[4-[[4-(dimethylamino)phenyl][4-(methylamino)phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]dimethylammonium acetate

Endpoint summary

Description of key information

The skin sensitization potential of N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene} cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was predicted to be non sensitizing to the skin of Hartley guinea pig.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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 and the supporting QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3.

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

Not specified.

Specific details on test material used for the study:

- Name of the test material: (4-((4-(Dimethylamino)phenyl)(4-(methylamino)phenyl)methylene)cyclohexa-2,5-dien-1-ylidene)dimethylammonium acetate
- IUPAC name: N-(4-{[4-(dimethylamino)phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate
- Molecular formula: C24H28N3.C2H3O2
- Molecular Weight: 417.5499 g/mol
- Substance type: Organic
- Smiles: CC(=O)[O-].CNc1ccc(cc1)C(=C2C=CC(=[N+](C)C)C=C2)c3ccc(cc3)N(C)C

Species:

guinea pig

Strain:

Hartley

Sex:

not specified

Details on test animals and environmental conditions:

No data available.

Route:

intradermal and epicutaneous

Vehicle:

unchanged (no vehicle)

Concentration / amount:

100%

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

100%

No. of animals per dose:

15 per test group, 6 in control group

Details on study design:

No data available.

Challenge controls:

yes 6 in control group.

Positive control substance(s):

not specified

Statistics:

No data available.

Reading:

other: challenge

Group:

test chemical

Dose level:

100%

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No skin sensitization effect were observed.

Remarks on result:

no indication of skin sensitisation

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acetoxy OR Alkene OR Ammonium salt OR Aromatic amine OR Aryl OR Carboxylic acid by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acetoxy OR Alkene OR Ammonium salt OR Aromatic amine OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Amino, aliphatic attach [-N<] OR Aromatic Carbon [C] OR Carbonyl, aliphatic attach [-C(=O)-] OR Miscellaneous sulfide (=S) or oxide (=O) 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 Anion OR Aromatic compound OR Carbonic acid derivative OR Carboxylic acid derivative OR Carboxylic acid salt OR Cation OR Secondary amine OR Secondary mixed amine (aryl, alkyl) OR Tertiary amine OR Tertiary mixed 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 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 >> 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 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) 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 >> Quinone methides 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 >> 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 >> 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 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 >> 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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 >> Direct Acylation Involving a Leaving group >> Anhydrides OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation >> Benzoyl phosphine oxides  OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments 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 Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 14 - Metalloids Si,Ge OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 8 - Trans.Metals Fe,Ru,Os by Chemical elements

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Amineptine (Hepatotoxicity) Alert OR Anilines (Hemolytic anemia with methemoglobinemia) Rank A OR Anilines (Hepatotoxicity) Rank C OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "t"

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: "u"

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

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.75

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.54

Interpretation of results:

other: Not sensitizing.

Conclusions:

The skin sensitization potential of N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene} cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was predicted to be non sensitizing to the skin of Hartley guinea pig.

Executive summary:

The skin sensitization potential of N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene} cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was predicted to be non sensitizing to the skin of Hartley guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

In different studies, N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)has been investigated for potential for dermal sensitization to a greater or lesser extent. The prediction and studies are based on in vivo experiments in guinea pig for target chemical N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9) and its structurally similar read across substances Basic violet 1 (CAS No:8007-87-3) and Basic violet 3(CAS No: 548-62-9). The predicted data using the OECD QSAR toolbox have also been compared with the experimental data of read acros.

 

The skin sensitization potential of N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across substances. N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(CAS No:84434-47-9)was predicted to be non-sensitizing to the skin of Hartley guinea pig.

 

The above results were further supported by experimental data conducted by JOE DINARDOet al.(j. Cosmet. Sci., 2007) on structurally similar read across substance Basic violet 1 (CAS No: 8007-87-3) and Basic violet 3(CAS No: 548-62-9) on guinea pigs. The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on skin sensitization from the analogue substances. Skin sensitization test for both the chemicals were conducted in guinea pig using modified Buehler and Klecak method for open Epicutaneous test. For the induction phase, the left flanks of 10 albino guinea pigs were shaved and the dye test material applied three times weekly (Monday, Wednesday Friday) for three consecutive weeks. Each animal received 0.1 ml of the dye test material over a 1.8-cm circular area. Following the induction period, the guinea pigs entered the challenge phase. The challenge phase began after a two-week rest period when the right flank of each guinea pig was shaved and exposed to three different dye test material concentration (10.0%,5.0%, and 2.5% of the induction concentration). Twenty-four hours after the last induction and challenge application, the animals were depilated to clearly observe dermal reactions. The test sites were graded for erythema and edema 24 and 48 hours post-application using a four-point ordinal scale (0 = no reaction, 1 -- slight reaction, 2 = moderate reaction, 3 = severe reaction. A positive reaction was defined as an erythema/edema value during the challenge phase of at least one skin grade higher than during the last induction phase.  No erythema/edema was observed after 24 and 48 hours post-application. Hence both the chemicals Basic violet 1 (CAS No: 8007-87-3) and Basic violet 3(CAS No: 548-62-9) were considered as not sensitizing to the guinea pigs skin.

 

Thus based on the above predictions on N-(4-{[4-(dimethylamino) phenyl][4-(methylamino) phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9) as well as its read across substances and applying weight of evidence, it can be concluded that N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium acetate(84434-47-9)can be considered as not classified for skin sensitization effects.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above annotations with the criteria of CLP regulation, N-(4-{[4-(dimethylamino) phenyl][4-(methylamino)phenyl] methylene}cyclohexa-2,5-dien-1-ylidene) -N-methylmethanaminium acetate(84434-47-9)can be considered as not classified for skin sensitization effects.