N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride

Endpoint summary

Description of key information

The skin sensitization potential of N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

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 version 3.3

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride
- Molecular formula: C37H29N3.ClH
- Molecular weight: 552.118 g/mol
- Smiles notation: C(\c1ccc(Nc2ccccc2)cc1)(c1ccc(Nc2ccccc2)cc1)=C1/C=C\C(=N/c2ccccc2)C=C1.Cl
- InChl: 1S/C37H29N3.ClH/c1-4-10-31(11-5-1)38-34-22-16-28(17-23-34)37(29-18-24-35(25-19-29)39-32-12-6-2-7-13-32)30-20-26-36(27-21-30)40-33-14-8-3-9-15-33;/h1-27,38-39H;1H
- Substance type: Organic
- Physical state: solid

Details on the study design:

No data available

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

not specified

Details on test animals and environmental conditions:

No data available

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Day(s)/duration:

48 hours

Adequacy of challenge:

not specified

No. of animals per dose:

No data available

Details on study design:

No data available

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Clinical observations:

No signs of sensiization was observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No signs of sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes mode value from the 9 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 ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and "u" )  and "v" )  and "w" )  and "x" )  and ("y" and ( not "z") )  )  and ("aa" and "ab" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene OR Aromatic amine OR Aryl OR Azomethine OR Ketimine OR No functional group found by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene OR Aromatic amine OR Aryl OR Azomethine OR Ketimine OR No functional group found OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Nitrogen, two or tree olefinic attach [>N-] OR No functional group found OR Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amine OR Aromatic compound OR No functional group found OR Secondary amine OR Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found AND Non-specific AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives AND SN1 AND SN1 >> Nucleophilic substitution on diazonium ions AND SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation >> Dicarbonyl compounds OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides 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 Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 >> 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 P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, MW>500 AND Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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: "j"

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: "k"

Referential boundary: The target chemical should be classified as Aldehydes by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Exclusion rules not met AND Group All log Kow > 9 AND Group All Melting Point > 200 C AND Group CN Aqueous Solubility < 0.0001 g/L AND Group CN Aqueous Solubility < 0.1 g/L AND Group CN log Kow > 4.5 AND Group CN log Kow > 5.5 AND Group CN Melting Point > 180 C AND Group CN Molecular Weight > 290 g/mol AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group All log Kow < -3.1 OR (!Undefined)Group All log Kow > 9 OR (!Undefined)Group All Melting Point > 200 C OR (!Undefined)Group C Surface Tension > 62 mN/m OR Group All log Kow < -3.1 OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 350 g/mol OR Group C Vapour Pressure < 0.0001 Pa OR Group CHal log Kow > 4.5 OR Group CN Molecular Weight > 540 g/mol by Skin irritation/corrosion Exclusion rules by BfR

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 Azide and triazene groups (Genotox) OR Metals, oxidative stress (Nongenotox) OR o-phenylphenol (Nongenotox) OR Structural alert for genotoxic carcinogenicity OR Structural alert for nongenotoxic carcinogenicity OR Substituted n-alkylcarboxylic acids (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Inorganic chemical AND Not covered by current version of the decision tree AND Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Di-substituted hydrocarbons (24a) OR Known precedent reproductive and developmental toxic potential OR Metal atoms were identified OR Metals (1a) OR Organophosphorus compounds (1b) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aliphatic nitriles (Hepatotoxicity) Rank B by Repeated dose (HESS)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND No functional group found AND Secondary amine AND Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] AND Aliphatic Nitrogen, two aromatic attach [-N-] AND Aromatic Carbon [C] AND Nitrogen, two or tree olefinic attach [>N-] AND No functional group found AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as days - weeks AND weeks - months by Biodeg primary (Biowin 4) ONLY

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Not categorized by US-EPA New Chemical Categories ONLY

Domain logical expression index: "x"

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

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as DSSTOX AND ECHA PR AND EINECS AND NICNAS AND REACH ECB AND TSCA AND US HPV Challenge Program by Inventory Affiliation

Domain logical expression index: "z"

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

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.32

Domain logical expression index: "ab"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.09

Interpretation of results:

other: not sensitising

Conclusions:

The substance N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Executive summary:

The skin sensitization potential of N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization:

Various studieshas been investigated for the test chemicalN-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs for target chemicalN-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) and its structurally similar read across substancesBasic Violet 3(CAS No: 548-62-9) and Octamethylcyclotetrasiloxane (CAS No: 556-67-2). .The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) was estimated to be not sensitising to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

 

The JOE DINARDO, Raleigh, NC and ZOE DIANA DRAELOS 2007 conducted an open epicutaneous testing (OET) ofstructurally similar read across substanceBasic Violet 3 (CAS No: 548-62-9) was performed by Buehler test and the Klecak method in 10 guinea pigs. In induction phase, induction given using0.1ml of 10% solution in polyethylene glycol (PG) on left flank (1.8-cm circular area) by topical application for three times weekly ( Monday, Wednesday Friday) for three consecutive weeks. 0.5%. 2,4-dinitrochlorobenzene (DNCB) in ethanol was used as positive control.  In challenge phase, After 2 weeks rest period, challenge application given in dose concentration0.1ml of 10%, 5%, 2.5% in PG on right flank. Evaluation done at 24hr and 48 hr after challenge application. No indication of skin sensitization was observed. Hence it is considered that Basic Violet 3(CAS No: 548-62-9) was not skin sensitizing in guinea pig.

 

The above results were supported by the Magnusson-Kligman maximization test reported by the SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS (SCCP, 2005) conducted on 20 female Albino guinea pigs forstructurally similar read across substanceOctamethylcyclotetrasiloxane (CAS No: 556-67-2).During induction, guinea pigs were induced with 1% D4 in vehicle (paraffin oil) including Freund's complete adjuvant by intracutaneous injections and later topically by application of undiluted test compound for 48 h on the shaved neck and back area. After rest period of 14 days, the treated guinea pigs were challenged with undiluted and with 10% test substance were in with undiluted and with 10% test substance by closed patch test. Skin reactions were examined at 24 and 48 hours. Since no skin reaction were observed at any timepoint, the chemicalOctamethylcyclotetrasiloxane (CAS No: 556-67-2) was considered to be not sensitizing to the skin of Albino guinea pigs.

Thus on the basis of available data for thetarget chemicalN-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) and its structurally similar read across substancesBasic Violet 3(CAS No: 548-62-9) and Octamethylcyclotetrasiloxane (CAS No: 556-67-2),it can be concluded thatchemical N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) is unable to cause skin sensitization and considered as non skin sensitizer.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) and its structurally similar read across substances Basic Violet 3(CAS No: 548-62-9) and Octamethylcyclotetrasiloxane (CAS No: 556-67-2) were observed in various studies. From the results obtained from these studies it is concluded that the chemical N-phenyl-4-[[4-(phenylamino)phenyl][4-(phenylimino)cyclohexa-2,5-dien-1-ylidene]methyl]aniline monohydrochloride (CAS No: 2152-64-9) is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.