Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate

Endpoint summary

Description of key information

The skin sensitization potential of  Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated by SSS (2017) using OECD QSAR toolbox v3.4/3.3 with log kow as the primary descriptor.

(Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was predicted to be non sensitizing to the skin of mice.

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 (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

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: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Type of study:

other: Predicted data

Specific details on test material used for the study:

Name of test material (IUPAC name): Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate
- Common name: Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate
- Molecular formula: C21H21N3O2
- Molecular weight: 347.416 g/mol
- Smiles notation: N=C1C=C\C(C=C1)=C(\c1ccc(N)cc1)c1ccc(N)cc1.C(C)(=O)O
- InChl: 1S/C19H17N3.C2H4O2/c20-16-7-1-13(2-8-16)19(14-3-9-17(21)10-4-14)15-5-11-18(22)12-6-15;1-2(3)4/h1-12,20H,21-22H2;1H3,(H,3,4)
- Substance type: Organic
-Physical state: solid

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

No data available

Vehicle:

unchanged (no vehicle)

Concentration:

Not specified

No. of animals per dose:

Not specified

Details on study design:

No data available

Positive control substance(s):

not specified

Parameter:

other: Not specified

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes mode value from the 7 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" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) AND Dianilines by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Michael Addition AND Michael Addition >> Quinoide type compounds AND Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  by Protein binding by OASIS v1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) 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 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >>  Michael-type addition, quinoid structures >> Quinones 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 >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Quinones OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Diazenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 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 >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines 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 >> Nitroaniline Derivatives 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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 Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Very strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as 4,4'-Methylenedianilines/benzidines (Hepatobiliary toxicity) Rank B  OR Aliphatic amines (Mucous membrane irritation) Rank C OR Allyl esters (Hepatotoxicity) Rank A OR Anilines (Hemolytic anemia with methemoglobinemia) Rank A OR Anilines (Hepatotoxicity) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.078

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.1

Interpretation of results:

not sensitising

Conclusions:

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was considered Non-skin sensitizing on the skin of mice.

Executive summary:

The skin sensitization potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated by SSS (2017) using OECD QSAR toolbox v3.4/3.3 with log kow as the primary descriptor.

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was predicted to be non sensitizing to the skin of mice

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization :

Various studies has been investigated for 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1) (CAS No: 6035-94-5) to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs and humans for target and its functionally similar read across substances, (CAS No: 3248-91-7) Basic Violet 2 and Basic violet 14 (632-99-5).

 The skin sensitization potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate) was estimated by SSS (2017) using OECD QSAR toolbox v3.4/3.3 with log kow as the primary descriptor. Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was predicted to be non sensitizing to the skin of mice.

This was supported by the result mentioned in Scientific committee on consumer products – SCCP, COLIPA no B115 during 12th plenary meeting of 20 September 2011 and Scientific Committee On Cosmetic Products And Non-Food Products (SCCNFP) 2004; for the functionally similar read across substance, Basic violet 2 (CAS: 3248-91-7)

Basic Violet 2 was assessed for its skin sensitizing potential by Buehler test on Dunkin-Hartley guinea pigs. 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 skin non sensitizing on guinea pig skin.

This was also supported by the result mentioned in Environment and Quality of Life - Reports (Seventh Series)- Basic violet 14 European Commission (EC) - Scientific Committee on Cosmetology (SCC) 1988; functionally similar read across substance, Basic violet 14 (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 chemical4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1) (6035-94-5), and read across substances, and applying the weight of evidence approach, it can be concluded that chemical is unable to cause skin sensitization and considered as not sensitizing .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 for 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1) suggests that it is not likely to cause any dermal sensitization to guinea pig skin.

4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1)  can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.