Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was predicted to be not sensitizing to the skin of male/female guinea pigs.

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 v3.4 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Specific details on test material used for the study:

- Name of test material (IUPAC name): Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium
- Substance type: Organic

Species:

guinea pig

Strain:

not specified

Sex:

male/female

Details on test animals and environmental conditions:

no data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

intradermal and epicutaneous

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

10

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

no reactions 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 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 "p" )  and ("q" and "r" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anion by Substance Type

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 AN2 OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Schiff base formation with carbonyl compounds (AN2) OR AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives OR Schiff base formation OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones by Protein binding by OASIS v1.4 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 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.1.4

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 OR AN2 >> Schiff base formation >> Polarized Haloalkene Derivatives 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 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Organic Azides 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 >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Organic Azides OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives 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 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after nitrene formation OR SN1 >> Nucleophilic attack after nitrene formation >> Organic Azides OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polarized Haloalkene Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom 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 >> Haloalkanes Containing Heteroatom 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 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives by DNA binding by OASIS v.1.4

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 Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Activated N-heterocycles OR Aromatic amines OR Esters of organic sulfonic or sulfuric esters OR Ketones OR Phenols OR Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr AND Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At AND Group 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group 12 - Trans.Metals Zn,Cd,Hg OR Group 17 - Halogens F by Chemical elements

Domain logical expression index: "o"

Similarity boundary:Target: CC1C{-}(N=Nc2cc(Cl)ccc2O{-}.[Cr]{2+}.O{-}c2ccc(Cl)cc2N=NC{-}2C(C)=NN(c3cccc(S(=O)(=O)O{-}.[Na]{+})c3)C2=O)C(=O)N(c2ccccc2)N=1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Similarity boundary:Target: CC1C{-}(N=Nc2cc(Cl)ccc2O{-}.[Cr]{2+}.O{-}c2ccc(Cl)cc2N=NC{-}2C(C)=NN(c3cccc(S(=O)(=O)O{-}.[Na]{+})c3)C2=O)C(=O)N(c2ccccc2)N=1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 757 Da

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 913 Da

Interpretation of results:

other: Negative

Conclusions:

Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was predicted to be not sensitizing to the skin of male/female guinea pigs.

Executive summary:

The skin sensitization potential of Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor. Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was predicted to be not sensitizing to the skin of male/female guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:                                      

Various studies have been investigated to ascertain the degree of dermal sensitization caused by Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium. These include in vivo experiments in guinea pigs for the target chemical as well as its structurally similar read across chemicals, Trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate(Tartrazine)[CAS: 1934-21-0] anddisodium 5-acetamido-4-hydroxy-3-(phenyldiazenyl)naphthalene-2,7-disulfonate [CAS: 3734-67-6]. The experimental results have also been compared with the predictions obtained from OECD QSAR toolbox.

The skin sensitization potential of Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2 -hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor.

Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2 -phenyl-3H-pyrazol-3-onato(2-)]-, sodium was predicted to be non sensitizing to the skin of male/female guinea pigs.

A modified Buehler and Klecak method for open epicutaneous testing[OET] was performed by JOE DINARDO et.al [JOURNAL OF COSMETIC SCIENCE, 58, 209-214 May/June 2007] to assess the sensitization potential of the structurally similar read across chemical, Tartrazine [CAS: 1934-21-0].

Tartrazine was tested at an induction concentration of 10% and challenge concentrations of 10.0%, 5.0%, and 2 .5%.

For the induction phase, the left flanks of ten albino guinea pigs were shaved and the dye test material applied three times weekly (Monday, Wednesday, Friday) for three consecutive weeks. Each animal received 0.1 ml of the dye test 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 concentrations(10.0%, 5.0%, and 2 .5%). Twenty-four hours after the last induction and challenge application, the animals were depilated to clearly observe dermal reactions.

All test sites were graded for erythema and edema 24 and 48 hours post-application using a four-point ordinal scale. A positive control of 0.5% 2,4-dinitrochlorobenzene(DNCB) in ethanol was included for both the induction and challenge phases. Since a positive response was observed in the challenge exposure at 10% challenge exposure, Tartrazine was retested using a 1% induction exposure and challenge concentrations of 1.0%, 0.5%, and 0.25%.

Tartazine produced a positive reaction at 10% challenge exposure, but in the retest no reactions were observed at 1%, 0.5 and 0.25% challenge concentrations.

Hence, it was considered that Tartrazine does not induce any sensitization in guinea pigs when tested below 10% concentration.

The above results are supported Double-blind, placebo-controlled food challenge (DBPCFC) performed by S. Pestana et.al [Allergol Immunopathol (Madr), 2010;38(3):142–146]to assess the sensitization potential of the structurally similar read across chemical, Tartrazine[CAS: 1934-21-0] in humans.

Double-blind placebo controlled cross-over challenge (DBPCC) was 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.

These results are further supported by the experimental study summarized in Scientific Committee on Cosmetology (seventh series), 1988;thestructurally similar read across chemical, Disodium 5-acetylamino-4-hydroxy-3-(phenylazo)naphthalene-2,7-disulphonate[CAS: 3734-67-6].Guinea pigs were given two times 4 intradermal injections of 0.1 ml of a 7.5% solution in saline during the induction phase.14 days after second injection, a challenge exposure was conducted.

In the challenge exposure, single intradermal injection of a 3% solution in saline was administered to the guinea pigs.

Signs of sensitization were not observed. Hence RED 2G (3734-67-6)was considered  to be non sensitizing after challenge exposure in guinea pig.

Based on the available studies for the target as well as its structurally similar read across chemicals and applying the weight of evidence approach, 4,5-dihydro-5-oxo-4-[[4-[[2 -(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid, sodium salt  can be considered to be not sensitizing to skin. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

Available data forChromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium indicates that it is not likely to cause any dermal sensitization to skin.

Chromate(2-), [4-[4-[(5-chloro-2-hydroxyphenyl)azo]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzenesulfonato(3-)][4-[(5-chloro-2-hydroxyphenyl)azo]-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)]-, sodium can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.