N-(4-chlorophenyl)-3-hydroxy-4-[(2-methyl-5-nitrophenyl)azo]naphthalene-2-carboxamide

Endpoint summary

Description of key information

The skin sensitization potential of N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated to be not sensitizing to the skin of female guinea pigs. Based on the estimated result N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) failed to induce skin sanitization effects and hence is considered to be not sensitizing to female guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

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 v3.4 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 v3.4

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

not specified

Sex:

female

Details on test animals and environmental conditions:

no data available

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of induction:

not specified

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

no data available

Challenge controls:

not completed

Positive control substance(s):

not specified

Positive control results:

no data available

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

not specified

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

no data available

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
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 ("i" and ( not "j") )  )  and "k" )  and "l" )  and ("m" and "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain by DNA binding by OASIS v.1.4

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 >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Aromatic nitro by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides AND AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides by Protein binding by OASIS v1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Amides AND Phenol Amines AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides AND AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides by Protein binding by OASIS v1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation >> Acylation involving an activated (glucuronidated) ester group OR Acylation >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Direct acylation involving a leaving group >> N-Haloacylamides  OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR AN2 >> Michael addition to activated double bonds OR AN2 >> Michael addition to activated double bonds >> alpha,beta-Unsaturated Carbonyls and Related Compounds OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha,beta-Unsaturated Carboxylic Acids and Esters OR AN2 >> Michael type addition to activated double bond of pyrimidine bases OR AN2 >> Michael type addition to activated double bond of pyrimidine bases >> Pyrimidines and Purines OR AN2 >> Michael type nucleophilic addition and Schiff base formation OR AN2 >> Michael type nucleophilic addition and Schiff base formation >> Halogenated Vicinal Hydrocarbons OR AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines OR AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines OR AN2 >> Michael-type addition to quinoid structures  >> Substituted Phenols OR AN2 >> Schiff base formation with carbonyl compounds (AN2) OR AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases >> Pyrimidines and Purines OR Michael addition OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups  OR No alert found OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Radical reactions OR Radical reactions >> ROS Generation OR Radical reactions >> ROS Generation >> Sterically Hindered Piperidine Derivatives OR Schiff base formation OR Schiff base formation >> Direct acting Schiff base formers OR Schiff base formation >> Direct acting Schiff base formers >> 1,2-Dicarbonyls and 1,3-Dicarbonyls  OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic type substitution together with ring-opening of an episulfonium ion intermediate OR SN2 >> Nucleophilic type substitution together with ring-opening of an episulfonium ion intermediate >> Halogenated Vicinal Hydrocarbons OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds OR SNVinyl OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom >> Vinyl type compounds with electron withdrawing groups  by Protein binding by OASIS v1.4

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Similarity boundary:Target: Cc1ccc(N(=O)=O)cc1N=Nc1c2ccccc2cc(C(=O)Nc2ccc(Cl)cc2)c1O
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: Cc1ccc(N(=O)=O)cc1N=Nc1c2ccccc2cc(C(=O)Nc2ccc(Cl)cc2)c1O
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 7.01

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 13.6

Interpretation of results:

other: not sensitzing

Conclusions:

N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide was predicted to be non sensitizing to the skin of female guinea pigs.

Executive summary:

The skin sensitization potential of N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated to be not sensitizing to the skin of female guinea pigs. Based on the estimated result N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) failed to induce skin sanitization effects and hence is considered to be not sensitizing to female 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:

Skin sensitization:

Various studieshas been investigated for the test chemicalN-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) 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 chemicalN-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) and its structurally similar read across substances2-Nitro-4’-hydroxydiphenylamine (CAS No: 54381-08-7) and Sudan III (CAS No: 85-86-9).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 N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) was estimated to be not sensitizing to the skin of female guinea pigs. Based on the estimated result N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) failed to induce skin sanitization effects and hence is considered to be not sensitizing to female guinea pigs.

 

 

The Cosmetic Ingredient Review Expert Panel (1988) conducted Skin sensitization studyfor structurally similar read across substance2-Nitro-4’-hydroxydiphenylamine (CAS No: 54381-08-7) on 10 female Hartley albino guinea pigs.In induction, the guinea pigs were received a single intradermal injection of 0.1%2-Nitro-4’-hydroxydiphenylamine inpropylene glycol and Freund's complete adjuvant (FCA). One week after injection, an occlusive patch containing 25% chemical in propylene glycol was applied to an area over the injection site.The test site was pretreated 24 hours earlier with 10% sodium lauryl sulfate.After a non treatment period of 2 weeks, animals were challenged to a previously untreated site at concentration of 25%in propylene glycol and later skin reactions were examined.Since there was no known evidence of contact sensitization, the chemical 2-Nitro-4’-hydroxydiphenylamine (CAS No: 54381-08-7)was considered to be not sensitizing to the skin of10 female Hartley albino guinea pigs.

 

                                              

The above results were further supported by the patch test study carried out by TAKEHITO KGZUKA, MINORU TASHIR0, SHIGEHARU SANO, KEIICHI FUJIMOTO,YUMI NAKAMURA, SEIICHI HASHIMOTO AND GEN NAKAMINAM (1980) forstructurally similar read across substance(CAS No: 85-86-9) in human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R. The patch of Sudan III was applied onto the back of each patient for24 hours by usingFinn Chambers® on Scanpor® (Epitest, Ltd. Oy) at a dose of 1% in petrolatum. After removal of patch, skin reactions were assessedaccording to the ICDRG classification for 2 days.Twenty-eight healthy female volunteers, aged 20 and 21, were also tested with the sample as controls. None gave a positive reaction.The negative skin sensitizing effects were observed in all treated patients. Thusthe test chemicalSudan III (CAS No: 85-86-9)was considered to be not sensitizingin human patients suffering from pigmented contact dermatitis caused by the commercial Brilliant Lake Red R.

 

 

Thus on the basis of available data for thetarget chemicalN-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) and its structurally similar read across substances2-Nitro-4’-hydroxydiphenylamine (CAS No: 54381-08-7) and Sudan III (CAS No: 85-86-9),it can be concluded thatchemical N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) 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 N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6)  and its structurally similar read across substances 2-Nitro-4’-hydroxydiphenylamine (CAS No: 54381-08-7) and Sudan III (CAS No: 85-86-9) were observed in various studies. From the results obtained from these studies it is concluded that the chemical N-(4-chlorophenyl)-3-hydroxy-4-[(E)-2-(2-methyl-5-nitrophenyl)diazen-1-yl]naphthalene-2-carboxamide (CAS No: 6410-30-6) is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.