Registration Dossier

Skin Irritation:

The dermal irritation potential of C.I. Pigment red 81 was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

C.I. Pigment red 81 was estimated to be not irritating to the skin of rabbits.

Based on the estimated result; C.I. Pigment red 81 can be considered not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation..

Eye Irritation:

The ocular irritation potential of C.I. Pigment red 81 was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

C.I. Pigment red 81 was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated result; C.I. Pigment red 81 can be considered not irritating to the 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 adequate and reliable documentation / justification

Justification for type of information:

data is from OECD QSAR toolbox v3.3 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 v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): C.I. Pigment red 81
- IUPAC name: Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatetungstatephosphate
- Molecular formula: C28H31N2O3.x-Unspecified
- Molecular weight: 443.5639 g/mol
- Smiles: CCNc1cc2c(cc1C)c(c3cc(c(cc3[o+]2)NCC)C)c4ccccc4C(=O)OCC
- InChI: 1S/C28H31N2O3/c1-6-29-23-15-25-21(13-17(23)4)27(19-11-9-10-12-20(19)28(31)32-8-3)22-14-18(5)24(30-7-2)16-26(22)33-25/h9-16, 29-30H,6-8H2,1-5H3/q+1
- Substance type: Organic
- Physical state: Solid powder (dark pink)

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

no data available

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

3

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 signs of irritation observed

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 ( not "h") ) ) and ("i" and ( not "j") ) ) and "k" ) and ("l" and ( not "m") ) ) and ("n" and ( not "o") ) ) and "p" ) and ("q" and ( not "r") ) ) and ("s" and "t" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Chronic toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Esters by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Esters by Aquatic toxicity classification by ECOSAR

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 >> 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 >> 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 AN2 >> Schiff base formation >> Dicarbonyl compounds 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 AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols 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 (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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 >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 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 >> 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 >> Nitroaniline Derivatives 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 >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes 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 >> Haloalkane Derivatives with Labile Halogen 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 OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates 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 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Sultones OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline 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 No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates, Isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides) OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-Acylated heteroaromatic amines OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion OR SN2 OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters 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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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 Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical 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 OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Carbon, two phenyl attach [-C-] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Aliphatic Oxygen, two aromatic attach [-O-] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Carbonyl, olefinic attach [-C(=O)-] AND Carbonyl, one aromatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, two olefinic attach [-O-] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as 2-Oxyalkyl-1,2-ethanediol deriv. [HOCH2CH(OH)CO] OR Acyclic carbonyl, two aromatic attach OR Alcohol, olefinic attach [-OH] OR Aliphatic 1,2,3-triol [-C(COH)(COH)C-OH] OR Aliphatic Carbon [C] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aliphatic-C=N-Aliphatic OR Alpha-diether [C-O-C-O-C] OR Amino Triazine/Pyrazine/Pyrimidine OR Amino, aliphatic attach [-NH-] OR Aromatic Nitrogen OR Azomethine, aliphatic attach [-N=C] OR Carbonate, aliphatic attach [-OC(=O)O-] OR Carbonyl, aliphatic attach [-C(=O)-] OR Carbonyl, non-cyclic, two aromatic attach [-C(=O)-] OR Ether-alcohols [-OC(COH)CO-] OR Fused Aliphatic ring unit OR Hydroxy, aliphatic attach [-OH] OR Hydroxy, aromatic attach [-OH] OR Imine, linear [-CH=NC-] OR Multi alcohol OR Nitrogen, two or tree olefinic attach [>N-] OR Ortho-hydroxy to misc. -CO- OR Oxygen, aliphatic attach [-O-] OR Oxygen, one aromatic attach [-O-] OR Sym-Triazine ring by Organic functional groups (US EPA)

Domain logical expression index: "p"

Similarity boundary:Target: CCNc1cc2c(cc1C)C(c1ccccc1C(=O)OCC)c1cc(C)c(NCC)cc1O2
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

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 Phthalate esters (Testicular toxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.19

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.39

Interpretation of results:

other: not irritating

Conclusions:

C.I. Pigment red 81 was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of C.I. Pigment red 81 was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

C.I. Pigment red 81 was estimated to be not irritating to the skin of rabbits.

