Tris(2-ethylhexyl)-4,4',4''-(1,3,5-triazine-2,4,6-triyltriimino)tribenzoate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Interpretation of results (migrated information):
negative with metabolic activation
negative without metabolic activation

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in mammalian cells

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE CATEGORY APPROACH
1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
By using different grouping methods to group chemicals into chemical categories according to different measures of similarity so that within a category a QSAR model can be established. We select profiles related to generic toxicity, including “in vitro mutagenicity (Ames test) alerts by ISS”, “in vivo mutagenicity (Micronucleus) alerts by ISS”, “Aquatic toxicity classification by ECOSAR”, “in vitro mutagenicity (Ames test) alerts by ISS with Rat liver S9 metabolism simulator” and “in vivo mutagenicity (Micronucleus) alerts by ISS with Rat liver S9 metabolism simulator”. Besides, generic toxicity depends on the solubility, shape and reactivity of the chemicals. Therefore, we select "logkow" to describe solubility, “US-EPA New Chemical Categories”, “Chemical elements” and “Organic functional groups, Norbert Haider (checkmol)” to describe the shape of molecule, empiric profiles “DNA binding by OECD” and “Protein binding by OECD” to describe the reactivity.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
Reliable predicted value obtained by the OECD QSAR Toolbox 4.5 SP1 using Read-across within category members.The prediction fulfilling the OECD criteria for the validation of QSAR models with respect to • a defined endpoint • unambiguous algorithm • a defined domain of applicability • appropriate measure of goodness-of-fit, robustness and predictivity • a mechanistic interpretation.

OECD Principle 1 - Defined endpoint: Human Health Hazards -> Genetic Toxicity -> in Vitro -> Mammalian Cell Gene Mutation Assay -> in vitro gene mutation study in mammalian cells.

OECD principle 2 - Unambiguous algorithm: takes the mode value from the 5 nearest neighbours
Active descriptor: log Kow (calculated)
Data usage: All values*
*When multiple values are available for the same chemical, all of them are taken individually in prediction calculations

OECD principle 3 - Applicability domain
Database(s) used:
- ECHA REACH
Category boundaries (applicability domain):
- Active descriptor(s) range:
- log Kow: from from 8.12 to 18.5 target chemical is in domain
- Response range:
- in vitro gene mutation study in mammalian cells: negative (x6)
Profilers:
- No alert found (in vitro mutagenicity (Ames test) alerts by ISS) (primary grouping) target chemical is in domain
- in vivo mutagenicity (Micronucleus) alerts by ISS (subcategorization) target chemical is in domain
- DNA binding by OECD (subcategorization) target chemical is in domain
- Aquatic toxicity classification by ECOSAR (subcategorization) target chemical is in domain
- US-EPA New Chemical Categories (subcategorization) target chemical is in domain
- Protein binding by OECD (subcategorization) target chemical is in domain
- Chemical elements (subcategorization) target chemical is in domain
- in vitro mutagenicity (Ames test) alerts by ISS with Rat liver S9 metabolism simulator (subcategorization) target chemical is in domain
- in vivo mutagenicity (Micronucleus) alerts by ISS with Rat liver S9 metabolism simulator (subcategorization) target chemical is in domain
- Organic functional groups, Norbert Haider (checkmol) (subcategorization) target chemical is in domain

OECD principle 4 - Uncertainty of the prediction:
The prediction is based on 6 values, 6 of them (100%) equal to predicted value
Prediction confidence is measured by the p-value: 8.5E-06

OECD principle 5 - Chemical and biological mechanisms
No alert found (in vitro mutagenicity (Ames test) alerts by ISS) (primary grouping): No alert found
in vivo mutagenicity (Micronucleus) alerts by ISS (subcategorization): No alert found
DNA binding by OECD (subcategorization): No alert found
Aquatic toxicity classification by ECOSAR (subcategorization): Esters; Melamines
US-EPA New Chemical Categories (subcategorization): Not categorized
Protein binding by OECD (subcategorization): No alert found
Chemical elements (subcategorization): Group 14 - Carbon C; Group 15 - Nitrogen N; Group 16 - Oxygen O
in vitro mutagenicity (Ames test) alerts by ISS with Rat liver S9 metabolism simulator (subcategorization): No alert found; Simple aldehyde
in vivo mutagenicity (Micronucleus) alerts by ISS with Rat liver S9 metabolism simulator (subcategorization): No alert found; Simple aldehyde
Organic functional groups, Norbert Haider (checkmol) (subcategorization): Amine; Aromatic compound; Carboxylic acid derivative; Carboxylic acid ester; Heterocyclic compound; Secondary amine; Secondary aromatic amine

Key result

Species / strain:

mammalian cell line, other: mouse lymphoma L5178Y cells, Chinese hamster Ovary (CHO), Chinese hamster lung fibroblasts (V79)

Metabolic activation:

not specified

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Conclusions:

The predicted value of in vitro gene mutation study in mammalian cells is "negative".

