1,3-Benzenedisulfonic acid, 4-[[5-(aminocarbonyl)-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridinyl]azo]-6-[[4-[[3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl]amino]-6-chloro-1,3,5-triazin-2-yl]amino]-

Endpoint summary

Description of key information

Skin sensitization

The skin sensitization potential of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was predicted to be not sensitizing to the skin of female Pirbright-Hartley guinea pig.

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 v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

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: 1,3-Benzenedisulfonic acid, 4-[[5-(aminocarbonyl)-1-ethyl-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridinyl]azo]-6-[[4-[[3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl]amino]-6-chloro-1,3,5-triazin-2-yl]amino]-
- IUPAC name: 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid
- Molecular formula: C27H24Cl2N14O12S3
- Molecular weight: 903.6766 g/mole
- Smiles : CCN1C(=O)C(=C(C(=NNC2=C(C=C(C(=C2)NC3=NC(=NC(=N3)NC4=CC(=C(C=C4)S(=O)
(=O)O)NC5=NC(=NC(=N5)N)Cl)Cl)S(=O)(=O)O)S(=O)(=O)O)C1=O)C)C(=O)N
- Inchl: 1S/C27H24Cl2N14O12S3/c1-3-43-20(45)17(19(30)44)9(2)18(21(43)46)42-41-13-7-12(15(57(50,51)52)8-16(13)58(53,54)55)34-27-38-23(29)37-25(40-27)32-10-4-5-14(56(47,48)49)11(6-10)33-26-36-22(28)35-24(31)39-26/h4-8,46H,3H2,1-2H3,(H2,30,44)(H,47,48,49)(H,50,51,52)(H,53,54,55)(H3,31,33,35,36,39)(H2,32,34,37,38,40)/b42-41+
- Substance type: Organic
- Physical state: Solid powder (red)

Species:

guinea pig

Strain:

Pirbright-Hartley

Sex:

female

Details on test animals and environmental conditions:

No data available

No. of animals per dose:

No data available

Details on study design:

No data available

Challenge controls:

No data available

Positive control substance(s):

not specified

Statistics:

No data available

Positive control results:

No data available

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Clinical observations:

No skin sensitization effect was observed

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((("a" or "b" or "c" or "d" or "e" or "f" )  and ("g" and ( not "h") )  )  and "i" )  and "j" )  and ("k" and "l" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Non-specific AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives AND SN1 AND SN1 >> Nucleophilic substitution on diazonium ions AND SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "d"

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 SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones 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: "f"

Referential boundary: The target chemical should be classified as Acid moiety OR Acrylamides OR Anilines (Unhindered) OR Hydrazines OR Imides OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group All Melting Point > 200 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 400 g/kg OR (!Undefined)Group CNS Surface Tension > 62 mN/m OR Exclusion rules not met OR Group All log Kow < -3.1 OR Group All log Kow > 9 OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 350 g/mol OR Group C Vapour Pressure < 0.0001 Pa OR Group CHal log Kow > 4.5 OR Group CHal Melting Point > 65 C OR Group CHal Molecular Weight > 280 g/mol OR Group CHal Molecular Weight > 370 g/mol OR Group CN Aqueous Solubility < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN log Kow > 5.5 OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Molecular Weight > 540 g/mol OR Group CN Vapour Pressure < 0.001 Pa OR Group CNHal Aqueous Solubility < 0.001 g/L OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNHal log Kow > 3.8 OR Group CNHal Molecular Weight > 370 g/mol OR Group CNHal Molecular Weight > 380 g/mol OR Group CNS log Kow < 0.5 OR Group CNS log Kow < -2 OR Group CNS Melting Point > 120 C OR Group CNS Melting Point > 50 C OR Group CNS Molecular Weight > 620 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Similarity boundary:Target: CCN1C(=O)C(C(N)=O)=C(C)C(=NNc2cc(Nc3nc(Nc4ccc(S(O)(=O)=O)c(Nc5nc(N)nc(Cl)n5)c4)nc(Cl)n3)c(S(O)(=O)=O)cc2S(O)(=O)=O)C1=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.99

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.227

Interpretation of results:

other: not sensitizing

Conclusions:

The skin sensitization potential of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was predicted to be not sensitizing to the skin of female Pirbright-Hartley guinea pig.

