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Description of key information

The skin sensitization potential estimated trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6- [(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)- 2-sulfonatophenyl ]diazenyl} -3-methyl- 5-oxo-4,5-dihydro-1H-pyrazo l-1-yl)benzenesulfonate(50662-99-2) by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read acrosstrisodium 2,5-dichloro-4- (4-{[5-({4-chloro-6-[(4-sulfonatophenyl) amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl] diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl) benzenesulfonate(50662-99-2)was predicted to be not sensitizing to the skin of Himalayan guinea pig.

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 v3.3 and the QMRF report has been attached.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3
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 (as cited in study report): trisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate
Molecular Formula: C25H18Cl3N9O10S3.3Na
Molecular Weight: 872.974 g/mole
Smiles notation: c1(\N=N\c2c(n(c3cc(c(S([O-])(=O)=O)cc3Cl)Cl)nc2C)O)cc(ccc1S(=O)(=O)[O-])Nc1nc(nc(n1)Cl)Nc1ccc(cc1)S(=O)(=O)[O-].[Na+].[Na+].[Na+]
Substance type: Organic
Physical state: not specified



Species:
guinea pig
Strain:
Himalayan
Sex:
male
Details on test animals and environmental conditions:
no data avaliable
Route:
intradermal and epicutaneous
Vehicle:
physiological saline
Concentration / amount:
5% Bi-distilled water
Day(s)/duration:
24hr and 48hr
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
physiological saline
Concentration / amount:
Bi-distilled water 15%
Day(s)/duration:
24hr and 48hr
No. of animals per dose:
Total :30
Control group: 10 males
Test group: 20 males
Details on study design:
No data avaliable
Challenge controls:
yes
Positive control substance(s):
yes
Remarks:
2-MERCAPTOBENZOTHIAZOL
Statistics:
no data avaliable
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
15% in bi-distilled water.
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Skin effects (erythema and edema) were not observed.
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
15%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
Skin effects (erythema and edema) were not 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 mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "c"

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: "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 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: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation 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-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical 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) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 >> 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 >> Nitro Azoarenes 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 >> Polynitroarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives 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: "g"

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 >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as (!Undefined)Group All log Kow < -3.1 OR (!Undefined)Group All log Kow > 9 OR (!Undefined)Group All Melting Point > 200 C 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 Group All log Kow < -3.1 OR Group All log Kow > 9 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 Melting Point > 120 C OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.67

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.2

Interpretation of results:
other: not sensitising
Conclusions:
The skin sensitization potential of
trisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) 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 substances trisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) was predicted to be not sensitizing to the skin of Himalayan guinea pig
Executive summary:

The skinsensitization potential estimated trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read acrosstrisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2)was predicted to be not sensitizing to the skin of Himalayan guinea pig

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Skin sensitization

In different studies,trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2)has been investigated for its potential for dermal sensitization to a greater or lesser extent. The prediction and studies are based on in vivo experiments in guinea pig for target chemical disodium trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) and its structurally similar read across substancesDisodium 6-hydroxy-5-[(2-methoxy-4-sulphonato-m-tolyl)azo]naphthalene-2-sulphonate(25956-17-6).The predicted data using the OECD QSAR toolbox and DANISH QSAR have also been compared with the experimental data.

The skin sensitization potential estimated trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and considering the six closest read acrosstrisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2)was predicted to be not sensitizing to the skin of Himalayan guinea pig.

Another prediction done using the Danish (Q) SAR Database, the skin sensitization was estimated to be negative on guinea pig and human for trisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) . Using Battery algorithm model of Danish QSAR, Allergic Contact Dermatitis for estimatedtrisodium 2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) estimated to be not sensitizing when applied to human and guinea pig skin.

Further supported by experimental data conducted by European Commission (Evaluation and opinion on Curry Red, 2004) on structurally similar read across substance Disodium 6-hydroxy-5-[(2-methoxy-4-sulphonato-m-tolyl)azo]naphthalene-2-sulphonate(25956-17-6)on mouse by LLNA mode.The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on skin sensitization from the analogue substance. Local lymph node assay (LLNA) of Disodium6-hydroxy-5-[(2-methoxy-4-sulphonato-m-tolyl)azo]naphthalene-2-sulphonate (25956-17-6)was performed on female miceCBA/J by measuring the cell proliferation in the draining lymph nodes after topical application onto the ears.

In test group ,fallowing concentration were used

 a)concentration of test substance as 0.5, 1, 2, 4 % (w/v) in DMSO

 b)concentration of test substance as 0.5, 1, 2, 4 % in aqua/acetone (1:1) mixed with olive oil (4:1)

All the animals were observed twice daily for any clinical signs andmorbidity/mortality before and after given dose. Body weight was determined on day 1 and day 5. On day 5 the mice received an intravenous injection of 250 μl phosphate buffered saline containing 20.8 μCi of [H3] methyl thymidine. After 5hr animals were died by giving CO2-inhalation and the draining auricular lymph node was removed and weighed. The cell suspension for each animal prepared. The cells were predicated by TCA.The liquid scintillation counting as disintegration per minute (dpm) was used to determined radioactivity due to incorporation of [H3] methyl thymidine in the pellets. The stimulation index was calculated by comparing test material with concurrent vehicle control.

Result was noted using mean stimulation index

For a)test substance as 0.5, 1, 2, 4 % (w/v) in DMSO mean stimulation indices of 0.6, 0.7, 0.9 and 0.9 were obtained

b) test substance as 0.5, 1, 2, 4 % in aqua/acetone (1:1) mixed with olive oil (4:1)

mean stimulation indices of1.2, 1.0, 0.9 and 0.9 were obtained

c)The positive control (PPD, 1 % in DMSO) caused an increase in the stimulation index by a factor of 7.8.

As no relevant increase in the mean stimulation indices was observed (all figures were well below the trigger value of three), Hence it is considered thatDisodium6-hydroxy-5-[(2-methoxy-4-sulphonato-m-tolyl)azo]naphthalene-2-sulphonate (25956-17-6) was not skin sensitizer in mice by using Local lymph node assay (LLNA).

Thus based on the above predictions on trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2) as well as its read across substances and applying weight of evidence, it can be concluded that trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate is not a skin sensitizer. Thus comparing the above annotations with the criteria of CLP regulation, trisodium2,5-dichloro-4-(4-{[5-({4-chloro-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2)can be considered as not classified for skin sensitization effects.

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Thus comparing the above annotations with the criteria of CLP regulation, trisodium2,5-dichloro-4-(4- {[5-({4-chloro-6-[(4-sulfonatophenyl) amino]-1,3,5-triazin-2-yl}amino) -2-sulfonatophenyl] diazenyl}-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonate(50662-99-2)can be considered as not classified for skin sensitization effects.