Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatetungstatephosphate

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of C.I. Pigment red 81 was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. C.I. Pigment red 81 was predicted to be not sensitizing to the skin of male Hartley guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

data is from OECD QSAR toolbox v 3.3 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

Type of study:

other: Estimated data

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:

guinea pig

Strain:

Hartley

Sex:

male

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:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

20

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Clinical observations:

no dermal 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 9 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 ( not "q") )  )  and ("r" and "s" )  )

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 >> 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) >> 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) >> 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 >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids 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, 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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "j"

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 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: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester AND Diarylether AND Ether AND Heterocyclic compound AND Secondary amine AND Secondary mixed amine (aryl, alkyl) by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as 1,2-diol OR Alcohol OR Dialkylether OR Hydroxy compound OR Phosphoric acid derivative OR Phosphoric acid ester OR Primary alcohol OR Secondary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Aromatic amine AND Aryl AND Carboxylic acid ester AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Xanthene by Organic Functional groups

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.2

Interpretation of results:

other: not sensitizing

Conclusions:

C.I. Pigment red 81 was predicted to be not sensitizing to the skin of male Hartley guinea pigs.

Executive summary:

The skin sensitization potential of C.I. Pigment red 81 was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. C.I. Pigment red 81 was predicted to be not sensitizing to the skin of male Hartley guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:

In different studies,C.I. Pigment red 81has been investigated for potential for dermal sensitization to a greater or lesser extent. The studies are based on in vivo experiments in humans and guinea pigs along with predicted data for target chemicaland its functionally similar read across substances,D&C yellow 8(SSodium Fluorescien)[CAS: 518-47-8] 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.

The skin sensitization potential of C.I. Pigment red 81 was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. C.I. Pigment red 81 was predicted to be not sensitizing to the skin of male Hartley guinea pigs.

Guin JD(Contact Dermatitis, 2003: 49: 217–218) performed patch tests on human skin to ascertain the extent of dermal sensitization caused by thefunctionally similar read across substance,D&C yellow 8(SSodium Fluorescien)[CAS: 518-47-8].The dye was applied in Finn Chambers and read first at 2 or (more commonly) 3 days and again at 4–7 days. The reactions of the patients were graded as ‘?+ ‘ , ‘+’ and ‘++’ categories. 16 patients were tested with the dye.

Only one positive reaction was observed of 16 patients tested.

Hence, D&C yellow 8 can be considered as a non- sensitizer in humans

These results are 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 sensitization 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].The study was performed as per OECD 406 Guidelines. 10 female were used for and 5 female Himalayan spotted guinea pigs were used in the test and control groups respectively. In induction treatment, 10 females in test group, 5 females in control group were used. Animals were induced with intradermal induction of Freund´s Complete Adjuvant (FCA) and physiological saline (1:1), test item at 5% in 1 % CMC and 5 % dilution of the test item in 1% CMC in a 1:1 mixture with FCA / physiological saline on day 1. After 7 days, epidermal induction of sensitization (day 8) was conducted under occlusion with the test item at 50 % in 1 % CMC for 48 hours.The challenge was performed at day 22 by application of the test item at 10 % in 1 % CMC under occlusive patch for 24 h at a different part of the skin. Observations were made at 24 and 48 hours removal of the dressing.

After challenge exposure, no skin reactions were observed. Hence, sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate was considered to be non sensitizing to theHimalayan spotted albino guinea pigs.

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 sensitizing to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Available data for C.I. Pigment red 81 indicates that it is not likely to cause any dermal sensitization to skin.

C.I. Pigment red 81 can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.