bis(2-ethylhexyl) 4,4’-{6-[4-tert-butylcarbamoyl)anilino]-1,3,5-triazine-2,4-diyldiimino}dibenzoate

Endpoint summary

Description of key information

Repeated dose toxicity: oral:
The no observed adverse effect level (NOAEL) for test material benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester in rats was found to be 621.799987793 mg/kg bw/day (actual dose received)

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

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from QSAR Toolbox Version 3.3

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: The prediction is done using QSAR Toolbox version 3.3

Principles of method if other than guideline:

Dose range-finding study performed to determine the appropriate dose levels for a combined repeated dose toxicity study with reproduction/developmental toxicity screening test according to OECD guideline 422. As far as possible, the study was performed in

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No Data Available

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

No Data Available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
148, 622, 1100 mg/kg bw/day (actual dose received)
Basis:
no data

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Observations and examinations performed and frequency:

No data available

Sacrifice and pathology:

No data available

Other examinations:

No data available

Statistics:

No data available

Clinical signs:

no effects observed

Mortality:

no mortality observed

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

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

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" or "c" )  and "d" )  and ("e" and ( not "f") )  )  and "g" )  and ("h" and "i" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain by DNA binding by OASIS v.1.3

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "d"

Similarity boundary:Target: CCCCC(CC)COC(=O)c1ccc(Nc2nc(Nc3ccc(C(=O)NC(C)(C)C)cc3)nc(Nc3ccc(C(=O)OCC(CC)CCCC)cc3)n2)cc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid amide AND Carboxylic acid derivative AND Carboxylic acid ester AND Carboxylic acid sec. amide by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as 1,2-diol OR Alcohol OR Alkyl fluoride OR Alkyl halide OR Alkylthiol OR Amine OR Anion OR Aryl chloride OR Aryl halide OR Azo compound OR Carbamic acid ester (uretane) OR Carboxylic acid OR Carboxylic acid salt OR Cation OR CO2 derivative (general) OR Dialkylether OR Ether OR Halogen derivative OR Heterocyclic compound OR Hydroxy compound OR Lactone OR No functional group found OR Phenol OR Primary alcohol OR Primary aliphatic amine OR Primary amine OR Quaternary ammonium salt OR Secondary alcohol OR Secondary aliphatic amine OR Secondary amine OR Sulfonic acid OR Sulfonic acid derivative OR Tertiary aliphatic amine OR Tertiary amine OR Tertiary mixed amine OR Thioether OR Thiol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.81

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is <= 20.5

Conclusions:

The no observed adverse effect level (NOAEL) for test material benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester in rats was found to be 621.799987793 mg/kg bw/day (actual dose received)

Executive summary:

The repeated dose toxicity of benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester to rats was estimated using QSAR Toolboox version 3.3

The no observed adverse effect level (NOAEL) for test material benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester in rats was found to be 621.799987793 mg/kg bw/day (actual dose received)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

621.8 mg/kg bw/day

Species:

rat

Quality of whole database:

Data is from QSAR Toolbox Version 3.3

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Repeated dose toxicity: oral:

The repeated dose toxicity of benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester to rats was estimated using QSAR Toolboox version 3.3

The no observed adverse effect level (NOAEL) for test material benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester in rats was found to be 621.799987793 mg/kg bw/day (actual dose received)

Repeated dose toxicity: Inhalation

The chemical Bis(2-ethylhexyl) 4,4’-{6-[4-tert-butylcarbamoyl)anilino]-1,3,5-triazine-2,4-diyldiimino}dibenzoate has a low vapour pressure and thus repeated exposure by the inhaltion route is highly unlikely. In addition, the likelihood of inhlation of the particulates of the chemical is also low considering the particle size of the chemical. Thus, the chemical is not likely to have repeated dose toxicity effects via the inhalation route.

Repeated dose toxicity: dermal

This end point was considered for waiver since reports suggest that the dermal absorption potential indicate very low degree of percutaneous absorption when the radioactive form of the chemical was used on living human skin samples (ex-vivo). Thus, even in case of repeated exposure by the dermal route toxic effects are highly unlikely. Also, the oral route is recommended in the guidelines for testing of cosmetic ingredients for their safety evaluation.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The no observed adverse effect level (NOAEL) for test material benzoic acid, 4,4'-[[6-[[4-[[(1,1-dimethylethyl)amino]carbonyl]phenyl]amino]-1,3,5-triazine-2,4-diyl]diimino]bis-,1,1'-bis(2-ethylhexyl) ester in rats was found to be 621.799987793 mg/kg bw/day (actual dose received)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The chemical Bis(2-ethylhexyl) 4,4’-{6-[4-tert-butylcarbamoyl)anilino]-1,3,5-triazine-2,4-diyldiimino}dibenzoate has a low vapour pressure and thus repeated exposure by the inhaltion route is highly unlikely. In addition, the likelihood of inhlation of the particulates of the chemical is also low considering the particle size of the chemical. Thus, the chemical is not likely to have repeated dose toxicity effects via the inhalation route.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
This end point was considered for waiver since reports suggest that the dermal absorption potential indicate very low degree of percutaneous absorption when the radioactive form of the chemical was used on living human skin samples (ex-vivo). Thus, even in case of repeated exposure by the dermal route toxic effects are highly unlikely. Also, the oral route is recommended in the guidelines for testing of cosmetic ingredients for their safety evaluation.

Justification for classification or non-classification

From the information presently available, the chemical Bis(2-ethylhexyl) 4,4’-{6-[4-tert-butylcarbamoyl)anilino]-1,3,5-triazine-2,4-diyldiimino}dibenzoate is not classified for repeated dose toxicity by the oral, inhlation or dermal route of exposure.