9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium, salt with 4,5-dihydro-5-oxo-1-(4-sulphophenyl)-4-[(4-sulphophenyl)azo]-1H-pyrazole-3-carboxylic acid (3:1)

Endpoint summary

Description of key information

The skin sensitization potential of 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs and can be classified as non skin sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

Data is from OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Type of study:

Buehler test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

- Name of test material (IUPAC name): 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium
- Molecular formula: C28H31N2O3.1/3C16H9N4O9S2
- Molecular weight: 1796.09 g/mol
- Smiles notation: c1(C)c(cc2[o+]c3c(c(c4c(cccc4)C(OCC)=O)c2c1)cc(C)c(NCC)c3)NCC.C1([C@@H](\N=N/c2ccc(cc2)S([O-])(=O)=O)C(=NN1c1ccc(S([O-])(=O)=O)cc1)C([O-])=O)=O.c1(cc2c([o+]c3c(c2c2ccccc2C(OCC)=O)cc(c(NCC)c3)C)cc1NCC)C.c1(cc2c([o+]c3c(c2c2ccccc2C(OCC)=O)cc(c(NCC)c3)C)cc1NCC)C
- InChl: 1S/3C28H31N2O3.C16H12N4O9S2/c3*1-6-29-23-15-25-21(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;21-15-13(18-17-9-1-5-11(6-2-9)30(24,25)26)14(16(22)23)19-20(15)10-3-7-12(8-4-10)31(27,28)29/h3*9-16,29-30H,6-8H2,1-5H3;1-8,13H,(H,22,23)(H,24,25,26)(H,27,28,29)/q3*+1;/p-3/b;;;18-17-
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of induction:

not specified

Route:

epicutaneous, occlusive

Vehicle:

water

Concentration / amount:

No data available

Day(s)/duration:

No data available

Adequacy of challenge:

not specified

No. of animals per dose:

12

Details on study design:

No data available

Challenge controls:

No data available

Reading:

1st reading

Group:

test chemical

Dose level:

No data available

No. with + reactions:

0

Total no. in group:

12

Clinical observations:

no skin sensitization was observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

no skin sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 11 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 "o" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Chronic toxicity) AND Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as No alert found AND Non-specific AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    AND Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives AND SN1 AND SN1 >> Nucleophilic substitution on diazonium ions AND SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as No alert found AND SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Esters OR Inorganic Compound OR Schiff Bases-Azomethine OR Vinyl/Allyl Ethers by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines 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 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 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) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups 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 >> N-Hydroxylamines 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 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, 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 >> 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 Non binder, MW>500 OR Non binder, non cyclic structure 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 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 Acylation >> Direct Acylation Involving a Leaving group >> Azlactone 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 OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-pyrimidines 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 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: "m"

Referential boundary: The target chemical should be classified as 2-Oxyalkyl-1,2-ethanediol deriv. [HOCH2CH(OH)CO] OR Aliphatic 1,2,3-triol [-C(COH)(COH)C-OH] OR Aliphatic Carbon [C] OR Aliphatic-C=N-Aliphatic  OR Azomethine, aliphatic attach [-N=C] OR Carbonyl, aliphatic attach [-C(=O)-] OR Ether-alcohols [-OC(COH)CO-] OR Fused Aliphatic ring unit  OR Hydroxy, aliphatic attach [-OH] OR Imine, linear [-CH=NC-]  OR Multi alcohol  OR Oxygen, aliphatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Interpretation of results:

other: not sensitizing

Conclusions:

The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

Executive summary:

The skin sensitization potential of 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs and humans for target chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)and its structurally similar read across substancesBis(2-ethylhexyl)phthalate (CAS no: 117-81-7) and1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

The skin sensitization potential of 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

 

The European Chemicals Bureau (2008) and HSDB (2016) conductedMagnusson-Kligman guinea pig maximization testofstructurally similar read across substanceBis(2-ethylhexyl)phthalate (CAS no: 117-81-7)in female albino Dunkin-Hartley guinea pigs to assess its skin sensitization potential.The induction procedure consisted of an intradermal injection of the test material followed by a topical application 7 days later. The guinea pigs received intradermal injection (actually 3 injections) of 0.1 ml Freund’s adjuvant alone, 0.1 ml 10% DEHP in paraffin oil, and 0.05 ml 10% DEHP in paraffin oil emulsified with 0.05 ml Freund’s adjuvant into the skin of the shoulder region. The control group received 2 injections of Freund’s adjuvant only. For the topical application, a 2.2 cm patch of filter paper was wetted with 50% DEHP in paraffin oil and applied for 48 hours to the pre-treated area. The control group was not subjected to topical application. After rest period of 14 days, the animals were challenged topically at higher non irritating concentration of concentrations 50% DEHP. A 2.2 cm patch wetted with 50% DEHP was applied to a challenge site (on the right flank) of all animals for 24 hours. The degree of response was assessed 24 hours after removal of the challenge patch and rated. Any animal showing erythema at the challenge site was considered to have shown a positive response. Since there were no positive responses, the chemical Bis(2-ethylhexyl)phthalate (CAS no: 117-81-7)can be considered as not skin sensitizing to the guinea pigs’ skin.

 

 

The above results were further supported bya Human Repeat Insult Patch Testreported by theEuropean Chemicals Agency (ECHA, 2016) forstructurally similar read across substance1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) on skin of human volunteers (9/sex).Each volunteer were exposed to nine dermal applications of 0.5% DEHTP in acetone under semi-occlusive conditions over a three-week induction period. Following a two weeks rest period a challenge dose of 0.5% was applied to the skin. None of the volunteer showed any sign of skin sensitization. Hence the chemical 1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) was considered to be not sensitizing to the skin of human volunteers.

 

Thus on the basis of available data for thetarget chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)and its structurally similar read across substancesBis(2-ethylhexyl)phthalate (CAS no: 117-81-7) and1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) is unable to cause skin sensitization and considered as non skin sensitizer.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1) and its structurally similar read across substances Bis(2-ethylhexyl)phthalate (CAS no: 117-81-7) and1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.