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

Skin irritation:

The dermal irritation 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 logPow 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 irritating to the skin of New Zealand White rabbits. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1) can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

 

Eye irritation:

The ocular irritation 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 logPow 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 irritating into the eyes of New Zealand White rabbits. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

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 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

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:

other: rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

not specified

Duration of treatment / exposure:

4 hour

Observation period:

7 days

Number of animals:

3

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no skin irritation was observed.

Estimation method: Takes mode value from the 10 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 ("j" and ( not "k") )  )  and "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) 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 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 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) >> p-Substituted Mononitrobenzenes 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 metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation 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, 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Lysine peptide depletion

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Vinylene dicarboxylates by DPRA Lysine peptide depletion

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "j"

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: "k"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Similarity boundary:Target: CCNc1cc2c(cc1C)C(c1ccccc1C(=O)OCC)c1cc(C)c(NCC)cc1O2
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Phthalate esters (Testicular toxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as 1-phenoxy-benzene AND Aromatic mono- and dialkylamine AND H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group OR Oxolane by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 6.15

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.23

Interpretation of results:

other: not irritating

Conclusions:

The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation 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 logPow 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 irritating to the skin of New Zealand White rabbits. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

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 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

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:

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:

No data available

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

7 days

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:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no eye irritation was observed.

Estimation method: Takes 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 "j" )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

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) >> p-Substituted Mononitrobenzenes 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 metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation 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, 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 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, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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: "l"

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

Domain logical expression index: "m"

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: "n"

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-] OR Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.37

Interpretation of results:

other: not irritating

Conclusions:

The substance 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not irritating into the eyes of New Zealand White rabbits. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)can be considered to be not irritating to eye.

Executive summary:

The ocular irritation 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 logPow 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 irritating into the eyes of New Zealand White rabbits. Based on the estimated result 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

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 dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits 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 substancesIsopropyl myristate (CAS no: 110-27-0)andRhodamine B(CAS No: 81-88-9).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for test chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1) .The chemical 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)was estimated to be not irritating to skin of New Zealand White rabbits.

 

The JAMES E. FULTON, JR (1989) conducted a test by using a single rabbit ear to indicate the Comedogenicity and irritancy ofstructurally similar read across substanceRhodamine B(CAS No: 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. Rhodamine B falls under Grade 0 (no irritation observed). Hence it can be concluded that Rhodamine B(CAS No: 81-88-9).was not irritating to rabbit ears.

The above results were further supported by theprimary skin irritation study conducted bythe Cosmetic Ingredients Review(CIR) Expert Panel(1982)for structurally similar read across substanceIsopropyl myristate (CAS no: 110-27-0)in 15 subjects to assess the degree of skin irritancy caused by the chemical.In this study, each subject received undiluted Isopropyl myristate for 24 hours under occlusive condition and later observed for adverse skin effects.Since all the observations for skin irritation were negative, the chemical Isopropyl myristate (CAS no: 110-27-0)was considered as not irritatingto the human’s skin.

 

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 substancesIsopropyl myristate (CAS no: 110-27-0)andRhodamine B(CAS No: 81-88-9),it can be concluded thatchemical 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

Eye irritation:

In different studies,the test chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)has been investigated for potential for ocular irritationto a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)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;

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the eye irritation potential was estimated for test chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1).The chemical 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1) was estimated to be not irritating to eye of New Zealand White rabbits.

 

The European Chemicals Bureau (2008) and HSDB (2016) examined thelocal eye irritative potential ofstructurally similar read across substanceBis(2-ethylhexyl)phthalate (CAS no: 117-81-7)in threemale Little White Russianrabbits’ eye in accordance with OECD guideline 405.During the study, each rabbit received volume of 0.1 ml of into the conjunctival sac of in the right eye. The left eye served as control. The ocular lesions were scored after 1, 24, 48, and 72 hours, and after 6 days of application, using the grading system of the OECD guideline.At 1 hour, the conjunctivae of all three rabbits showed mild redness and one rabbit showed mild discharge. No conjunctival reactions were observed at the later observation times. All observations for chemosis, corneal opacity and lesions of the iris were negative.Hence the chemical Bis(2-ethylhexyl)phthalate (CAS no: 117-81-7)can be considered as not irritatingto the threemale Little White Russianrabbits’ eye.

 

The above results were further supported by the experimental study reported byEuropean Chemicals Agency (ECHA, 2016) forstructurally similar read across substance1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) in three (1 male and 2 female) New Zealand white rabbits according to OECD guideline 405.The undiluted1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate was installed into the one eye of each rabbit for 4 hours and observations were made for 72 hours following application. No corneal opacity or iritis was observed during the study. Conjunctivitis and redness were reported up to 48 hours after administration. All reported effects were fully reversible within 72 hours. Since all the effects were cleared within 72 hours, the chemical 1,4-bis(2-ethylhexyl) benzene-1,4-dicarboxylate (CAS No: 6422-86-2) can be considered asnot irritatingto theNew Zealand whiterabbits’ eye.

 

 

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 eye irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

The skin and eye irritation potential of test chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)and its structurally similar read across substanceswere observed in various studies. The results obtained from these studies indicate that the chemical9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)is unlikely to cause skin and eye irritation. Hence9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethylxanthylium (CAS No: 65138-66-1)can be classified under the category “Not Classified” for skin and eye as per CLP.