Based on the estimated result; C.I. Pigment red 81 can be considered 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:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Predicted data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): C.I. Pigment red 81
- IUPAC name: Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatetungstatephosphate
- Molecular formula: C28H31N2O3.x-Unspecified
- Molecular weight: 443.5639 g/mol
- Smiles: CCNc1cc2c(cc1C)c(c3cc(c(cc3[o+]2)NCC)C)c4ccccc4C(=O)OCC
- InChI: 1S/C28H31N2O3/c1-6-29-23-15-25-21(13-17(23)4)27(19-11-9-10-12-20(19)28(31)32-8-3)22-14-18(5)24(30-7-2)16-26(22)33-25/h9-16, 29-30H,6-8H2,1-5H3/q+1
- Substance type: Organic
- Physical state: Solid powder (dark pink)

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:

0.1 ml

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

6

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 signs of irritation

Estimation method: Takes mode value from the 8 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 ("n" and ( not "o") ) ) and "p" ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and "w" ) and ("x" and "y" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Chronic toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Esters by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Esters by Aquatic toxicity classification by ECOSAR

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 >> 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 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 AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols 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 via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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 SN1 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 >> 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 >> Nitroaniline Derivatives 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 >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes 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 >> Haloalkane Derivatives with Labile Halogen 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 OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates 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 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Sultones OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline 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 No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates, Isothiocyanates OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides) OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives OR Acylation >> Direct acylation involving a leaving group >> Carbamates OR Acylation >> Direct acylation involving a leaving group >> N-Acylated heteroaromatic amines OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion OR SN2 OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters 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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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 Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> Miscellaneous Alkyl 2-halo alkenoates (SN2) OR Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) by Protein binding potency

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "n"

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: "o"

Referential boundary: The target chemical should be classified as Organic sulphonic salts OR Thiazoles and thiazolidines by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Carbon, two phenyl attach [-C-] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Aliphatic Oxygen, two aromatic attach [-O-] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Carbonyl, olefinic attach [-C(=O)-] AND Carbonyl, one aromatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Oxygen, two olefinic attach [-O-] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as 2-Oxyalkyl-1,2-ethanediol deriv. [HOCH2CH(OH)CO] OR Acyclic carbonyl, two aromatic attach OR Alcohol, olefinic attach [-OH] OR Aliphatic 1,2,3-triol [-C(COH)(COH)C-OH] OR Aliphatic Carbon [C] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aliphatic-C=N-Aliphatic OR Alpha-diether [C-O-C-O-C] OR Amino Triazine/Pyrazine/Pyrimidine OR Aromatic Nitrogen OR Azomethine, aliphatic attach [-N=C] OR Carbonate, aliphatic attach [-OC(=O)O-] OR Carbonyl, aliphatic attach [-C(=O)-] OR Carbonyl, non-cyclic, two aromatic attach [-C(=O)-] OR Ether-alcohols [-OC(COH)CO-] OR Fused Aliphatic ring unit OR Hydroxy, aliphatic attach [-OH] OR Hydroxy, aromatic attach [-OH] OR Imine, linear [-CH=NC-] OR Multi alcohol OR Nitrogen, two or tree olefinic attach [>N-] OR Ortho-hydroxy to misc. -CO- OR Oxygen, aliphatic attach [-O-] OR Oxygen, one aromatic attach [-O-] OR Sym-Triazine ring by Organic functional groups (US EPA)

Domain logical expression index: "w"

Similarity boundary:Target: CCNc1cc2c(cc1C)C(c1ccccc1C(=O)OCC)c1cc(C)c(NCC)cc1O2
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.18

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 10.4

Interpretation of results:

other: not irritating

Conclusions:

C.I. Pigment red 81 was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of C.I. Pigment red 81 was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

C.I. Pigment red 81 was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated result; C.I. Pigment red 81 can be considered not irritating to the 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,C.I. Pigment red 81 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 chemicaland its functionally similar read across substances, Rhodamine B[CAS:81-88-9] and C.I. Acid Red 52(sodium 4-[3,6-bis(diethylamino)-2,7 -dimethylxanthenium-9-yl]benzene-1,3-disulfonate) [CAS: 3520-42-1].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the skin irritation potential was estimated forC.I. Pigment red 81.C.I. Pigment red 81 was estimated to be not irritating to rabbit skin.

This result is supported by the experimental study performed by JAMES E. FULTON, JR (J. Soc. Cosmet. Chem., 40, 321-333 (November/December), 1989), to assess the dermal irritation potential of functionally similar read across substance, Rhodamine B[CAS:81-88-9].Rhodamine B was mixed in propylene glycol at a 9 to 1 dilution for testing unless otherwise indicated (10% concentration). A colony of New Zealand albino rabbits that have genetically good ears and free from mites were used. Three rabbits, weighing two to three kilograms, were used for each assay. Animals were housed singly in suspended cages and fed Purina Rabbit Chow and water ad libitum. Animals were maintained on a 12-hour light and 12-hour dark cycle. A dose of 1 ml of the test material was applied and spread once daily to the entire inner surface of once for five days per week for two weeks. The opposite untreated ear of each animal served as an untreated control. The irritancy produced by repeated application of the chemical on the surface epidermis in the rabbit ear is evaluated on a scale of 0 to 5. The grades are summarized as follows:

0 = No irritation; 1 = few scales, no Erythema; 2 = diffuse scaling, no Erythema; 3 = Generalized scaling with Erythema; 4 = Scaling, Erythema and Edema; 5 = Epidermal necrosis and slough.

