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

Endpoint summary

Description of key information

Skin irritation :

The dermal irritation potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the skin of   rabbits.

Eye irritation :

The ocular irritation potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the eye of   rabbits.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: 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 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 by using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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 appereance-Solid

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

Not specified

Duration of treatment / exposure:

4 hrs

Observation period:

72 hrs

Number of animals:

no data available

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Estimation method: Takes mode 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 ( not "m") )  )  and ("n" and "o" )  )

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) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Aminobiphenyl Analogs 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 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 >> 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 >> p-Aminobiphenyl Analogs 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 >> Nitroarenes with Other Active Groups 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 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 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, without OH or NH2 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 Non-Metals by Groups of elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alkali Earth OR Halogens by Groups of elements

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Interpretation of results:

other: not irritating

Conclusions:

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the skin of  rabbits.

Executive summary:

The dermal irritation potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the skin of   rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

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 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 by using OECD QSAR toolbox v3.3

GLP compliance:

not specified

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:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

No data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

Not specified

Duration of treatment / exposure:

24 hrs

Observation period (in vivo):

72 hrs

Duration of post- treatment incubation (in vitro):

No data Available

Number of animals or in vitro replicates:

No data Available

Details on study design:

No data Available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of ocular changes were observed.

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 ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and "r" )  )

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 Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

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 Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Primary aromatic amine,hydroxyl amine and its derived esters by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Nitro-aromatic OR No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor AND Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as 1-phenoxy-benzene by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Allyl esters (Hepatotoxicity) Rank A OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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 by Protein binding by OECD

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Interpretation of results:

other: not irritating

Conclusions:

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was considered not irritating to rabbit eye

Executive summary:

The ocular irritation potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the eyes of rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In different studies, 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1) (6035-94-5) has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits by its functionally similar read across substances, Basic violet 2 (CAS: 3248-91-7) and Basic violet 14 (CAS: 632-99-5). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The dermal irritation potential of Bis(p-amino phenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptorBis (p-amino phenyl)-4-methylenecyclohexa-2,5 dienylideneammonium acetate  was estimated to be not irritating to the skin of   rabbits.

Primary skin irritation study 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 substancesBasic violet 2 (CAS: 3248 -91-7). Basic Violet 2 of purity 94% was used as a test substance for determining its skin irritation potential. 3 females New Zealand albino white rabbit were used as test animals. A gauze square with 0.5 g test material mixed to a paste with sterile water was placed on the shaved skin of three female rabbits and covered with a semi-occlusive dressing for 4 hours. After the 4-hour application time, the area was wiped with cotton wool soaked with water. The animals were checked daily for mortality and systemic symptoms. Skin reactions were evaluated 1, 24, 48, and 72 hours after removing the patches according to the Draize scoring system. No irritation was recorded in any test animals. Erythema could not be assessed due to intense staining of the skin. No oedema was noted in any of the test animals. Measurement of skin-fold thickness after 72 hours revealed no differences between treated skin and untreated (naive) skin. Erythema assessments after a longer period (when discolouration of the skin had disappeared) have not been performed.   Basic Violet 2 was considered to be skin non - irritant to the skin of rabbits.

The above studies were also supported by results mentioned in Environment and Quality of Life - Reports (Seventh Series)- Basic violet 14 European Commission (EC) - Scientific Committee on Cosmetology (SCC) 1988; for the functionally similar read across substance, Basic violet 14 (CAS: 632-99-5).

Skin irritation test was performed using basic violet 14 as a test material in concentration 0.5%  Propylene glycol was used as vehicle. The test did not produce edema and no microscopic changes were observed on the treated skin sites. Basic violet 14 when topically applied on rabbit skin produced no skin reaction.

Based on the available data for the target and read across substances and applying the weight of evidence approach, Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified.”

Eye irritation:

In different studies, 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1) (6035-94-5) has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits by its functionally similar read across substance Basic violet 14 (CAS: 632-99-5) and the predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The ocular irritation potential of Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate  was estimated to be not irritating to the eye of   rabbits.

Primary eye irritation study was supported by the result mentioned in European Commission (EC) - Scientific Committee on Cosmetology (SCC) forfunctionally similar read across substance; Basic violet 14 (CAS: 632-99-5).

Basic violet 14 when applied on guinea pig eye in the concentration 0.1 ml particularly showed no ocular reaction on the treated eye. As per the above test Basic violet 14 is considered non eye irritant.

Based on the available data for the target and read across substances and applying the weight of evidence approach, Bis(p-aminophenyl)-4-methylenecyclohexa-2,5-dienylideneammonium acetate can be considered to be not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified.”

Justification for classification or non-classification

Based on the available information,4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1)   is not likely to cause any irritation to eyes and skin. Hence, 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl)-, acetate (1:1)   can be evaluated as Not Irritating to eyes and skin and can be classified under the category “Not Classified” as per CLP regulation.