Registration Dossier

Skin Irritation:

The dermal irritation potential of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the skin of New Zealand White rabbits.

Based on the estimated result;1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered corrosive to skin and can be classified under the category “Category 1” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the eyes of New Zealand White rabbits.

Based on the estimated result;1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered corrosive to the eyes and can be classified under the category “Category 1” as per CLP regulation.

Reference

Endpoint:

skin irritation: in vivo

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 v3.3 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 v.3.3

GLP compliance:

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:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5ml

Duration of treatment / exposure:

4 hours

Observation period:

20 hours

Number of animals:

1

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 20 hours

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Corrosive effects observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((((((("a" or "b" or "c" or "d" or "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and ("j" and ( not "k") ) ) and ("l" and ( not "m") ) ) and ("n" and ( not "o") ) ) and "p" ) and ("q" and ( not "r") ) ) and "s" ) and ("t" and ( not "u") ) ) and ("v" and ( not "w") ) ) and "x" ) and "y" ) and ("z" and "aa" ) )

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 Aliphatic Amines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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 AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Carbenium ion formation OR SN1 >> Carbenium ion formation >> Alpha-Haloethers OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sp3-carbon atom OR SN2 >> SN2 at sp3-carbon atom >> Alpha-Haloethers by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Thiophenes-Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal >> Ethanolamines (including morpholine) OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal >> Ethylenediamines (including piperazine) OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes OR Schiff base formers >> Chemicals Activated by P450 to Mono-aldehydes >> Benzylamines-Schiff base OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Tertiary (unsaturated) heterocyclic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> P450 Mediated Epoxidation OR SN2 >> P450 Mediated Epoxidation >> Thiophenes-SN2 by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR SN2 OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates by Protein binding by OASIS v1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic N-nitro group (Genotox) OR alpha,beta-unsaturated carbonyls (Genotox) OR Halogenated benzene (Nongenotox) OR Hydrazine (Genotox) OR Metals, oxidative stress (Nongenotox) OR Structural alert for genotoxic carcinogenicity OR Structural alert for nongenotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Narcotic Amine by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "q"

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: "r"

Referential boundary: The target chemical should be classified as Alkylalkanol-amines OR Ketones OR Tertiary aliphatic amine by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "v"

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: "w"

Referential boundary: The target chemical should be classified as Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "x"

Similarity boundary:Target: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "y"

Similarity boundary:Target: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.526

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.47

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the skin of New Zealand White rabbits.

Based on the estimated result;1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered corrosive to skin and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (corrosive)

Reference

Endpoint:

eye irritation: in vivo

Type of information:

calculation (if not (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 v3.3 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 v3.3

GLP compliance:

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:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1ml

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

7 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

1

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

7 d

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Corrosive effects were observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

((((((((((("a" or "b" or "c" or "d" or "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and ("j" and ( not "k") ) ) and ("l" and ( not "m") ) ) and "n" ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and "s" ) and "t" ) and ("u" and "v" ) )

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 Aliphatic Amines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Transition Metals by Groups of elements

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "j"

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: "k"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S OR Group 17 - Halogens F by Chemical elements

Domain logical expression index: "l"

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: "m"

Referential boundary: The target chemical should be classified as Aminal OR Anion OR Azo compound OR Carboxylic acid amidine OR Cation OR CO2 derivative (general) OR Guanidine OR Nitrile OR No functional group found OR Primary aliphatic amine OR Primary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

Similarity boundary:Target: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

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: "p"

Referential boundary: The target chemical should be classified as Group All log Kow > 9 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aryl AND Aryl halide AND Piperazine AND Saturated heterocyclic amine AND Saturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Amidine by Organic Functional groups

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Does NOT Biodegrade Fast by Biodeg probability (Biowin 2) ONLY

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Biodegrades Fast by Biodeg probability (Biowin 1) ONLY

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.523

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.42

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

1-[(4-chlorophenyl)(phenyl)methyl]piperazine was estimated to be corrosive to the eyes of New Zealand White rabbits.

Based on the estimated result;1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered corrosive to the eyes and can be classified under the category “Category 1” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irreversible damage)

Endpoint conclusion:

no study available

Skin Irritation:

Several studies were performed to ascertain the degree of dermal irritation 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, 1-Phenylpiperazine[CAS: 92-54-6] and 1-methyl-3 -phenylpiperazine[CAS: 5271-27-2]. Thepredicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for1-[(4-chlorophenyl)(phenyl)methyl]piperazine.1-[(4-chlorophenyl)(phenyl)methyl]piperazine was corrosive to New Zealand White rabbit skin.

