N-(4-chlorobenzhydryl)piperazine

Endpoint summary

Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity,LD50 value was predicted based on OECD QSAR toolbox for target substance1-(4-Chlorobenzhydryl) Piperazine (303-26-4)was estimated to be 2982.55 mg/kg bw for rats,and for different studies available on the structurally similar read across substance buclizine (82-95-1) was considered to be 2100 mg/kg bw for mice and 1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazin (298-57-7) was considered to be >6500 mg/kg bw for rats. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation,1-(4-Chlorobenzhydryl) Piperazine (303-26-4)can be classified as category V of acute oral toxicity.

Acute Dermal Toxicity:

In Acute dermal toxicity,LD50 value was predicted based on OECD QSAR toolbox for target substance1-(4-Chlorobenzhydryl) Piperazine (303-26-4)was estimated to be 4010.08 mg/kg bw for rabbits,and for different studies available on the structurally similar read across substance Diphenyl acetonitrile (86-29-3) was considered to be >2000 mg/kg bw for rats and for functionally similar read across substance Piperazine (110-85-0) was considered to be 4000 mg/kg bw for rabbits. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation,1-(4-Chlorobenzhydryl) Piperazine (303-26-4) can be classified as category V of acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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 predicted using OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3,2017

GLP compliance:

not specified

Test type:

other: estimated data

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

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

No data available

Doses:

2982.55 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 982.55 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

No data available

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average 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 "m" )  and "n" )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "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) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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 SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives 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 Schiff base formers >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes 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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Similarity boundary:Target: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

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 Primary and secondary aliphatic amines by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Developmental & Reproductive Toxicity (DART) by Database Affiliation

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Biodegradation NITE by Database Affiliation

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as ECHA PR AND EINECS AND REACH ECB by Inventory Affiliation

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as (N/A) by Inventory Affiliation

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as ECHA PR AND EINECS AND REACH ECB by Inventory Affiliation

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as METI Japan by Inventory Affiliation

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Discrete chemical by Substance Type ONLY

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.32

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.45

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The LD50 was estimated to be 2982.55 mg/kg bw,when male and female Sprague-Dawley rats were orally exposed with 1-(4-Chlorobenzhydryl) Piperazine (303-26-4) via gavage.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 1-(4-Chlorobenzhydryl) Piperazine (303-26-4).The LD50 was estimated to be 2982.55 mg/kg bw,when male and female Sprague-Dawley rats were orally exposed with 1-(4-Chlorobenzhydryl) Piperazine(303-26-4)orally via gavage.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 982.55 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 predicted using OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3,2017

GLP compliance:

not specified

Test type:

other: no data available

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:

rabbit

Strain:

Vienna White

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

No data available

Duration of exposure:

4010.08 mg/kg bw

Doses:

24 hours

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 010.08 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% Mortality was observed

Mortality:

No data available

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average 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 ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and "r" )  )

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 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: "g"

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 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 by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Dithiocarbamates by Protein binding by OASIS v1.3

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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: "n"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary by Organic Functional groups

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Developmental & Reproductive Toxicity (DART) by Database Affiliation

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aquatic OASIS by Database Affiliation

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.385

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.24

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The LD50 value was estimated to be 4010.08 mg/kg bw,when male and female Vienna White rabbits were exposed occlusively with 1-(4-Chlorobenzhydryl) Piperazine (303-26-4) by dermal application for 24 hours.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 1-(4-Chlorobenzhydryl) Piperazine(303-26-4).TheLD50 was estimated to be 4010.08 mg/kg bw,when male and female Vienna White rabbits were exposed occlusively 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) by dermal application for 24 hours.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 010.08 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Additional information

Acute Oral Toxicity: 

In different studies,1-(4-Chlorobenzhydryl) Piperazine (303-26-4)has been investigated for acute oral toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for1-(4-Chlorobenzhydryl) Piperazine (303-26-4)along with the study available on the structurally similar read across substance buclizine (82-95-1) and 1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazin (298-57-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 1-(4-Chlorobenzhydryl) Piperazine (303-26-4).The LD50 was estimated to be 2982.55 mg/kg bw,when male and female Sprague-Dawley rats were orally exposed with 1-(4-Chlorobenzhydryl) Piperazine(303-26-4)orally via gavage.