Executive summary:

The skin sensitization potential of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was predicted to be not sensitizing to the skin of female Pirbright-Hartley guinea pig.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin sensitization 

In different studies, 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)has been investigated for potential of skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pig and human for target chemical 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1) and its function aly similar read across substancestrisodium 5-amino-3-[(E)-2-(4-{4-[(E)-2-(7-amino-1-hydroxy-3-sulfonatonaphthalen-2-yl)diazen-1-yl]phenyl}phenyl)diazen-1-yl]-4-hydroxynaphthalene-2,7-disulfonate (2429-73-4)anddisodium 4-amino-3-[(E)-2-{4-[(E)-2-(2,4-diaminophenyl)diazen-1-yl]phenyl}diazen-1-yl]-5-hydroxy-6-[(E)-2-phenyldiazen-1-yl]naphthalene-2,7-disulfonate(68877-33-8),the predicted data using the OECD QSAR toolbox has also been compared with the experimental data of read across.

The skin sensitization potential of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read across of 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)was predicted to be not sensitizing to the skin of female Pirbright-Hartley guinea pig.

These results are supported by the experimental study conducted by NTRL (NTRL, OTS0215029, 1982) for the structurally similar read across substance, trisodium 5-amino-3-[(E)-2-(4-{4-[(E)-2-(7-amino-1-hydroxy-3-sulfonatonaphthalen-2-yl)diazen-1-yl]phenyl}phenyl)diazen-1-yl]-4-hydroxynaphthalene-2,7-disulfonate (2429-73-4) in human. The skin sensitization study of trisodium 5-amino-3-[(E)-2-(4-{4-[(E)-2-(7-amino-1-hydroxy-3-sulfonatonaphthalen-2-yl)diazen-1-yl]phenyl}phenyl)diazen-1-yl]-4-hydroxynaphthalene-2,7-disulfonate (2429-73-4)was performed by patch test method in 200 subjects. In induction phase, the sixteen dyed paper were applied to the skin of the back of all subjects under occlusive dressing for one week. In challenge phase, after 7 days on the same site occlusive dressing applied for 1 week. Evaluation was made at the end of the first and second week’s exposure. Faint Yellow stain on skin after one and two weeks was observed in six subjects .No indication of skin sensitization was observed. Hence it is considered that trisodium 5-amino-3-[(E)-2-(4-{4-[(E)-2-(7-amino-1-hydroxy-3-sulfonatonaphthalen-2-yl)diazen-1-yl]phenyl}phenyl)diazen-1-yl]-4-hydroxynaphthalene-2,7-disulfonate (2429-73-4) was not skin sensitizing in human.

 Also ,these results are supported by the experimental study conducted by NTRL (NTRL, OTS0215029, 1982) for the structurally similar read across substance, disodium 4-amino-3-[(E)-2-{4-[(E)-2-(2,4-diaminophenyl)diazen-1-yl]phenyl}diazen-1-yl]-5-hydroxy-6-[(E)-2-phenyldiazen-1-yl]naphthalene-2,7-disulfonate(68877-33-8) in human. The skin sensitization study of disodium 4-amino-3-[(E)-2-{4-[(E)-2-(2,4-diaminophenyl)diazen-1-yl]phenyl}diazen-1-yl]-5-hydroxy-6-[(E)-2-phenyldiazen-1-yl]naphthalene-2,7-disulfonate(68877-33-8)was performed by patch test methodin200 subjects.In induction phase, the sixteen dyed paper were applied to the skin of the back of all subjects under occlusive dressing for one week.

In challenge phase, after 7 days on the same site occlusive dressing applied for 1 week. Evaluation was made at the end of the first and second week’s exposure. Faint Yellow stain on skin after one and two weeks was observed in six subjects .No indication of skin sensitization was observed. Hence it is considered that disodium 4-amino-3-[(E)-2-{4-[(E)-2-(2,4-diaminophenyl)diazen-1-yl]phenyl}diazen-1-yl]-5-hydroxy-6-[(E)-2-phenyldiazen-1-yl]naphthalene-2,7-disulfonate(68877-33-8)was not skin sensitizing in human.

 Thus based on the above predictions on 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)as well as its read across and applying weight of evidence, it can be concluded 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1)is not skin sensitizer. Thus comparing the above studies with the criteria of CLP regulation, 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1) can be not classified for skin sensitization.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus comparing the above studies with the criteria of CLP regulation, 4-{[4-({3-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-4-sulfophenyl}amino)-6-chloro-1,3,5-triazin-2-yl]amino}-6-[(E)-2-(5-carbamoyl-1-ethyl-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridin-3-yl)diazen-1-yl]benzene-1,3-disulfonic acid (93941-80-1) can be not classified for skin sensitization.