4-[[5-[[4-chloro-6-[(3-sulphophenyl)amino]-1,3,5-triazin-2-yl]amino]-2-sulphophenyl]azo]-4,5-dihydro-5-oxo-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid

Endpoint summary

Description of key information

The skin sensitization potential of target chemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  was assessedin various experimental studies which were conducted on guinea pigs and humans for target chemicalits structurally similar read across substancetartrazine (CAS No: 1934-21-0) and itsfunctionally similar read across substancealuminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9). 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-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  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 of test material (IUPAC name): 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid
- Molecular formula: C25H18ClN9O12S3
- Molecular weight: 768.1192 g/mol
- Smiles notation: C1=CC(=CC(=C1)S(=O)(=O)O)NC2=NC(=NC(=N2)NC3=CC(=C(C=C3)S(=O)(=O)O)N=NC4C(=NN(C4=O)C5=CC=C(C=C5)S(=O)(=O)O)C(=O)O)Cl
- InChl: 1S/C25H18ClN9O12S3/c26-23-29-24(27-12-2-1-3-16(10-12)49(42,43)44)31-25(30-23)28-13-4-9-18(50(45,46)47)17(11-13)32-33-19-20(22(37)38)34-35(21(19)36)14-5-7-15(8-6-14)48(39,40)41/h1-11,19H,(H,37,38)(H,39,40,41)(H,42,43,44)(H,45,46,47)(H2,27,28,29,30,31)/b33-32+
- Substance type: Organic

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

not specified

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

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 reaction was observed in treated guinea pigs.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization reaction 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 ("g" and ( not "h") )  )  and "i" )  and "j" )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and "o" )  and ("p" and "q" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Hydrazines OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

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 OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  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 by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

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 ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo AND SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "j"

Similarity boundary:Target: OC(=O)C1C(N=Nc2cc(Nc3nc(Nc4cccc(S(O)(=O)=O)c4)nc(Cl)n3)ccc2S(O)(=O)=O)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Halogen derivative AND Heterocyclic compound AND Sulfonic acid AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Sulfuric acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfonic acid AND Triazine AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.492

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.3

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley guinea pigs.

Executive summary:

The skin sensitization potential of 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) failed to induce skin sanitization effects and hence is considered to be not sensitizing to Dunkin-Hartley 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 chemical4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  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-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) andits structurally similar read across substancetartrazine (CAS No: 1934-21-0) and itsfunctionally similar read across substancealuminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9).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 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The substance 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

 

The S. Pestana, M. Moreira and B. Oleja {Allergol Immunopathol (Madr). 2010;38(3):142–146} conducted double-blind, placebo-controlled food challenge (DBPCFC) study for read across chemical Tartrazine (CAS No: 1934-21-0) in humans. Double-blind placebo controlled cross-over challenge (DBPCC) used gold standard method in the diagnosis of allergic reactions to food and drugs. Capsules were manufactured by an external pharmacist who maintained the code until all the challenges were completed. Briefly, each volunteer was challenged either with tartrazine (Yellow dye no. 5, FD & C) in one visit, or placebo (talc) on another visit, one week apart. In the first visit, patients were randomised to receive three identical opaque capsules containing tartrazine or placebo (talc) in three steps. The administered dose of tartrazine was progressively increased from 5mg in the first administration to 10mg in the second one and to 20 mg in the last one. Patients were examined for Erythematous rash, Pruritus and Urticaria/angioedema fifty minutes after the ingestion of each capsule, and 2 h after the last one. All patients stayed under observation for three hours after taking the last dose. All the subjects answered a questionnaire about symptoms after this period and were interviewed by phone the next day. No Erythematous rash, Pruritus, Urticaria/angioedema observed in any of the 26 human volunteers. Tartrazine was considered to be not sensitizing when atopic adults were tested by using Double-blind placebo controlled challenge.

 

The above results were further supported by the Draize-Shelanski repeated insult patch test conducted by IPCS INCHEM {Allura red AC (WHO Food Additives Series 15); IPCS INCHEM; 1981} on 200 human subjects for read across chemical aluminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9).In this study, the chemical applied to the subjects volvar forearms (200 subjects) as an aqueous solution for 10 alternate days, for 24-hour periods, followed by a 14-day rest period. Challenge batches were then applied under occlusion to fresh skin sites on the subjects scapular backs for 24 hours. The colour did not produce either irritation or allergic responses during the induction phase nor contact dermatitis in the challenge period. Thereforealuminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9) was considered to be not sensitizing in a Draize-Shelanski repeated insult patch test conducted on 200 human subjects.

 

Thus on the basis of available data for thetarget chemical4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) and its structurally similar read across substancetartrazine (CAS No: 1934-21-0) and itsfunctionally similar read across substancealuminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9),it can be concluded that thechemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4)  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-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) and its structurally similar read across substancetartrazine (CAS No: 1934-21-0) and its functionally similar read across substancealuminium, 6-hydroxy-5-[(2-methoxy-5-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 68583-95-9) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (CAS No: 93858-25-4) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.