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

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. The study assumed the use of male and female Wistar rats. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate is predicted to be 658.866638184 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: Inhalation

1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate has very low vapor pressure (6.35E-008 Pa), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (as provided in section 7.2.3) is 7228.03 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to skin. Based on these considerations, the end point is considered as waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

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 the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (IUPAC name): 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- Common name: 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate
- Molecular formula: C18H21N6.C2H3O2
- Molecular weight: 380.4496 g/mol
- Smiles notation: 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

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

14 days

Frequency of treatment:

Daily

Remarks:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

658.867 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alterations were noted at the mentioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 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 ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and ( not "y") )  )  and ("z" and ( not "aa") )  )  and ("ab" and ( not "ac") )  )  and ("ad" and ( not "ae") )  )  and ("af" and ( not "ag") )  )  and ("ah" and ( not "ai") )  )  and ("aj" and "ak" )  )

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 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters 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 >> 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 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 >> 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 SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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: "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 OASIS v1.3

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion OR SN2 OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "h"

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

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 >> Acetates by Protein binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Multi Cyclic Hydrocarbons OR Phenylphenols by rtER Expert System ver.1 - USEPA

Domain logical expression index: "m"

Similarity boundary:Target: CC(=O)O{-}.N{+}1(C)C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Imine form - 1,3-H shift by Tautomers unstable

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Oxyphenistain (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "t"

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

Domain logical expression index: "u"

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

Domain logical expression index: "v"

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

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Tetrahydroquinoline/ Tetrahydroisoquinoline by Organic Functional groups

Domain logical expression index: "x"

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

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as Pyrimidine OR Saturated heterocyclic amine by Organic Functional groups

Domain logical expression index: "z"

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

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as Phenol OR Precursors quinoid compounds by Organic Functional groups

Domain logical expression index: "ab"

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

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as Alkane, branched with tertiary carbon by Organic Functional groups

Domain logical expression index: "ad"

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

Domain logical expression index: "ae"

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

Domain logical expression index: "af"

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

Domain logical expression index: "ag"

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

Domain logical expression index: "ah"

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

Domain logical expression index: "ai"

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

Domain logical expression index: "aj"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.67

Domain logical expression index: "ak"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.99

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate is predicted to be 658.866638184 mg/Kg bw/day.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. The study assumed the use of male and female Wistar rats. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate is predicted to be 658.866638184 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

658.867 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation, other

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of 1,4-dimethyl-5-[[4- [methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. The studies are as mentioned below:

Repeated dose toxicity: Oral

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate. The study assumed the use of male and female Wistar rats. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate is predicted to be 658.866638184 mg/Kg bw/day.

The predicted data for the target chemical is further supported by the data from read across chemical.

In a study by Halder et al ( Toxicology and Industrial Health, 1985) 28 days repeated dose oral toxicity study was performed to determine the toxic nature of structurally and functionally similar read across chemical light catalytic reformed naphtha (RA CAS no 67471 -63 -5; IUPAC name: Naphtha (petroleum), light catalytic reformed). The study was performed using using male Fischer 344 rats at dose levels of 0 (saline), 500 or 2000 mg/Kg/day for 28 days. The animals were doses daily for 5days/week. During the study period, the animals were observed for clinical signs, mortality, morbidity, body weight and organ weight changes, gross and histo-pathology.The test chemical doses were well tolerated but lethargy was the most prominent signs. The mean terminal body weights for all high-dose treatment group (2000 mg/Kg/day) was significantly reduced than the respective saline control group. Mean kidney weights gave no indication of nephrotoxicity. The most common pathologic findings were confined to the kidneys and stomachs. The kidney lesions generally consisted of discoloration and mottling, and may have been due to postmortem changes since they were mainly observed in the animals that died prematurely. The light catalytic-reformed naphtha induced a very weak nephrotoxic response at 2000 mg/Kg/day dose. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) forlight catalytic reformed naphtha is considered to be 500 mg/Kg/day during 28 days study conducted using male Fischer 344 rats.

Repeated dose toxicity: Inhalation

1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate has very low vapor pressure (6.35E-008 Pa), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (as provided in section 7.2.3) is 7228.03 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to skin. Based on these considerations, the end point is considered as waiver.

Based on the data available for the target chemical and its read across, 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate is not likely to be a toxicant upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across, 1,4-dimethyl-5-[[4-[methylbenzylamino]phenyl]azo]-1H-1,2,4-triazolium acetate (CAS no 84000 -82 -8) is not likely to be a toxicant upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.