3,4-dicyanoaniline

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) was assessedin various experimental studies which were conducted on guinea and humans for target chemical4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) and itsfunctionallysimilar read across substancebenzonitrile (CAS No: 100-47-0). The predicted data usingQSAR toolboxhas also been compared with the experimental data.Based on the available data for the target and read across substances and applying the weight of evidence approach, it can be concluded that chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) is unable to cause skin sensitization and thus can be considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

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 QMRF report has been attached

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

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

Name: 4-aminobenzene-1,2-dicarbonitrile
SMILES:Nc1ccc(C#N)c(C#N)c1
InChI: 1S/C8H5N3/c9-4-6-1-2-8(11)3-7(6)5-10/h1-3H,11H2
Mol. formula: C8H5N3
Molecular Weight: 143.148 g/mole

Species:

guinea pig

Strain:

other: Pirbright White

Sex:

male/female

Details on test animals and environmental conditions:

No data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

No data available

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Hours after challenge:

72

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

No skin sensitization was observed in treated guinea pigs.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed in treated guinea pigs.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 6 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 ( not "u") )  )  and ("v" and "w" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) 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 Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Phenols and Anilines by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) AND Phthalonitriles 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 >> 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 >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Polynitroarenes 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 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 SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom 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 No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

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 No Data by Ultimate biodeg

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as > 100 days OR 1 to 10 days OR 10 to 100 days by Ultimate biodeg

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Phenols and Anilines by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) AND Phthalonitriles by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) AND Phthalonitriles by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Salt OR Schiff Bases-Azomethine by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as 4,4'-Methylenedianilines/benzidines (Hepatobiliary toxicity) Rank B  by Repeated dose (HESS)

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Oxyphenistain (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.724

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.35

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

Executive summary:

The skin sensitization potential of 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White 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:

Various studieshas been investigated for the test chemical4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)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 chemical4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) anditsfunctionallysimilar read across substancebenzonitrile (CAS No: 100-47-0).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 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)was estimated to be not sensitizing to the skin of Pirbright White guinea pigs. Based on the estimated result 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Pirbright White guinea pigs.

 

The above result was supported by themaximisation testsconducted by D. L. J. Opdyke (Food and Cosmetics Toxicology ;Volume 17, Supplement, December 1979, Pages 723-725)in 35 volunteers to determine skin sensitization potential caused by the read across chemicalBenzonitrile(CAS No: 100-47-0). Each subject was treated with 2% ofBenzonitrilein petrolatum dermally and later observed for any signs of contact allergy. None of the volunteer showed any signs of contact sensitization. Hence the chemicalBenzonitrile(CAS No: 100-47-0) wasconsidered to be not sensitizing to theskin of human volunteers.

 

When the same materialBenzonitrile(CAS No: 100-47-0) was tested, again at a dose of 2% in petrolatum on 27 volunteers in a mixed panel, it produced no sensitization reaction.

 

Thus on the basis of available data for thetarget chemical4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)and its structurally similar read across substancesitsfunctionallysimilar read across substancebenzonitrile (CAS No: 100-47-0),it can be concluded thatchemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)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 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8) anditsfunctionallysimilar read across substancebenzonitrile (CAS No: 100-47-0)were observed in various studies. From the results obtained from these studies it is concluded that the chemical 4-aminobenzene-1,2-dicarbonitrile (CAS No: 56765-79-8)is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.