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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

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, gene mutation was predicted for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl] -5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino] -1,2,3,4-tetrahydro- 1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation

Link to relevant study records
Reference
Endpoint:
in vitro gene mutation study in bacteria
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: As mention below
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.3, 2018
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Specific details on test material used for the study:
- Name of test material (IUPAC name):4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4- [(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5 -triazin-2-ylidene]amino}-2-sulfophenyl)diazen- 1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid
- Molecular formula: C25H18ClN9O12S3
- Molecular weight: 768.1192 g/mol
- Smiles notation: C1=CC(=CC(=C1)S(=O)(=O)O)NC2=NC(=NC(=N2)NC3=CC(=C(C=C3)S(=O)(=O)O)N=NC4C(=NN(C4=O)C5=CC=C(C=C5)S(=O)(=O)O)C(=O)O)Cl
- InChl: 1S/C25H18ClN9O12S3/c26-23-29-24(27-12-2-1-3-16(10-12)49(42,43)44)31-25(30-23)28-13-4-9-18(50(45,46)47)17(11-13)32-33-19-20(22(37)38)34-35(21(19)36)14-5-7-15(8-6-14)48(39,40)41/h1-11,19H,(H,37,38)(H,39,40,41)(H,42,43,44)(H,45,46,47)(H2,27,28,29,30,31)/b33-32+
- Substance type: Organic
- Physical state: Solid
Target gene:
Histidine
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
Details on mammalian cell type (if applicable):
Not applicable
Additional strain / cell type characteristics:
not specified
Cytokinesis block (if used):
not specified
Metabolic activation:
with and without
Metabolic activation system:
S9 metabolic activation
Test concentrations with justification for top dose:
not specified
Vehicle / solvent:
not specified
Untreated negative controls:
not specified
Negative solvent / vehicle controls:
not specified
True negative controls:
not specified
Positive controls:
not specified
Details on test system and experimental conditions:
not specified
Rationale for test conditions:
not specified
Evaluation criteria:
Prediction was done considering a dose dependent increase in the number of revertants/plate.
Statistics:
not specified
Species / strain:
S. typhimurium, other: TA 1535, TA 1537, TA 98, TA 100 and TA 102
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Remarks on result:
other: No mutagenic effect were observed

The prediction was based on dataset comprised from the following descriptors: "Gene mutation"
Estimation method: Takes highest mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Substituted Triazines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Hydrazines OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

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 OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR 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 DNA binding by OASIS v.1.3 ONLY

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"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Group 17 - Halogens Br OR Group 17 - Halogens F OR Group 17 - Halogens I by Chemical elements

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Conjugated keto(scy) - 1,5-H shift by Tautomers unstable

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Halogen derivative AND Heterocyclic compound AND Sulfonic acid AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Sulfone OR Tertiary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aromatic amine AND Aromatic heterocyclic halide AND Aryl AND Aryl halide AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfonic acid AND Triazine AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.348

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.62

Conclusions:
4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4)was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro
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, gene mutation was predicted for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro- 1,3,5-triazin-2-ylidene]amino}- 2-sulfophenyl) diazen-1-yl] -5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro- 1,3,5-triazin-2-ylidene]amino} -2- sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result 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 (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Genetic mutation in vitro;

Prediction model based estimation and data from read across chemical have been reviewed to determine the mutagenic nature of 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4- [(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The studies are as mentioned below

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, gene mutation was predicted for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl] -5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

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, chromosomal aberration was predicted for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl)diazen-1-yl] -5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4) .The study assumed the use of Chinese hamster ovary (CHO) cell line with and without S9 metabolic activation system  for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl) imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1 -yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid was predicted to not induce chromosomal aberrations in Chinese hamster ovary (CHO) cell line in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by S. Venturini and M. Tamaro (Mutation Research,1979) to determine the mutagenic nature of Xylene (6359-98-4); IUPAC Name; Disodium 2,5-dichloro-4-(5-hydroxy-3-methyl-4-(sulphophenylazo)pyrazol-1-yl)benzenesulphonat e .The read across substances is functionally similar to target substance .Therefore, it is acceptable to derive information on mutation from the analogue substance. Bacterial gene mutation test was performed to evaluate the mutagenic response for the test chemical Xylene light yellow 2G (C.I. acid yellow 17). The test was performed using Salmonella typhimurium strainsTA1535, TA100, TA1538, and TA98 in the presence and absence of S9 metabolic activation system using the soft agar overlay method. The test compound was dissolved in DMSO and used at dose levels of 100, 500 or 1000µg/plate. Concurrent positive control chemicals were also included in the study. Xylene light yellow 2G (C.I. acid yellow 17) did not induce reversion of mutation when applied to Salmonella typhimurium strainsTA1535, TA100, TA1538, and TA98 in the presence and absence of S9 metabolic activation system and hence it is not likely to classify as a gene mutant in vitro.

In a study for structurally and functionally similar read across chemical, Gene mutation toxicity study was performed by M. Ishidate et al.( Fd Chem. Toxic., 1984) to determine the mutagenic nature of Tartrazine; IUPAC Name; trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo) pyrazole-3-carboxylate; trisodium 5-hydroxy-1- (4-sulphophenyl)-4-(4-sulphophenylazo)pyrazole-3-carboxylate (1934-21-0). The read across substances functionally similar to target substance .Therefore, it is acceptable to derive information on mutation from the analogue substance. Gene mutation toxicity study was performed to determine the mutagenic nature of tartrazine. The study was performed using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 with and without S9 metabolic activation system. The test was performed as per the preincubation assay at six different concentrations with 5.0 mg/plate being the maximum concentration. The chemical was dissolved in distilled water. Preincubation was performed for 20 mins and the exposure duration was for 48 hrs. The result was considered positive if the number of colonies found was twice the number in the control (exposed to the appropriate solvent or untreated). Tartrazine did not induce a doubling of revertant colonies over the control using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 in the presence and absence of S9 metabolic activation system and hence the chemical is not likely to classify as a gene mutant in vitro.

Based on the data available for the target chemical and its read across substance and applying weight of evidence of4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4- [(3-sulfophenyl)imino] -1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino}-2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). Hence the test chemical is not likely to classify as a gene mutant in vitro.

Justification for classification or non-classification

Based on the above annotation and CLP criteria for the target chemical 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4- [(3-sulfophenyl)imino] -1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl)diazen-1-yl]-5-oxo-1-(4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). Hence the test chemical is not likely to classify as a gene mutant in vitro.