Registration Dossier

Skin Irritation:

The dermal irritation potential of lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to skin and can be classified under the category ”Not Classified“ as per CLP regulation.

Eye Irritation:

The ocular irritation potential of Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Lithium bis[2-[(4,5-dihydro-3 -methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Reference

Endpoint:

skin irritation: 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 v3.4 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

Specific details on test material used for the study:

- Name of test material: Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- IUPAC name: lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- Molecular formula: C34H24CrN8O6.Li
- Molecular weight: 699.5506 g/mole
- Smiles : [Li+].CC1=NN(C(=O)C1\2[Cr-]3(OC(=O)c4c(cccc4)/N=N/C35C(=O)N(N=C5C)c6ccccc6)OC(=O)c7c(cccc7)/N=N2)c8ccccc8
- Inchl: 1S/2C17H13N4O3.Cr.Li/c2*1-11-15(16(22)21(20-11)12-7-3-2-4-8-12)19-18-14-10-6-5-9-13(14)17(23)24;;/h2*2-10H,1H3,(H,23,24);;/q;;2*+1/ p-2/b2*19-18+;;
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

no data available

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

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

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives AND AN2 >> Schiff base formation with carbonyl compounds (AN2) AND AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives AND Schiff base formation AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Acylation >> Direct Acylation Involving a Leaving group >> Sulphonyl halides OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR No alert found OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> 1-2-Dicarbonyls OR SN2 OR SN2 >> Epoxides and Related Chemicals OR SN2 >> Epoxides and Related Chemicals >> Epoxides OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halocarbonyls OR SN2 >> SN2 reaction at sp3 carbon atom >> Sulfonates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "f"

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: "g"

Referential boundary: The target chemical should be classified as Acid anhydrides OR Aromatic amines OR Esters including acrylic and methacrylic esters OR Esters of organic sulfonic or sulfuric esters OR Ethylenglycolethers OR Hydrazines,hydrazonium salts OR Ketones OR Lactones OR Phenols OR Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "m"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.29

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.41

Interpretation of results:

other: not irritating

Remarks:

Migrated information

Conclusions:

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to skin and can be classified under the category ”Not Classified“ as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye irritation: 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 v3.4 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

Specific details on test material used for the study:

- Name of test material: Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- IUPAC name: Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- Molecular formula: C34H24CrN8O6.Li
- Molecular weight: 699.5506 g/mole
- Smiles : [Li+].CC1=NN(C(=O)C1\2[Cr-]3(OC(=O)c4c(cccc4)/N=N/C35C(=O)N(N=C5C)c6ccccc6)OC(=O)c7c(cccc7)/N=N2)c8ccccc8
- Inchl: 1S/2C17H13N4O3.Cr.Li/c2*1-11-15(16(22)21(20-11)12-7-3-2-4-8-12)19-18-14-10-6-5-9-13(14)17(23)24;;/h2*2-10H,1H3,(H,23,24);;/q;;2*+1/ p-2/b2*19-18+;;
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1g

Duration of treatment / exposure:

1 hour

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

3

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no irritation observed

Estimation method: Takes mode value from the 7 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((((("a" or "b" or "c" ) and ("d" and ( not "e") ) ) and ("f" and ( not "g") ) ) and "h" ) and ("i" and ( not "j") ) ) and ("k" and ( not "l") ) ) and "m" ) and "n" ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and "v" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives AND AN2 >> Schiff base formation with carbonyl compounds (AN2) AND AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives AND Schiff base formation AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones by Protein binding by OASIS v1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Acyl halides (including benzyl and carbamoyl deriv.) OR Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Acylation >> Direct Acylation Involving a Leaving group >> Sulphonyl halides OR Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR No alert found OR SN2 OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halocarbonyls OR SN2 >> SN2 reaction at sp3 carbon atom >> Sulfonates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Pyrrolidones by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "m"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Anion AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Cation AND Heterocyclic compound AND Lactone by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Nitro compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Anion AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Cation AND Heterocyclic compound AND Lactone by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Secondary amine OR Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Anion AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Cation AND Heterocyclic compound AND Lactone by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Tertiary aliphatic amine OR Tertiary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.04

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.81

Interpretation of results:

other: not irritating

Conclusions:

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across chemicals, Chromium(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4 ,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1 -ylidene}cyclohexa-2,4-dien-1- ylidene]methanebis(olate)) (Acid yellow 121) [CAS:5601-29-6]; 4,4'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one](Pigment Orange 13)[CAS: 3520-72-7] and 2-{2-[2-chloro-4-(3-chloro-4 -{2-[2-oxo-1-(phenylcarbamoyl)propyl]diazen-1-yl}phenyl)phenyl]diazen-1-yl}-3-oxo-N-phenylbutanamide(C.I. Pigment Yellow 12)[CAS: 6358-85-6].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.4 with log kow as the primary descriptor, the skin irritation potential was estimated for Lithium bis[2-[(4,5-dihydro-3 -methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-). Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to New Zealand White rabbit skin.

This is supported by the experimental study summarized in Scientific Committee on Cosmetology (seventh series), 1988; for the structurally similar read across chemical,Chromium(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4 ,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1 -ylidene}cyclohexa-2,4-dien-1- ylidene]methanebis(olate)) (Acid yellow 121) [CAS:5601-29-6].

0.1% test chemical in Cremophor EL : water (15:85) was applied on the guinea pig skin three times a day on two successive days and washed away after 20 minutes exposure. The guinea pigs were observed for dermal reactions.

