Registration Dossier

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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride. 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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride is predicted to be 260.350006104 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

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride has very low vapor pressure (2.31E-007 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 for repeated inhalation toxicity was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (as provided in section 7.2.3) is >2000 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 for repeated dermal toxicity is considered as waiver.

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 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:

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:

91 (male rats) and 92 days (female rats)

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:

260.35 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 5 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((((("a" or "b" ) and "c" ) and "d" ) and ("e" and ( not "f") ) ) and ("g" and ( not "h") ) ) and "i" ) and "j" ) and "k" ) and "l" ) and "m" ) and "n" ) and ("o" and "p" ) )

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 ONLY

Domain logical expression index: "d"

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: "e"

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

Domain logical expression index: "f"

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: "g"

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

Domain logical expression index: "h"

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: "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 High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Similarity boundary:Target: CN{+}1(.Cl{-})C(N=Nc2ccc(N(C)Cc3ccccc3)cc2)N(C)C=N1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

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: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.313

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.31

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride is predicted to be 260.350006104 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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride. 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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride is predicted to be 260.350006104 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:

no adverse effect observed

Dose descriptor:

NOAEL

260.35 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Reference

Endpoint:: repeated dose toxicity: inhalation, other
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Reference

Endpoint:: repeated dose toxicity: dermal, other
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of 5-[[p-(benzylmethylamino) phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride. 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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride. 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 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride is predicted to be 260.350006104 mg/Kg bw/day.

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

Combined repeated dose toxicity with reproduction/ developmental toxicity screening test was performed as per the OECD 422 to determine the toxic nature of structurally and functionally similar read across chemical Cyclohexanamine, N,N-dimethyl-(DMCHA; RA CAS no 98 -94 -2). The study was performed using male and female rats at dose levels up to 1500 ppm(equivalent to 91-104 and 85-147 mg/kg bw/day for males and females, respectively) by the oral feed method. Repeated dietary administration of DMCHA did not produce systemic or local toxicity. Based on these considerations, the No observed adverse effect level (NOAEL) forCyclohexanamine, N,N-dimethyl-(DMCHA) is considered to be1500 ppm (equivalent to 91-104 and 85-147 mg/kg bw/day for males and females, respectively).

Repeated dose toxicity: Inhalation

5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride has very low vapor pressure (2.31E-007 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 for repeated inhalation toxicity was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (as provided in section 7.2.3) is >2000 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 for repeated dermal toxicity is considered as waiver.

Based on the data available for the target chemical and its read across, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride is not likely to classify as a toxicant upon repeated exposure by oral route.

Based on the data available for the target chemical and its read across, 5-[[p-(benzylmethylamino)phenyl]azo]-1,4-dimethyl-1H-1,2,4-triazolium chloride (CAS no 29508 -47 -2) is not likely to classify as a toxicant upon repeated exposure by oral route.