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Description of key information

The skin sensitization potential of target chemical [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    was assessedin various experimental studies which were conducted on guinea pigs and humans for target chemical[μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    and its structurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7) andfunctionally similar read across substancesD & C Red No. 6 (CAS no: 5858-81-1) and D & C Red no. 33 (CAS no: 3567-66-6). 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 [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    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:
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 : [μ-[[3,3'-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt
- Molecular weight : 1101.8036 g/mol
- Smiles notation : [Na+].[Na+].[Na+].[Na+].O=N(=Nc1ccc2N=Nc3c4O[Cu-2]5(Oc2c1)OS(=O)(=O)c6ccc4c(c6)cc3S(=O)(=O)O5)c7ccc8N=Nc9c%10O[Cu-2]%11(Oc8c7)OS(=O)(=O)c%12ccc%10c(c%12)cc9S(=O)(=O)O%11
- InChl : 1S/C32H22N6O17S4.2Cu.4Na/c39-25-13-17(1-7-23(25)33-35-29-27(58(50,51)52)11-15-9-19(56(44,45)46)3-5-21(15)31(29)41)37-38(43)18-2-8-24(26(40)14-18)34-36-30-28(59(53,54)55)12-16-10-20(57(47,48)49)4-6-22(16)32(30)42;;;;;;/h1-14,39-42H,(H,44,45,46)(H,47,48,49)(H,50,51,52)(H,53,54,55);;;;;;/q;2*+2;4*+1/p-8/b35-33+,36-34+,38-37+;;;;;;
- Substance type : Organic
- Physical state : Liquid
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 group
Dose level:
No data available
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No skin sensitization was observed in treated group.
Remarks on result:
no indication of skin sensitisation
Cellular proliferation data / Observations:
No skin sensitization was observed in treated group.

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 ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and ( not "z") )  )  and ("aa" and ( not "ab") )  )  and ("ac" and "ad" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anion OR Aromatic compound OR Azo compound OR Cation OR Hydroxy compound OR Phenol OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR Azo [-N=N-] OR Hydroxy, aromatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Suflur {v+4} or {v+6} OR Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Azo OR Azoxy OR Fused carbocyclic aromatic OR Overlapping groups OR Phenol OR Sulfonic acid by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aryl OR Azo OR Azoxy OR Fused carbocyclic aromatic OR Naphtalene OR Phenol OR Sulfonic acid by Organic Functional groups 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, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Radical 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) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines 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 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 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 >> Alkyl phenols 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 >> Hydroquinones 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 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Primary 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 Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Strong binder, OH group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Alkane branched with quaternary carbon OR Alkene by Organic Functional groups

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Biphenyl by Organic Functional groups

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Fused saturated heterocycles by Organic Functional groups

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Heterocyclic Phenol by Organic Functional groups

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Heterocyclic spiro rings by Organic Functional groups

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Azoxy AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Phosphite ester by Organic Functional groups

Domain logical expression index: "ac"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.385

Domain logical expression index: "ad"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.48

Interpretation of results:
other: Not sensitizing
Conclusions:
The chemical [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1) was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1) 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 [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The chemical [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)    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 chemical[μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     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 chemical[μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     and its structurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7) andfunctionally similar read across substancesD & C Red No. 6 (CAS no: 5858-81-1) and D & C Red no. 33 (CAS no: 3567-66-6). 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 [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     was estimated to be not sensitizing to the skin of Dunkin-Hartley guinea pigs. Based on the estimated result [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     can be considered to be not sensitizing to Dunkin-Hartley guinea pigs.

 

The Guin JD. (Contact Dermatitis 2003: 49: 217–218) conducted skin sensitization study forread across substanceD & C Red No. 6 (CAS no: 5858-81-1) to determine the allergic contact dermatitis caused by the chemical via performing patch test on human patients. The dye was applied on15patients in Finn Chambers and read first at 2 or (more commonly) 3 days and again at 4–7 days. The reactions of the patients were graded as ‘?+ ‘ , ‘+’ and ‘++’ categories. None of the treated patients showed any signs of allergic contact dermatitis. Hence the chemical D & C Red No. 6 (CAS no: 5858-81-1) can be considered as non-sensitizer to human 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) for read across chemical Acid Red 18 (CAS No: 2611-82-7) on 55 female (11 groups of 5 animals) mouse 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 substanceAcid Red 18 (CAS No: 2611-82-7)was considered as non-sensitizing in the vehicles tested.

 

 

The above results were further supported by the Maximization test reported by Scientific Committee on Consumer Safety (SCCS){ Opinion on Acid Red 33 ,Scientific Committee on Consumer Safety (SCCS), SCCP/1102/07} in female 15 (10 test and 5 control)Guinea pig for read across chemical D & C Red no. 33 (CAS no: 3567-66-6). The intradermal induction of sensitization in the test group was performed in the nuchal region with a 5% dilution of the test item in 1% CMC and in an emulsion of Freund's Complete Adjuvant (FCA) / physiological saline. The epidermal induction of sensitization was conducted for 18 hours under occlusion with the test item at 25% in 1% CMC one week after the intradermal induction. The test areas are pretreated with 10 sodium-laureth-sulfates (SLS) 24 hours prior to application of the test item. The animals of the control group were intradermally induced with 1% CMC and FCA/physiological saline and epidermally induced with 1% CMC under occlusion following pre-treatment with 10% SLS. Cutaneous reactions were evaluated at 24 and 48 hours after removal of the dressing. No known skin sensitization reactions were observed in treated as well as control group. Hence the chemical D& C Red no. 33 (CAS no: 3567-66-6) was considered to be not sensitizing.

 

 

Thus on the basis of available data for thetarget chemical[μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)     and its structurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7) andfunctionally similar read across substancesD & C Red No. 6 (CAS no: 5858-81-1) and D & C Red no. 33 (CAS no: 3567-66-6),it can be concluded thatchemical [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)  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 [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1)      and its structurally similar read across substanceits structurally similar read across substanceAcid Red 18 (CAS No: 2611-82-7) andfunctionally similar read across substancesD & C Red No. 6 (CAS no: 5858-81-1) and D & C Red no. 33 (CAS no: 3567-66-6) were observed in various studies. From the results obtained from these studies it is concluded that the chemical [μ-[[3,3’-[azoxybis[(2-hydroxy-p-phenylene)azo]]bis[4-hydroxynaphthalene-2,7-disulphonato]](8-)]]dicopper, tetrasodium salt (CAS No: 75173-68-1) is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.