The above study was further supported by S. Y. PAN et. al. (Journal of the American Pharmaceutical Association, Scientific Edition. Vol. 43, Pg. 653, 1954) for the structurally similar read across substance buclizine (82-95-1). Acute oral toxicity study was done in male albino Swiss mice weighing from 17 to 23 gm using test material buclizine(82-95-1).The LD50 and 95% confidence limits were determined according to the method of Litchfield and Wilcoxon.50% mortality was observed at dose 2100 mg/kg bw.Clinical signs like respiratory distress followed by excitement,convulsions were observed.Hence,LD50 value was considered to be 2100 mg/kg bw (95% CL 1824-2394),when mice were treated with buclizine(82-95-1)orally.

This is further supported by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) for the structurally similar read across substance 1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazin (298-57-7). Acute oral toxicity study was done in rats using test material 1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazin(298-57-7) .No mortality was observed at dose 6500 mg/kg bw.Clinical signs like altered sleep time (including change in righting reflex) and somnolence (general depressed activity) were observed.Hence,LD50 value was considered to be >6500 mg/kg bw,when rats were treated with 1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazin (298-57-7) orally.

Thus, based on the above studies on 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) and it’s structurally similar read across substance , it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) can be classified as category V of acute oral toxicity.

 

Acute Dermal Toxicity:

In different studies,1-(4-Chlorobenzhydryl) Piperazine (303-26-4)has been investigated for acute dermal toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rabbits for1-(4-Chlorobenzhydryl) Piperazine (303-26-4)along with the study available on the structurally similar read across substance Diphenyl acetonitrile (86-29-3) and on the functionally similar read across substance Piperazine (110-85-0).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 1-(4-Chlorobenzhydryl) Piperazine(303-26-4).TheLD50 was estimated to be 4010.08 mg/kg bw,when male and female Vienna White rabbits were exposed occlusively 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) by dermal application for 24 hours.

The above study was further supported by Sustainability Support Services (Europe) AB (study number: 19163, 2017-08-10)for the structurally similar read across substance Diphenyl acetonitrile (86-29-3). In acute dermal toxicity study,male and female Sprague Dawley rats were semiocclusivelytreated with Diphenyl acetonitrile (86-29-3)in the concentration of 2000 mg/kg bw by dermal applicationfor 24 hours following 14 days of observation period according to OECD Guideline 402 (Acute Dermal Toxicity). Young adult male and female rats aged between 8 – 12 weeks were used.The weight range of approximately 221.6 to 253.6 grams at initiation of dosing.Each rat was individually identified by the cage number.The rats were individually housed in polycarbonate cages with paddy husk as bedding.Rodent feed and water was provided ad libitum.animals were acclimatized for 5 days. The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight.Animals were observed for clinical signs, mortality, until sacrifice.Onset, duration and severity of any sign were recorded. The clinical signs and mortality observations were conducted at 10, 30, 60 minutes, 2, 4 and 6 hours on the day of dosing and once daily thereafter for 14 day. Daily observation was done as far as possible at the same time.The observations were included general clinical signs, observations of eyes, mucous membranes, respiratory, circulatory system and behavior pattern.Dermal reaction was observed daily for study period of 14 days.Individual animal body weights were recorded pre-test (prior to administration of the test item), day 7 and at termination on day 14.Necropsy was performed on animals surviving at the end of the study. Macroscopic examination of all the orifices, cavities and tissues were made and the findings were recorded. All animals surviving the study period were sacrificed by the carbon dioxide asphyxiation technique (day 15).No gross abnormalities were observed in animals sacrificed terminally hence, no histopathology was performed. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days.Animals exhibited normal body weight gain through the study period of 14 days.Gross pathological examination did not reveal any abnormalities attributable to the treatment.Therefore, LD50 value was considered to be >2000 mg/kg bw,when rats were treated with Diphenyl acetonitrile (86-29-3) by dermal application.

This is further supported by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) for the functionally similar read across substance Piperazine (110-85-0). In acute dermal toxicity study,rabbits were treated with Piperazine(110-85-0)  in the concentration of 4000 mg/kg bw by dermal application.50% mortality was observed in treated rabbits at dose 4000 mg/kg bw.Therefore, LD50 value was considered to be 4000 mg/kg bw,when rabbits were treated with Piperazine(110-85-0) by dermal application.

Thus, based on the above studies on 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) and it’s structurally similar read across substances and the functionally similar read across substance , it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) can be classified as category V of acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) and experimental data based on it’s structurally similar and functionally similar read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 1-(4-Chlorobenzhydryl) Piperazine(303-26-4) can be classified as category V for acute oral and dermal toxicity.