1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was predicted to be non sensitizing to the skin of male and female Dunkin- Hartley guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

data is from OECD QSAR toolbox v3.3 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: 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- IUPAC name: 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- Molecular formula: C18H21N6.C2H3O2
- Molecular weight: 380.4496 g/mole
- Smiles : CC(=O)[O-].Cn1cn[n+](c1/N=N/c2ccc(cc2)N(C)Cc3ccccc3)C
- Inchl: 1S/C18H21N6.C2H4O2/c1-22(13-15-7-5-4-6-8-15)17-11-9-16(10-12-17)20-21-18-23(2)14-19-24(18)3;1-2(3)4/h4-12,14H,13H2,1-3H3;1H3,(H,3,4)/q+1;/p-1
- Substance type: Organic
- Physical state: liquid

Species:

guinea pig

Strain:

Dunkin-Hartley

Sex:

male/female

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:

10

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Other effects / acceptance of results:

no data available

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Clinical observations:

no signs of sensitization 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 8 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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 >> 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation 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 >> N,N-Dialkyldithiocarbamate Derivatives OR Radical >> Generation of reactive oxygen species >> Thiols 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) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines 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 after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Direct acting epoxides formed after metabolic activation 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 >> 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 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes AND SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine AND SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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 Acylation >> Ring Opening Acylation OR Acylation >> Ring Opening Acylation >> alpha-Lactams OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR SN2 OR SN2 >> SN2 reaction at a sulphur atom OR SN2 >> SN2 reaction at a sulphur atom >> Disulfides OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halocarbonyls by Protein binding by OECD

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group C Surface Tension > 62 mN/m AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group C Melting Point > 55 C AND Group C Molecular Weight > 350 g/mol AND Group C Vapour Pressure < 0.0001 Pa AND Group CN Melting Point > 180 C AND Group CN Molecular Weight > 290 g/mol AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as (!Undefined)Group All log Kow < -3.1 OR (!Undefined)Group All log Kow > 9 OR (!Undefined)Group All Melting Point > 200 C OR (!Undefined)Group CNHal Lipid Solubility < 4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 400 g/kg OR (!Undefined)Group CNS Surface Tension > 62 mN/m OR Group All log Kow < -3.1 OR Group All log Kow > 9 OR Group C Aqueous Solubility < 0.0001 g/L OR Group CN Aqueous Solubility < 0.0001 g/L OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN log Kow > 5.5 OR Group CN Molecular Weight > 540 g/mol OR Group CNHal Aqueous Solubility < 0.001 g/L OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNHal log Kow > 3.8 OR Group CNHal Molecular Weight > 370 g/mol OR Group CNHal Molecular Weight > 380 g/mol OR Group CNS log Kow < 0.5 OR Group CNS Melting Point > 120 C OR Group CNS Melting Point > 50 C OR Group CNS Molecular Weight > 620 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkylalkanol-amines OR Aromatic amines OR Esters including acrylic and methacrylic esters OR Ketones OR Phenols OR Quaternary organic ammonium compounds OR Tertiary aliphatic amine by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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: "r"

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

Domain logical expression index: "s"

Similarity boundary:Target: CC(=O)O{-}.N{+}1(C)C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Similarity boundary:Target: CC(=O)O{-}.N{+}1(C)C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

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 Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Aromatic-N-C-Aromatic  AND Azo [-N=N-] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen {v+5}, nitrogen attach AND Nitrogen, hydrogen attach {v+5} AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Oxygen, aliphatic attach [-O-] by Organic functional groups (US EPA)

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Aromatic-N-C-Aromatic  AND Azo [-N=N-] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen {v+5}, nitrogen attach AND Nitrogen, hydrogen attach {v+5} AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Nitrogen, two or tree olefinic attach [>N-] by Organic functional groups (US EPA)

