Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate

Endpoint summary

Description of key information

The skin sensitization potential of target chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) was assessedin various experimental studies which were conducted on guinea pigs and mouse for target chemicalDisodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) and its functionally similar read across substancesBasic violet 1 (CAS No: 8007-87-3) andstructurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7). 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 Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) 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:

key study

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): Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate
- Common name: Methyl blue, Acid blue 93
- Molecular formula: C37H26N3Na2O9S3
- Molecular weight: 800.8182 g/mol
- Smiles notation: c1cc(ccc1C(=C2C=CC(=[NH+]c3ccc(cc3)S(=O)(=O)[O-])C=C2)c4ccc(cc4)Nc5ccc(cc5)S(=O)(=O)[O-])Nc6ccc(cc6)S(=O)(=O)O.[Na+].[Na+]
- InChl: 1S/C37H29N3O9S3.2Na/c41-50(42,43)34-19-13-31(14-20-34)38-28-7-1-25(2-8-28)37(26-3-9-29(10-4-26)39-32-15-21-35(22-16-32)51(44,45)46)27-5-11-30(12-6-27)40-33-17-23-36(24-18-33)52(47,48)49;;/h1-24,38-39H,(H,41,42,43)(H,44,45,46)(H,47,48,49);;/q;2*+1/p-1
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

Dunkin-Hartley

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.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

No skin sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest 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 ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and "s" )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Aryl OR Sulfonic acid by Organic Functional groups ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene OR Ammonium salt OR Aromatic amine OR Aryl OR Overlapping groups OR Sulfonic acid by Organic Functional groups (nested) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, hydrogen attach {v+5} OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Ortho-substitutes on N=C<, aromatic OR Suflur {v+4} or {v+6} OR Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amine OR Anion OR Aromatic compound OR Cation OR Secondary amine OR Secondary aromatic amine OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) 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 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 SN2 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 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group All log Kow < -3.1 AND Group All Melting Point > 200 C AND Group All Molecular Weight > 650 g/mol AND Group CNS log Kow < -2 AND Group CNS Melting Point > 200 C AND Group CNS Melting Point > 50 C AND Group CNS Molecular Weight > 620 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Aqueous Solubility < 0.000005 g/L OR (!Undefined)Group All Aqueous Solubility < 0.00002 g/L OR (!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 Exclusion rules not met OR Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All log Kow > 9 OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Aqueous Solubility < 0.0005 g/L OR Group C Melting Point > 55 C OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Molecular Weight > 290 g/mol OR Group CNS Aqueous Solubility < 0.006 g/l OR Group CNS log Kow > 1.5 OR Group CNS log Kow > 3.6 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Ketones OR Quaternary organic ammonium compounds OR Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNS Surface Tension > 62 mN/m AND Group All log Kow < -3.1 AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS log Kow < -2 AND Group CNS Melting Point > 120 C AND Group CNS Melting Point > 50 C AND Group CNS Molecular Weight > 620 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, two aromatic attach [-N-] AND Aromatic Carbon [C] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, hydrogen attach {v+5} AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Ortho-substitutes on N=C<, aromatic AND Suflur {v+4} or {v+6} AND Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Transition Metals by Groups of elements

Domain logical expression index: "v"

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

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Metalloids OR Metals by Groups of elements

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.65

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= -2.38

Interpretation of results:

other: Not sensitizing

Conclusions:

The chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) 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 Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) was estimated using OECD QSAR toolbox version 3.4 with log Pow as the primary descriptor. The chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4) 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:

Various studieshas been investigated for the test chemicalDisodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  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 mouse for target chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  and its functionally similar read across substance Basic violet 1 (CAS No: 8007-87-3) and structurally similar read across substance Acid Red 18 (CAS No: 2611-82-7). 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 Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  can be considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The JOE DINARDO, Raleigh, NC and ZOE DIANA DRAELOS conducted skin sensitization study of read across chemical Basic violet 1 (CAS No: 8007-87-3) {Journal of Cosmetic Science, 58, no. 3 (2007): 209-214} in guinea pig using modified Buehler and Klecak method. For the induction phase, the left flanks of 10 albino guinea pigs were shaved and the test material Disperse violet 4 was applied three times weekly (Monday, Wednesday Friday) for three consecutive weeks. Each animal received 0.1 ml of the material over a 1.8-cm circular area. Following the induction period, the guinea pigs entered the challenge phase. The challenge phase began after a two-week rest period when the right flank of each guinea pig was shaved and exposed to three different dye test material concentration (10.0%, 5.0%, and 2.50%of the induction concentration). Twenty-four hours after the last induction and challenge application, the animals were depilated to clearly observe dermal reactions. The test sites were graded for erythema and edema 24 and 48 hours post-application using a four-point ordinal scale (0 = no reaction, 1 -- slight reaction, 2 = moderate reaction, 3 = severe reaction. A positive reaction was defined as an erythema/edema value during the challenge phase of at least one skin grade higher than during the last induction phase. No erythema/edema was observed after 24 and 48 hours post-application. Hence the test substance Basic violet 1 (CAS No: 8007-87-3) was considered as not sensitizing to the guinea pigs skin.

The above results were supported by the Local Lymph Node Assay (LLNA) reported by The Scientific Committee On Cosmetic Products And Non-Food Products (SCCNFP) {The Scientific Committee On Cosmetic Products And Non-Food Products (SCCNFP), last updated 23 April 2004} on 55 female mouse for read across chemical Acid Red 18 (CAS No: 2611-82-7) according to OECD Guideline 429. On days 0, 1 and 2 the animals received 25 μl of one of the test preparations or vehicle on the dorsal surface of each ear. On day 5 all mice received intravenous injection of tritium labelled thymidine in phosphate buffered saline, and 5 hours later they were killed humanely and the draining auricular lymph nodes were removed. Single cell suspensions were prepared for each animal, appropriately treated and measured by liquid scintillation counting. The stimulation indices were less than 3 at all tested concentrations, hence an EC3 value could not be calculated, and thus the test substance Acid Red 18 (CAS No: 2611-82-7) was considered as non-sensitizing in the vehicles tested.

 

Thus on the basis of available data for thetarget chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  and its functionally similar read across substance Basic violet 1 (CAS No: 8007-87-3) and structurally similar read across substance Acid Red 18 (CAS No: 2611-82-7),it can be concluded thatchemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  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 Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)   and its functionally similar read across substanceBasic violet 1 (CAS No: 8007-87-3) and structurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7) were observed in various studies. From the results obtained from these studies it is concluded that the chemical Disodium [[4-[bis[4-[(sulphonatophenyl)amino]phenyl]methylene]cyclohexa-2,5-dien-1-ylidene]amino]benzenesulphonate (CAS No: 28983-56-4)  is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.