N-(4-chlorobenzhydryl)piperazine

Short-term toxicity to aquatic invertebrates

Link to relevant study record(s)

Reference

Endpoint:

short-term toxicity to aquatic invertebrates

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 version.3.3 and QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: Predicted data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3 with log kow as the primary discriptors.

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 (white to pale yellow)

Analytical monitoring:

not specified

Vehicle:

not specified

Test organisms (species):

Daphnia magna

Test type:

static

Water media type:

freshwater

Total exposure duration:

48 h

Key result

Duration:

48 h

Dose descriptor:

EC50

Effect conc.:

116.794 mg/L

Nominal / measured:

meas. (not specified)

Conc. based on:

test mat.

Basis for effect:

other: Intoxication

Remarks on result:

other: no toxic

The prediction was based on dataset comprised from the following descriptors: EC50
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 "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") )

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 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> N-methylol derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives 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 >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Conjugated Nitro Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> N-Nitroso Compounds OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups 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 nitrenium and/or carbenium ion formation OR SN1 >> Nucleophilic attack after nitrenium and/or carbenium ion formation >> N-Nitroso Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Conjugated Nitro Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives 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 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups 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 Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> Polarised Alkenes-Michael addition 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 >> Direct Acting Schiff Base Formers OR Schiff base formers >> Direct Acting Schiff Base Formers >> Mono aldehydes OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Halogenated polarised alkenes 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 OASIS v1.3

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Michael Addition OR Michael Addition >> Quinone type chemicals OR Michael Addition >> Quinone type chemicals >> Pyranones, Pyridones (and related nitrogen chemicals)  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.3

Domain logical expression index: "l"

Referential boundary:The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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: "p"

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

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 Cycloalkane by Organic Functional groups

Domain logical expression index: "s"

Referential boundary:The target chemical should be classified as Aliphatic amine   [-NH2  or  -NH-] AND Aromatic chloride   [-CL] AND Aromatic-CH AND Aromatic-H AND -CH2-  [cyclic] AND Tertiary amine by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "t"

Referential boundary:The target chemical should be classified as Aliphatic ether  [C-O-C] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "u"

Referential boundary:The target chemical should be classified as Aliphatic amine   [-NH2  or  -NH-] AND Aromatic chloride   [-CL] AND Aromatic-CH AND Aromatic-H AND -CH2-  [cyclic] AND Tertiary amine by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "v"

Referential boundary:The target chemical should be classified as -C=CH  [alkenyl hydrogen] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "w"

Referential boundary:The target chemical should be classified as Aliphatic Amines by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "x"

Referential boundary:The target chemical should be classified as Nicotinoids by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.906

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.46

Conclusions:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the closest read across substances, the toxicity to aquatic invertebrate was predicted 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4). EC50 intoxication value was estimated to be 116.794 mg/l for Daphnia magna for 48 hrs duration. It was concluded that 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) was likely to be not toxic to aquatic invertebrate.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the closest read across substances, the toxicity to aquatic invertebrate was predicted 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4). EC50 intoxication value was estimated to be 116.794 mg/l for Daphnia magna for 48 hrs duration. It was concluded that 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) was likely to be not toxic to aquatic invertebrate.

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the closest read across substances, the toxicity to aquatic invertebrate was predicted 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4). EC50 intoxication value was estimated to be 116.794 mg/l for Daphnia magna for 48 hrs duration. It was concluded that 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) was likely to be not toxic to aquatic invertebrate.

Key value for chemical safety assessment

Fresh water invertebrates

Fresh water invertebrates

Effect concentration:

116.794 mg/L

Additional information

Following studies of target chemical and structurally similar read across includes predicted data and experimental data to conclude the toxicity extent of 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) towards aquatic invertebrate is summarized as follows:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the closest read across substances, the toxicity to aquatic invertebrate was predicted 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4). EC50 intoxication value was estimated to be 116.794 mg/l for Daphnia magna for 48 hrs duration. It was concluded that 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) was likely to be not toxic to aquatic invertebrate.

The above predicted data of target chemical is supported by the experimental study of structurally similar read across disodium 2-dibutylaminoethanol (CAS: 102 -81 -8) from the J-CHeck, suggests that the Short term toxicity test was carried out acoording to the OECD Guideline 202 (Daphnia sp. Acute Immobilisation Test) to study the effects on aquatic environment. mobility was measured during the test. The effective concentration to 50% of Daphnia magna when exposed to 2-dibutylaminoethanol for 48 hr is >110 mg/L. It can be concluded from the value that 2-dibutylaminoethanol (CAS: 102 -81 -8) is not toxic/toxic to the aquatic invertebrate and can be considered as “not classified” as per the classification criteria for aquatic environment.

Another supporting experimental study for the structurally similar read across piperazine (CAS: 110-85-0) from the J-CHeck 2017, also suggests that the Short term toxicity to aquatic invertebrates was performed according to the OECD guideline 202.The test was conducted for 48 hrs and EC 50 value was observed.

After experiment the EC50 value for short term toxicity to aquatic invertebrates for piperazine (CAS: 110-85-0) was determined to be 110 mg/l.

On the basis of results for toxicity to aquatic invertebrates, it can be considered that the substance is not likely to be toxic to aquatic invertebrates and can be considered as not classified as per the CLP regulation.

Thus based on the effect concentrations which is in the range 110 mg/l to 116.794 mg/l give the conclusion that test substance 1-[(4-chlorophenyl)(phenyl)methyl]piperazine (CAS: 303-26-4) was likely to be not toxic to aquatic invertebrate at environmentally relevant concentrations and can be considered to be “not classified” as per the CLP classification criteria.