitization study, 0.1ml intradermal induction injections containing 50% (v/v) Freunds complete adjuvant (FCA) water emulsion, 5% test material, and the test material in FCA/water emulsion or FCA/water emulsion were injected on 2 sites each of the clipped shoulder skin of guinea pigs. After 7 days of intradermal induction, epicutaneous inductions were performed. 0.2 ml of 50% piperazine was applied in saturation to a 2*4cm filter paper, which was then placed on the test site and secured with a tape. The patches were left in place for 48 hours and after removal of the patches, the skin was wiped free of the excess test material. During the challenge phase, 25% piperazine was soaked in 2*2 cm filter paper squares was applied to a previously untreated site(right flank) 14 days after epicutaneous induction. Patches were left in place for 24 hours, and the sites were inspected for signs of irritation and scored 24 -48 hours after removal of patches.
The skin sensitization response for piperazine was 5% when tested in 19 guinea pigs. The normalized skin sensitization response was 0.004.
Piperazine appeared to be moderate sensitizer based on the normalized response.
Hence, Piperazine can be considered to be sensitizer to the skin of Dunkin Hartley Haz:(DH)fBR albino male and female guinea pigs.
The same study (Journal of Toxicology: Cutaneous and Ocular Toxicology 16, no. 3 (1997): 189-195) was performed to assess the dermal sensitization potential of another functionally similar read across substance, 1 -(2-Aminoethyl) piperazine [CAS: 140-31-8]. 10 male and 10 female Dunkin Hartley Haz:(DH)fBR albino male and female guinea pigs weighing 278-444 grams were used for the study. Range finding studies were conducted to select the appropriate concentration for induction and challenge exposures.
Animals were inspected 24 and 48 h after dosing for signs of necrosis and ulceration. The concentration that produced only local necrosis (i.e., no extensive necrosis or ulceration) was used for the intradermal induction. The highest concentration that produced only mild irritation was appropriate for the epicutaneous induction, and the highest concentration that did not produce irritation was used for the epicutaneous challenge.
The concentrations obtained for 1-(2-Aminoethyl) piperazine were – 5% intradermal induction, 50% epicutaneous induction,25% epicutaneous challenge. In the main sensitization study, 0.1ml intradermal induction injections containing 50% (v/v) Freunds complete adjuvant (FCA) water emulsion, 5% test material, and the test material in FCA/water emulsion or FCA/water emulsion were injected on 2 sites each of the clipped shoulder skin of guinea pigs. After 7 days of intradermal induction, epicutaneous inductions were performed. 0.2 ml of 50% piperazine was applied in saturation to a 2*4cm filter paper, which was then placed on the test site and secured with a tape. The patches were left in place for 48 hours and after removal of the patches, the skin was wiped free of the excess test material. During the challenge phase, 25% piperazine was soaked in 2*2 cm filter paper squares was applied to a previously untreated site(right flank) 14 days after epicutaneous induction. Patches were left in place for 24 hours, and the sites were inspected for signs of irritation and scored 24 -48 hours after removal of patches.
The skin sensitization response for 1-(2-Aminoethyl) piperazine was 25% when tested in 20 guinea pigs. The normalized skin sensitization response was 0.020.
1-(2-Aminoethyl) piperazine appeared to be moderate sensitizer based on the normalized response
Hence, 1-(2-Aminoethyl) piperazine can be considered to be sensitizer to the skin of Dunkin Hartley Haz:(DH)fBR albino male and female guinea pigs.
The above results are further supported by the Guinea pig Maximization study summarized in Hazardous Substances Databank –HSDB, HSDB for the CAS: 140-31-8, U S National Library of Medicine, last updated 2010, for the functionally similar read across substance, 1 -(2-Aminoethyl) piperazine [CAS: 140-31-8]. The study was performed as per OECD 406 Guidelines. 0.5% w/w aqueous solution was applied to the skin of 15 guinea pigs during the induction phase (duration, number of exposures not mentioned). In the challenge phase,2.0% w/w aqueous solution was applied to the test animals and observed for dermal reactions (duration of exposure, observation period not mentioned). No reactions were observed in non-induced controls. Extreme sensitizing reactions were observed in 15 guinea pigs tested. Hence, 1-(2-Aminoethyl) piperazine was considered to be strong sensitizer to guinea pig skin.
Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach,1-[(4-chlorophenyl)(phenyl)methyl]piperazinecan be considered to be sensitizer to skin.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Available data for 1-[(4-chlorophenyl)(phenyl)methyl]piperazine indicates that it is likely to cause dermal sensitization to skin.1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered to be sensitizer to skin and can be classified under the category “Skin Sensitizer 1” as per CLP regulation.
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