Registration Dossier

Skin irritation:

The dermal irritation potential of 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloridewa s estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Eye irritation:

The ocular irritation potential of 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloridewa s estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was estimated to be not irritating to the eye of New Zealand White rabbits.

Based on the estimated results, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to eye and can be classified under the category “Not Classified” as per CLP regulation.

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from safety assessment report

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Principles of method if other than guideline:

To assess dermal irritation potential of 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride on New Zealand White Rabbits.

GLP compliance:

not specified

Specific details on test material used for the study:

IUPAC name: 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride
- Name of test material (as cited in study report): Basic Red 51
- Molecular formula (if other than submission substance): C13H18ClN5
- Molecular weight (if other than submission substance): 279.6 g/mol
- Substance type: organic
- Physical state: Powder
- Purity:97.2% by UV-VIS ; 98.8% by HPLC
- Impurities (identity and concentrations): approx 2%
InChI :1S/C13H18N5.ClH/c1-16(2)12-7-5-11(6-8-12)14-15-13-17(3)9-10-18(13)4;/h5-10H,1-4H3;1H/q+1;/p-1
Smiles :c1([n+](ccn1C)C)\N=N\c1ccc(cc1)N(C)C.[ClH-]

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

sex:Male and female

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5g

Duration of treatment / exposure:

4 hrs

Observation period:

0.5, 1, 24, 48 and 72 hours

Number of animals:

Total = 3
1 male, 2 females

Details on study design:

TEST SITE
- Area of exposure: back and flanks (6.25cm2)
- % coverage: semi-occlusive dressing.
- Type of wrap if used: No data

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data
- Time after start of exposure: 4 hrs
SCORING SYSTEM: primary irritation index

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No erythema or oedema was observed

Interpretation of results:

other: Not irritating

Conclusions:

2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was applied on the back and flank of New Zealand white Rabbit in concentration 0.5 g. No erythema or oedema was observed . The primary irritation index was 0.0. Hence , 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was considered to be not irritating to rabbit skin.

Executive summary:

2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was used as a test material to evaluate skin irritation potential of New Zealand white Rabbit . The study was conducted according to guideline 404 (1981). The test material was applied on the clipped back and flanks of the rabbits to an area of 6.25 cm²under a semi-occlusive dressing. The patches were removed after 4 hours and observations made at 0.5, 1, 24, 48 and 72 hours after removal.

No erythema or oedema was observed. The primary irritation index was 0.0. Hence, 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was considered to be not-irritating to the rabbit skin.

Endpoint conclusion:

no adverse effect observed (not irritating)

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 predicted using 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 was done by using OECD QSAR toolbox v3.3,

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- IUPAC name: 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride
- Molecular formula: C18H21N6Cl
- Moleclar weight: 356.8589 g/mol
- Substance type: Organic
- Smiles: Cc1cn[n+](n1/N=N/c2ccc(cc2)N(C)Cc3ccccc3)C.[Cl-]
- Inchi: 1S/C18H21N6.ClH/c1-15-13-19-23(3)24(15)21-20-17-9-11-18(12-10-17)22(2)14-16-7-5-4-6-8-16;/h4-13H,14H2,1-3H3;1H/q+1;/p-1/b21-20+;

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:

No data available

Duration of post- treatment incubation (in vitro):

No data available

Number of animals or in vitro replicates:

No data available

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: Not speciified

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No indication of ocular irritation estimated

Estimation method: Takes mode value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

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

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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR 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: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Similarity boundary:Target: CN{+}1(.Cl{-})C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: CN{+}1(.Cl{-})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: "m"

Referential boundary: The target chemical should be classified as Amine AND Anion AND Aromatic compound AND Cation AND Heterocyclic compound AND Tertiary amine AND Tertiary mixed amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Hydroperoxide OR Hydroxy compound OR Ketone OR Lactam OR Nitrile OR Oxime OR Peroxide OR Primary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "o"

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 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: "p"

Referential boundary: The target chemical should be classified as Olefinic carbon [=CH2] by Organic functional groups (US EPA)

Domain logical expression index: "q"

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 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: "r"

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: "s"

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 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: "t"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [C] by Organic functional groups (US EPA)

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 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 Amino, aliphatic attach [-NH2] by Organic functional groups (US EPA)