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Aromatic-N-C-Aromatic  AND Azo [-N=N-] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen {v+5}, nitrogen attach AND Nitrogen, hydrogen attach {v+5} AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Aldehyde, aliphatic attach [-N-CHO] OR Aliphatic Carbon, two phenyl attach [-C-]  OR Aliphatic Carbon, two phenyl attach [-CH2-]  OR Amide, aliphatic attach [-C(=O)N] OR Amino, aliphatic attach [-NH-] OR Amino, aliphatic attach [-NH2] OR Amino-carbonyl compound [NCC(=O)-C] OR Ester, aliphatic attach [-C(=O)O] OR Hydroxy, aliphatic attach [-OH] OR Oxygen, one aromatic attach [-O-] OR Tertiary Carbon OR Urea [-OC(=O)N-] by Organic functional groups (US EPA)

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.572

Domain logical expression index: "ab"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.75

Interpretation of results:

other: not sensitizing

Conclusions:

1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was predicted to be non sensitizing to the skin of male and female Dunkin- Hartley guinea pigs.

Executive summary:

The skin sensitization potential of 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was predicted to be non sensitizing to the skin of male and female Dunkin- Hartley guinea pigs.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:

Several studies have been investigated to assess the dermal sensitization potential of 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. These studies include in vivo as well as predicted results for the target and its structurally similar read across substances, 2-[[4-(Di-methyl amino)phenyl] azo]-1,3 -dimethyl-1H-imidazolium chloride [CAS: 77061-58-6] and 2-[(4-Aminophenyl)azo]-1,3-dimethyl-1H-imidazolium chloride [CAS: 97404-02-9].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The skin sensitization potential of 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate was predicted to be non sensitizing to the skin of male and female Dunkin- Hartley guinea pigs.

This result is supported by the Magnusson and Kligman Guinea pig maximisation test summarized in Opinion of the SCCNFP on Basic red 51 during the 25th plenary meeting 2003; for thestructurally similar read across substance, 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride [CAS: 77061-58-6]. The test was performed according to OECD guideline 406.

The test material was subjected to the guinea pig by intadermal and topical induction. In intradermal induction 5% aqueous solution with and without

Freund’s Complete Adjuvant was subjected to test animal whereas, in topical induction , 50% preparation of test material under occlusion for 48 hours. Controls received vehicle only.

After 14 days of induction challenge dode was introduced on the guinea pigs by exposing 25% aqueous dilution of the test substance for 24 hours under occlusion. Animals were observed after 24 and 48 hrs

None of the animals of the control or test group were observed with skin reactions after challenge with a non-irritating preparation of 25% of the test material. Hence,2-[[4 -(Di-methyl aminophenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was considered to be not sensitizing to guinea pig skin.

These results are further supported by the experimental study summarized in Basic Orange 31 (COLIPA n° B118) European Commission (EC) - Scientific Committee on Consumer Safety (SCCS) 2010; for the structurally similar read across substance, 2-[(4-Aminophenyl)azo]-1,3-dimethyl-1H-imidazolium chloride [CAS: 97404-02-9]. The test was conducted as per OECD 406.

The test animals were subjected as a intradermal and topical induction with the concentration 5% aqueous solution with Freund’s Complete Adjuvant and 50% dilution of test material under occlusion for 48 hours respectively, Controls received vehicle only. Skin pretreated with 10% sodium lauryl sulphate in liquid paraffin. Challenge treatment was subjected via epidermal application for 14 days by exposing 50% aqueous dilution of the test substance 24 hours, occlusion.

Animals were examined 24 and 48 hours after removal of the patches for signs of erythema and oedema. Brown-red discoloration was noted directly after removal of patches. To remove discoloration, all animals were depilated 3 hours prior to challenge reading with a depilatory cream.

None of the animals of the control or test group were observed with skin reactions after challenge with a non-irritating dilution of 50 % of the test material.

Hence, 2-[(4-Aminophenyl)azo]-1,3-dimethyl-1H-imidazolium chloride is considered to benot irritating to guinea pigs skin.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. 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 for1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate suggests that it is not likely to cause any dermal sensitization to skin.

1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.