Skin irritation effects were also 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, severe skin irritation effects were known when 1-[(4-chlorophenyl)(phenyl)methyl]piperazine was exposed to rabbit skin.Hence,1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be considered severely irritating to skin.

Both the estimated results indicate a possibility of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine being irritating to skin.

These results are supported by the experimental study summarized in American Industrial Hygiene Association Journal, 1962, 23:2, 95-107; for the functionally similar read across substance, 1-Phenylpiperazine[CAS: 92-54-6]. Primary skin irritation on rabbits was recorded in a 10-grade ordinal series and was based upon the severest reaction that develops on the clipped abdominal skin of each of five albino rabbits within 24 hours of the uncovered application of 0.01 ml of undiluted sample or of solutions in water, propylene glycol, or acetone. Grade 1 indicates no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted and Grade 10 indicates necrosis from a 0.01% solution. Primary Irritation score after 24 hours for 1-phenyl piperazine was Grade 6.

Based on this grade,1-phenyl piperazine can be considered moderately irritating to rabbit skin.

The above results are further supported by the experimental study summarized in ATLA, 37, 671–689, 2009; for thefunctionally similar read across substance, 1-methyl-3-phenylpiperazine[CAS: 5271-27-2]. 1-methyl-3-phenylpiperazine was exposed to rabbit skin and observed for signs of irritation (no further details mentioned). Erythema was observed when1-methyl-3 -phenylpiperazine was applied to rabbit skin.The Primary Irritation Index was 3.3.

Hence,1-methyl-3-phenylpiperazine can be considered to be irritating to 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 irritating to skin. Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

Eye Irritation:

Several studies were performed to ascertain the degree of ocular irritation caused by1-[(4-chlorophenyl)(phenyl)methyl]piperazinein 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-phenylpiperazine[CAS: 92-54 -6]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated for 1-[(4-chlorophenyl)(phenyl)methyl]piperazine.1-[(4-chlorophenyl)(phenyl)methyl]piperazine was corrosive to New Zealand White rabbit eyes.

This is supported by the experimental study summarized inAmerican Journal of Ophthalmology, 29, 1363–1372, 1946; for the functionally similar read across substance, Piperazine[CAS: 110-85-0].Normal rabbit eyes were selected on basis of visual inspection after staining with a 5% aqueous solution of fluorescein, and flushed out with distilled water 20 seconds after application. After a 2-hour resting period, 0.005 ml of a 5% solution was applied to the centre of the cornea while the lids were retracted. About one minute later the lids were released, and 18-24 hours later the eyes were stained with fluorescein and the injury scored.

Together with sulphuric acid and ammonium hydroxide, piperazine was given the grade 9 on a scale ranging from 1 to 10, with necrosis covering 60-90% of the cornea. An aqueous solution containing 1-5% piperazine (assumingly piperazine base) caused etching and necrosis of the rabbit cornea.

Hence piperazine was considered to be corrosive to rabbit eyes.

These results are supported by the experimental study summarized in American Industrial Hygiene Association Journal, 1962, 23:2, 95-107; for the functionally similar read across substance, 1-phenylpiperazine[CAS: 92-54-6]. Eye injury in rabbits is recorded in a 10- grade ordinal series and is based upon the degree of corneal necrosis that results from instillation of various volumes and concentrations of chemical.

Grade 1 indicates at most a very small area of necrosis resulting from 0.5 ml of undiluted chemical in the eye. Grade 5 indicates a so-called severe burn from 0.005 ml, and Grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol.

Primary Irritation score after 24 hours for 1-phenyl piperazine was Grade 9.

In the acute eye irritation study conducted in albino rabbits, 1-phenyl piperazine was considered to be corrosive to rabbit eyes.

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]piperazine can be considered to be corrosive to skin. Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 1”.

Available data for 1-[(4-chlorophenyl)(phenyl)methyl]piperazine indicates that it is likely to cause severe irritation (corrosion) to skin and eyes.Hence,1-[(4-chlorophenyl)(phenyl)methyl]piperazine can be classified under the category “Category 2” for skin irritation and " Category 1" for eye irritation as per CLP regulation.