Repeated exposures to the test chemical didnot cause any dermal irritation/corrosion in guinea pigs. Hence, chromium(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4,5 -dihydro-1H-pyrazol-4-ylidene]hydrazin-1-ylidene}cyclohexa-2,4-dien-1-ylidene]methanebis(olate)) was considered to be not irritating to skin.

These results are further supported by the experimental study summarized in IUCLID DATASET, EUROPEAN COMMISSION – European Chemicals Bureau, last updated 2000; for the structurally similar read across chemical,4,4'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one](Pigment Orange 13)[CAS: 3520-72-7]. 4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl)didiazene-2,1-diyl]bis(5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one) [Pigment Orange 13] was applied to the skin of rabbits and observed for signs of irritation (dose, duration of exposure and observation period).

4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl)didiazene-2,1-diyl]bis(5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one) [Pigment Orange 13] was considered to be not irritating to rabbit skin.

The above results are supported by the experimental study summarized in OECD HPV Chemical Programme, SIDS Dossier, approved at SIAM 16 (27/05/2003); for the structurally similar read across chemical, 2-{2-[2-chloro-4-(3-chloro-4-{2-[2-oxo-1-(phenylcarbamoyl)propyl]diazen-1-yl}phenyl)phenyl]diazen-1-yl}-3-oxo-N-phenylbutanamide(C.I. Pigment Yellow 12)[CAS: 6358-85-6].

C. I. Pigment Yellow 12 was applied on each rabbit for 24 hours under occlusive conditions and observed for signs of irritation. No skin reactions were observed. Hence the chemical C. I. Pigment Yellow 12 (CAS no: 6358-85-6) was considered as not irritating to the skin of rabbits.

Based on the available data for the target chemical as well as its structurally similar read across chemicals, and applying the weight of evidence approach, Hydrogen [2,4-dihydro-4-[(2 -hydroxy-5-nitrophenyl)azo]-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)][2-[(4,5-dihydro-3-methyl -5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to skin. Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Eye Irritation:

In different studies, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across chemicals, Chromium(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4 ,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1 -ylidene}cyclohexa-2,4-dien-1- ylidene]methanebis(olate)) (Acid yellow 121) [CAS:5601-29-6]; 4,4'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one](Pigment Orange 13)[CAS: 3520-72-7] and 2-{2-[2-chloro-4-(3-chloro-4 -{2-[2-oxo-1-(phenylcarbamoyl)propyl]diazen-1-yl}phenyl)phenyl]diazen-1-yl}-3-oxo-N-phenylbutanamide(C.I. Pigment Yellow 12)[CAS: 6358-85-6].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.4 with log kow as the primary descriptor, the eye irritation potential was estimated for Lithium bis[2-[(4,5-dihydro-3 -methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-). Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) was estimated to be not irritating to New Zealand White rabbit eyes.

This is supported by the experimental study summarized in Scientific Committee on Cosmetology (seventh series), 1988; for the structurally similar read across chemical, Chromium

(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4 ,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1 -ylidene}cyclohexa-2,4-dien-1- ylidene]methanebis(olate)) (Acid yellow 121) [CAS:5601-29-6].

0.1% test chemical in Cremophor EL : water mixture was instilled into the guinea pig eyes and observed for reactions.

No positive ocular irritation reactions were observed. Hence, Chromium(3+) ion hydrogen bis([(6E)-6-{2-[(4Z)-3-methyl-5-oxo-1-phenyl-4 ,5-dihydro-1H-pyrazol-4-ylidene]hydrazin-1 -

ylidene}cyclohexa-2,4-dien-1- ylidene]methanebis(olate)) was considered to be not eye irritant.

These results are further supported by the experimental study summarized in Scientific Committee on Cosmetology (seventh series), 1988; for the structurally similar read across chemical,4,4'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3-one](Pigment Orange 13)[CAS: 3520-72-7].

100 mg undiluted test chemical was instilled into the eyes of rabbits and observed for effects till 7 days.

Slight irritation effects were observed which were fully recovered within 7 days. Hence, 4,4'-[(3,3'-dichloro[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol-3 -one was considered to be not irritating to rabbit eye.

The above results are supported by the experimental study summarized in OECD HPV Chemical Programme, SIDS Dossier, approved at SIAM 16 (27/05/2003); for the structurally similar read across chemical, 2-{2-[2-chloro-4-(3-chloro-4-{2-[2-oxo-1-(phenylcarbamoyl)propyl]diazen-1-yl}phenyl)phenyl]diazen-1-yl}-3-oxo-N-phenylbutanamide(C.I. Pigment Yellow 12)[CAS: 6358-85-6]. The study was performed according to OECD Guideline 405 “Acute Eye Irritation/Corrosion” Guidelines.

When chemical C. I. Pigment Yellow 12 was instilled into the eyes of each rabbit, no ocular lesions were observed. Hence, C. I. Pigment Yellow 12 (CAS: 6358-85-6) was considered as not irritating to the eye of rabbits.

Based on the available data for the target chemical as well as its structurally similar read across chemicals, and applying the weight of evidence approach, Hydrogen [2,4-dihydro-4-[(2 -hydroxy-5-nitrophenyl)azo]-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)][2-[(4,5-dihydro-3-methyl -5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be considered to be not irritating to eyes. Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Based on the available information, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) is not likely to cause any irritation to eyes and skin.

Hence, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) can be classified under the category “Not Classified” as per CLP regulation.