Rhodamine B falls under Grade 0 (no irritation observed).Hence it can be concluded that Rhodamine B was not irritating to rabbit ears.

These results are also supported by the experimental study summarized in THE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS (SCCNFP) /0803/ 23 April 2004; to assess the dermal irritation potential of functionally similar read across substance, C.I. Acid Red 52(sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate) [CAS: 3520-42-1].C.I. Acid Red 52 was applied topically at concentration of500mg to one intact and one additionally scarified flank of each of6Albino-Himalaya rabbits under occlusion for 24 hours exposure period. The scoring of skin reactions was performed immediately, 48 hours and 73 hours after removal of the occlusive patch.

Since the test chemical did not elicit any skin reactions at the application site of any animal, C.I. Acid Red 52 (CAS No: -3520-42-1) was considered to be non irritant on rabbits’ skin.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,C.I. Pigment red 81 was 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,C.I. Pigment red 81has 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 chemicaland its functionally similar read across substances, C.I. Acid Red 52(sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3 -disulfonate) [CAS: 3520 -42-1] and 2'-anilino-6'-(diethylamino)-3'-methylspiro[isobenzofuran-1(3H),9'-[9H]xanthene]-3-one[CAS: 29512-49-0].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the ocular irritation potential was estimated forC.I. Pigment red 81.C.I. Pigment red 81 was estimated to be not irritating to New Zealand White rabbit eyes.

This result is supported by the experimental study summarized in THE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS (SCCNFP) /0803/ 23 April 2004; to assess the dermal irritation potential of functionally similar read across substance, C.I. Acid Red 52(sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3 -disulfonate) [CAS: 3520-42-1]. 0.1 g of Acid Red 52 was instilled into the conjunctival sac of the left eye of six Albino-Himalaya rabbits. The right eye remained untreated and served as reference control. Scoring of irritation was performed 1, 7, 24, 48 and 72 hours after application with a magnifying glass. After 24 hours all eyes were rinsed with physiological saline.Because of colour interference, an exact judgement was not possible in the area of the cornea (1 and 7 hours after post application).

The overall irritation score after 72 hours was as follows: Cornea = 0.00, iris = 0.00, conjunctiva redness = 0.67, conjunctiva chemosis = 0.06.

Hence it can be considered that Acid Red 52 was not irritating to rabbit eyes.

These results are also supported by the experimental study summarized in Robust Summary & Test Plans: Color Former Category: Robust Summary, EPA HPV Challenge Color Former Category,2 May 2003; for the functionally similar read across substance, 2'-anilino-6'-(diethylamino)-3'-methylspiro[isobenzofuran-1(3H),9'-[9H]xanthene]-3-one[CAS: 29512-49-0]. The study was performed as per OECD 405 Guidelines. 3 male New Zealand White rabbits, thirteen to sixteen weeks old were used for the study.

The eyes of each animal were examined prior to administration instillation of the test substance to ensure that there was no pre-existing corneal damage, iridial or conjunctival inflammation. One animal was treated in advance of the others, to ensure that if a severe response was produced, no further animals would be exposed. Approximately 70 mg of the test substance, the weight occupying a volume of 0.1 ml, was placed into the lower everted lid of one eye of each animal. The eyelids were then gently held together for one second before releasing. The contralateral eye remained untreated as control. Examination of the eyes was made after 1 hour and 1, 2, 3 days (equivalent to 24, 48, and 72 hours) after instillation. Additional observations were made for two animals four days after treatment. : Observation of the eyes was aided by the use of a handheld light. Ocular irritation was assessed on the cornea, iris, conjunctivae, and chemosis. There were no signs of toxicity or ill health in any rabbit during the observation period. No corneal damage or iridial inflammation was observed. Transient hyperemia of blood vessels to a diffuse crimson coloration of the conjunctivae with slight swelling or partial eversion of the eyelids was observed in all animals. These responses had resolved completely by two days after instillation.

Since, the effects were completely resolved by 2 days, 2'-anilino-6'-(diethylamino)-3'-methylspiro[isobenzofuran-1(3H),9'-[9H]xanthene]-3-one can be considered to be not irritating to New Zealand White rabbit eyes.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,C.I. Pigment red 81 was not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Available data for C.I. Pigment red 81 indicates that it is not likely to cause severe irritation or corrosion to skin and eyes.

Hence, C.I. Pigment red 81 can be classified under the category “Not Classified” for skin and eyes as per CLP regulation.