4-[(4-amino-m-tolyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-o-toluidine monohydrochloride

Endpoint summary

Description of key information

The skin sensitization potential of 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was estimated by SSS (2017) using OECD QSAR toolbox v 3.3 with log kow as the primary descriptor. 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was predicted to be non sensitizing to the skin of guinea pigs.

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 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

Type of study:

other: Estimated data

Specific details on test material used for the study:

- Name of test material: C.I. Basic Violet 2 / (4-[(4-amino-m-tolyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-o-toluidine monohydrochloride)
- IUPAC name: 4-[(4-amino-3-methylphenyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-2-methylaniline hydrochloride
- Molecular formula: C22H24ClN3
- Molecular weight: 365.906 g/mole
- Smiles :C(\c1cc(c(N)cc1)C)(c1cc(c(N)cc1)C)=C1\C=C(C(=[NH+])C=C1)C.[ClH-]
- Inchl: 1S/C22H23N3.ClH/c1-13-10-16(4-7-19(13)23)22(17-5-8-20(24)14(2)11-17)18-6-9-21(25)15(3)12-18;/h4-12,23H,24-25H2,1-3H3;1H
- Substance type: Organic
- Physical state: Solid Green crystalline powder

Details on the study design:

No data

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

Not specified

Route:

epicutaneous, occlusive

Vehicle:

not specified

Day(s)/duration:

3 weeks

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Day(s)/duration:

6 hrs

Adequacy of challenge:

not specified

No. of animals per dose:

Not specified

Details on study design:

No data available

Challenge controls:

Not specified

Positive control substance(s):

no

Positive control substance(s):

not specified

Key result

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

not specified

Clinical observations:

no signs of dermal sensitization 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 mode value from the 13 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 ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and "u" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) AND Dianilines AND Not categorized AND Triarylmethane Pigments/Dyes with Non-solubilizing Groups by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Anilines (Hindered) AND Inorganic Compound by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkene OR Alkyl arenes OR Allyl OR Aniline OR Aryl OR Dianilines OR Ketimine OR No functional group found OR Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkene OR Alkyl arenes OR Allyl OR Dianilines OR Ketimine OR No functional group found OR Overlapping groups OR Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "e"

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 Aromatic Carbon [C] OR No functional group found OR Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "f"

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: "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 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 >> 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found AND SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aliphatic esters of chloro formic acid by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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: "q"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Oxygen O OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens F by Chemical elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Polarised alkenes AND Michael Addition >> Polarised alkenes >> 4-Methylenecyclohexa-2,5-dien-1-imines AND No alert found by Respiratory sensitisation

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Pro-Michael Addition OR Pro-Michael Addition >> Pro-quinone and related OR Pro-Michael Addition >> Pro-quinone and related >> Phenylenediamines by Respiratory sensitisation

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.18

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.86

Interpretation of results:

other: not sensitizing

Conclusions:

((4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride) was considered to be non skin sensitizing

Executive summary:

The skin sensitization potential of 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was estimated by SSS (2017) using OECD QSAR toolbox v 3.3 with log kow as the primary descriptor. 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was predicted to be non sensitizing to the skin of guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:

Various studies have been investigated for assessing the dermal sensitization potential of 4-[(4-amino-3-methylphenyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-2-methylaniline hydrochloride to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs along with predicted data for target chemical and its structurally and functionally similar read across substances, N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride [CAS: 548-62-9] and ((4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride)[CAS: 632-99-5]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The skin sensitization potential of 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was estimated by SSS (2017) using OECD QSAR toolbox v 3.3 with log kow as the primary descriptor. 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride was predicted to be non sensitizing to the skin of guinea pigs.

This result is supported by the experimental study performed on Dunkin Hartley guinea pigs according to Buehler test which is summarized in The Scientific Committee on Consumer Products, SCCS/1340/10,2011. The test group consisted of 20 female Guinea pigs, two control groups of ten female Guinea pigs each. During the induction phase, the test group was treated with the test substance in sterile water at 75% at the left flank. The negative control groups were treated with the vehicle (sterile water) in the same manner. The gauze patches with test substance or vehicle under occlusive dressing were removed after 6 hours. Approximately 24 hours after removal of the patches, skin reactions were scored. These procedures were repeated at weekly intervals (days 8/9 and 15/16 of the study). On study day 29, sensitisation reactions were challenged in the test as well as in one negative control group by topical administration of the test substance in sterile water (50% on one side and vehicle alone on the contralateral flank) under occlusive dressing for 6 hours.