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Overlapping groups AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups (nested)

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Piperidine by Organic Functional groups (nested)

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Amidine AND Ammonium salt AND Aromatic amine AND Aryl AND Azo AND Benzyl AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "z"

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

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C 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: "ab"

Referential boundary: The target chemical should be classified as Group CNHal Aqueous Solubility < 0.001 g/L OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNHal log Kow > 3.8 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ae"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Aliphatic halogen OR Aliphatic N-nitro group OR Aromatic mono- and dialkylamine by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ag"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.593

Domain logical expression index: "ah"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.5

Interpretation of results:

other: Not irritating

Conclusions:

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was considered to be not irritating to rabbit eye.

Executive summary:

The ocular irritation potential of 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloridewa s estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was estimated to be not irritating to the eye of New Zealand White rabbits.

Based on the estimated results, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to eye and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin irritation :

In different studies, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with human data for target chemical and its structurally similar read across substance 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride (77061-58-6) and closely related read across substance 1,3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) . The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The dermal irritation potential of 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloridewa s estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

The above estimated data was supported by the experimental result summarized in Hazardous Substances Data Bank (HSDB) for caffeine U.S National Library of Medicine 2017 for the closely related read across substance 1,3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

1,3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione was used as a test material to evaluate its skin irritation potential onWhite Vienna rabbits. The test material was applied on the skin of rabbit in the concentration 500mg 50 % (w/w) aqueous solution in a semiocclusive condition for 4 hrs. the application patches were removed, and the application sites were washed with water and Lutrol/water

(1/1). The skin was scored at 30-60 minutes after removal of the patches and at 24, 48, and 72 h.

No signs of irritation were observed; irritation indices (erythema and edema) were 0 in each animal at each reading time. Hence,1,3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione is considered to be not irritating to rabbit skin.

The above result was supported by experimental study summarized in Opinion of the SCCNFP on Basic red 51 during the 25th plenary meeting 2003 for the structurally similar read across substance 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride (77061-58-6).

2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was used as a test material to evaluate skin irritation potential of New Zealand white Rabbit . The study was conducted according to guideline 404 (1981). The test material was applied on the clipped back and flanks of the rabbits to an area of 6.25 cm2under a semi-occlusive dressing. The patches were removed after 4 hours and observations made at 0.5, 1, 24, 48 and 72 hours after removal.

No erythema or oedema was observed. The primary irritation index was 0.0. Hence, 2-[[4-(Di-methyl amino)phenyl] azo]-1,3-dimethyl-1H-imidazolium chloride was considered to be not-irritating to the rabbit skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified.”

Eye irritation:

In different studies, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with human data for target chemical and its structurally similar read across substance Benzyldimethylamine(103-83-3) and closely related read across substance 1-phenylethyl acetate(93-92-5) . The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The ocular irritation potential of 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloridewa s estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride was estimated to be not irritating to the eye of New Zealand White rabbits.

Based on the estimated results, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to eye and can be classified under the category “Not Classified” as per CLP regulation.

The above estimated result was supported by experimental data summarized in GESTIS - Substance Database (Information system on hazardous substances of the Berufsgenossenschaften), 2017 for the structurally similar read across substance Benzyldimethylamine(103-83-3)

The ocular irritation potential of Benzyldimethylamine was assessed in Rabbits.

Five μl of the test chemical was instilled in the conjunctival sac of the rabbits (number not mentioned) for 24 hours. The animals were observed for signs of irritation till 7 days.

Inflammation of the conjunctiva and the iris in rabbit eyes after an exposure period of 24 hours, accompanied by a severe damage of large areas of the cornea was observed in the test animals. These effects were completely reversible in 7 days.

Since the effects were fully reversible, benzyldimethylamine can be considered to be not irritating to eyes.

The above result was supported by experimental data summarized in Food and cosmetology volume 14 page no.611 1976 for the closely related read across substance 1-phenylethyl acetate(93-92-5) .

1-phenylethyl acetate was used as a test material to evaluate ocular irritation potential on rabbits. No ocular irritation was observed. Hence, 1-phenylethyl acetate was considered to be not irritating to rabbit eye.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to eye.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified.”

Based on the available data for the target and read across substances and applying the weight of evidence approach, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride can be considered to be not irritating to skin and eye.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified.”