N-(4-chlorobenzhydryl)piperazine

Endpoint summary

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

Reference

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

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

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.

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.