Reference 2

Endpoint:

in vitro cytogenicity / chromosome aberration study in mammalian cells

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

OECD Guideline 473 (In Vitro Mammalian Chromosomal Aberration Test)

Qualifier:

according to guideline

Guideline:

EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)

Version / remarks:

92/69/EWG, B.10 (Säuger zytogenetischer in vitro-Test)

GLP compliance:

yes

Type of assay:

other: in vitro mammalian cytogenicity (B10)

Species / strain / cell type:

mammalian cell line, other: Chin. Hamster, V79-Zellen

Metabolic activation:

with and without

Metabolic activation system:

S9-Mix

Test concentrations with justification for top dose:

Concentration range in the main test (with metabolic activation): 10 - 100 μg/mL
Concentration range in the main test (without metabolic activation): 10 - 100 μg/mL

Vehicle / solvent:

DMSO

Details on test system and experimental conditions:

Exposure period (with metabolic activation): 4 hours
Exposure period (without metabolic activation): 18 hours
Expression time: 18 and 28 hours

Species / strain:

mammalian cell line, other: Chin. Hamster, V79-Zellen

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Additional information on results:

No findings

Conclusions:

Interpretation of results (migrated information):
negative with metabolic activation
negative without metabolic activation

Reference 3

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other: see remark

Principles of method if other than guideline:

Method : Dean, S. W. ; Lane, M. ; Dunmore, R. H. ; Ruddock, S.P. ; Martin, C. N. ; Kirkland, D. J. ;
Loprieno, N. : Development of assays for the detection of photomutagenicity of chemicals during exposure to UV light - I. Assay development. Carcinogenesis 6, 335 - 341 (1991).
Dean, S.W. ; Dunmore, R.H. ; Ruddock, S.P. ; Dean, J.C. ; Martin, C. N. ; Kirkland, D. J. : Development of assays for the detection of photomutagenicity of chemicals during exposure to UV light - II. Results of testing three sunscreen ingredients. Mutagenesis 7, 179 - 182 (1992).

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

bacteria, other: esc WP2

Metabolic activation:

without

Metabolic activation system:

none

Test concentrations with justification for top dose:

Concentration range in the main test (without metabolic activation) : 1.6 - 1000ug/plate

Vehicle / solvent:

Solvent : DMSO

Details on test system and experimental conditions:

Concentration of the test substance resulting in precipitation : 1000ug/plate

Species / strain:

bacteria, other: esc WP2

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

Observations : No findings.

Conclusions:

Interpretation of results (migrated information):
negative without metabolic activation

Executive summary:

Not classified as mutagenic.

Reference 4

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Additional strain / cell type characteristics:

not specified

Metabolic activation:

with and without

Metabolic activation system:

S9-mix

Test concentrations with justification for top dose:

Concentration range in the main test (with metabolic activation) : 20 - 5000ug/plate
Concentration range in the main test (without metabolic activation) : 20 - 5000ug/plate

Vehicle / solvent:

Solvent : DMSO

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Conclusions:

Interpretation of results (migrated information):
negative with metabolic activation
negative without metabolic activation

Executive summary:

not classified as mutagenic

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

No indications of a clastogenic or aneugenic effect. Interpretation of results (migrated information): negative.

Link to relevant study records

Reference

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Version / remarks:

1986

GLP compliance:

yes

Type of assay:

other: micronucleus assay chromosome aberration

Species:

mouse

Strain:

NMRI

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

olive oil

No. of animals per sex per dose:

Male : 525 mg/kg; number of animals : 5; sacrifice time : 16 hours
Male : 525 mg/kg; number of animals : 5; sacrifice time : 24 hours
Male : 525 mg/kg; number of animals : 5; sacrifice time : 48 hours
Male : 1050 mg/kg; number of animals : 5; sacrifice time : 16 hours
Male : 1050 mg/kg; number of animals : 5; sacrifice time : 24 hours
Male : 1050 mg/kg; number of animals : 5; sacrifice time : 48 hours
Male : 2100 mg/kg; number of animals : 5; sacrifice time : 16 hours
Male : 2100 mg/kg; number of animals : 5; sacrifice time : 24 hours
Male: 2100 mg/kg; number of animals : 5; sacrifice time : 48 hours
Female : 525 mg/kg; number of animals : 5; sacrifice time : 16 hours
Female : 525 mg/kg; number of animals : 5; sacrifice time : 24 hours
Female : 525 mg/kg; number of animals : 5; sacrifice time : 48 hours
Female : 1050 mg/kg; number of animals : 5; sacrifice time : 16 hours
Female : 1050 mg/kg; number of animals : 5; sacrifice time : 24 hours
Female : 1050 mg/kg; number of animals : 5; sacrifice time : 48 hours
Female : 2100 mg/kg; number of animals : 5; sacrifice time : 16 hours
Female : 2100 mg/kg; number of animals : 5; sacrifice time : 24 hours
Female : 2100 mg/kg; number of animals : 5; sacrifice time : 48 hours

Sex:

male/female

Genotoxicity:

negative

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Remarks on result:

other: not further specified

Additional information on results:

Observations:
Controls, 24h: 0.16% micronuclei containing PCE
Test substance: 0.11% - 0.17% micronuclei containing PCE
no change in the ratio of PCE/NCE

Conclusions:

Interpretation of results (migrated information): negative
Not classified as mutagenic

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)