Twenty-four and 48 hours after removal of the patches the skin reactions were scored. Following the 48 hour examination at challenge, skin fold thickness of the treated sites was measured using a digital micrometer. Body weights were recorded on days 1 and 31 (termination of the study). Body weights were not affected by the test compound.

Basic Violet 2 was considered non sensitizing to skin as no differences between values of the test group compared to values of the control group were apparent.

These studies are supported by the results of the Guinea pig maximization test summarized in The Scientific Committee on Consumer Products, SCCS/1340/10,2011; for the target chemical Basic Violet 2. The test group consisted of 20 female Guinea pigs, two control groups of ten female Guinea pigs each. In the first week of induction, the test group was treated with single intradermal injections of complete Freund's adjuvant/water mixture 1:1 (v/v), 1% of the test substance in sterile water and with 1% of the test substance emulsified in Freund's complete adjuvant.

The negative control groups were treated with the adjuvant and the vehicle (sterile water) in the same manner. Seven days after injection, a 50% solution of the test substance in sterile water was dermally applied under occlusive dressing for 48 h to the area of the intradermal injections. The negative control group was treated with the vehicle alone. After a period of 2 weeks without treatment, sensitisation reactions were challenged in the test group as well as in one negative control group by dermal administration of the test substance in sterile water (50%, on one flank and vehicle alone on the contralateral flank) under occlusive dressing for 24 hours. 24 and 48 hours after removal of the patches the skin reactions were scored. Following the 48 hour examination at challenge, skin fold thickness of the treated sites was measured using a digital micrometer. Body weights were recorded on days 1 and 25 (termination of the study). Body weights were not affected by the test compound. Basic violet 2 was considered non-sensitizing when induced by 1% intra-dermal injection and challenged by 50% dermal application

Basic violet 2 was considered non-sensitizing when induced by 1% intra-dermal injection and challenged by 50% dermal application.

Basic violet 2 was also assessed for dermal sensitization in a study summarized in Environment and Quality of Life - Reports (Seventh Series) Basic violet 2 European Commission (EC) - Scientific Committee on Cosmetology (SCC) 1984. 0.1 ml 1% aqueous solution by intra-dermal injection and 5% in vaseline by topical application for induction treatment. The challenge treatment after 14 days with 0.1 ml 0.1% aqueous solution did not induce any reaction.

No skin reactions were observed.

Basic violet 2 was considered to be non skin sensitizer when tested on guinea pigs by subjecting the test material by intradermal and epicutaneous induction and challenging after 14 days.

The above studies indicate a strong possibility of Basic Violet 2 being not sensitizing to skin.

These results are ably supported by the experimental study summarized in Journal of Cosmetic Science, 58, no. 3 (2007): 209-214; for the structurally and functionally similar read across substance, N-(4-{bis[4-(dimethylamino)phenyl]methylene}cyclohexa-2,5-dien-1-ylidene)-N-methylmethanaminium chloride [CAS: 548-62-9]. The study was performed according to Buehler test and the Klecak method for open epicutaneous testing (OET) 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 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 was done 24hr and 48 hr after challenge application. No indication of skin sensitization was observed. Hence it is considered that Basic Violet 3(548-62-9) was not skin sensitizing in guinea pig by Buehler test and the Klecak method for open epicutaneous testing (OET).

These results are further supported by the experimental study summarized in Environment and Quality of Life - Reports (Seventh Series)- Basic violet 14 European Commission (EC) - Scientific Committee on Cosmetology (SCC) 1988; for the structurally and functionally similar read across substance, ((4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride)[CAS: 632-99-5]. The test material was applied topically 5% in 25%Aqueous solution of gum Arabic to the skin of guinea pigs for 5 days. After 2 weeks of rest period the challenge treatment was provided by epicuteneous injection of concentration 0.1ml 0.01, 0.001, and 0.001% in saline. The guinea pigs were observed for signs of dermal sensitization after the challenge exposure.

No signs of any skin allergic reaction were observed. Hence, Basic Violet 14 can be considered to be not sensitizing to guinea pig skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 4-(4-aminophenyl)(4-iminocyclohexa-2,5-dienylidene)methyl)-2-methylaniline hydrochloride can be considered to be not sensitizing to skin.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

Available data for4-[(4-amino-3-methylphenyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-2-methylaniline hydrochloride suggests that it is not likely to cause any dermal sensitization to guinea pig skin.

4-[(4-amino-3-methylphenyl)(4-imino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-2-methylaniline hydrochloride can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.