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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
The carboxylic acid component of a structurally similar substance (tosyl salt) was tested for potential to cause genetic toxicity. The substance was found to be negative for genetic toxicity, with and without metabolic activation, in the Ames test (OECD 471), gene cell mutation test (OECD 476) and the micronucleus test (OECD 487).
Link to relevant study records
Reference
Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: genome mutation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study was conducted by a GLP accredited laboratory using OECD Testing Guideline 471. The study was conducted on 6-[(p-tosyl)amino]hexanoic acid, which is the carboxylic acid component of 6-[(p-tosyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrilotriethanol (1:1), a structurally similar substance to the registered substance.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Type of assay:
bacterial reverse mutation assay
Test material information:
Composition 1
Target gene:
TA100: his G46
TA98: his D3052
TA97: his D6610
TA102: his G428 (pAQ1)
TA1535: his G46
Species / strain:
S. typhimurium TA 100
Additional strain characteristics:
other: Strain is histidine-dependent
Metabolic activation:
with and without
Metabolic activation system:
Mammalian liver post-mitochondrial fraction (S9), prepared from Sprague Dawley male rats.
Species / strain:
S. typhimurium TA 98
Additional strain characteristics:
other: Strain is histidine-dependent
Metabolic activation:
with and without
Metabolic activation system:
Mammalian liver post-mitochondrial fraction (S9), prepared from Sprague Dawley male rats.
Species / strain:
S. typhimurium TA 97
Additional strain characteristics:
other: Strain is histidine-dependent
Metabolic activation:
with and without
Metabolic activation system:
Mammalian liver post-mitochondrial fraction (S9), prepared from Sprague Dawley male rats.
Species / strain:
S. typhimurium TA 1535
Additional strain characteristics:
other: Strain is histidine-dependent
Metabolic activation:
with and without
Metabolic activation system:
Mammalian liver post-mitochondrial fraction (S9), prepared from Sprague Dawley male rats.
Species / strain:
S. typhimurium TA 102
Additional strain characteristics:
other: Strain is histidine-dependent
Metabolic activation:
with and without
Metabolic activation system:
Mammalian liver post-mitochondrial fraction (S9), prepared from Sprague Dawley male rats.
Test concentrations with justification for top dose:
Range-Finding: 7 concentrations in the range of 0.01-5.0 mg/plate
Definitive assay: 8 concentrations in the range of 0.000001-1 mg/plate
Confirmatory assay with preincubation: 0.000000-0.5 mg/plate
Appropriate amount of test item was weighted and diluted in DMSO not earlier than 30 min prior to test start. For dilution of final doses, sterile DMSO was used.
Vehicle:
- Vehicle/solvent used: DMSO
Negative controls:
yes
Solvent controls:
yes
Positive controls:
yes
Positive control substance:
9-aminoacridine
2-nitrofluorene
sodium azide
mitomycin C
other: 2-acetamidofluorene
Details on test system and conditions:
METHOD OF APPLICATION: in agar (plate incorporation)

DURATION
- Exposure duration: 48-72 hr

NUMBER OF REPLICATIONS: 3
Evaluation criteria:
- concentration-related increase over the tested range and reproducible increase at one or more concentrations in the number of revertant colonies per plate in at least one strain with or without metabolic activation
- mutation factor >2
Statistics:
Student's t-test was used
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
not determined
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Species / strain:
S. typhimurium TA 97
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
not determined
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
not determined
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Species / strain:
S. typhimurium TA 102
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
not determined
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity:
not determined
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
yes
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.

No significant increase in the mutant frequency was observed for the 5 tested strains, neither in the standard plate incorporation nor in the preincubation assays with or without metabolic activation.

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

The test substance is considered to be non-mutagenic in the bacterial gene mutation test system.
Executive summary:

The genetic toxicity of the test substance was determined in accordance with the OECD Guideline for Testing of Chemicals 471. The test substance was dissolved in DMSO and tested with the 5 strains of Salmonella typhimurium: TA100, TA98, TA97, TA102 and TA1535. There was no induction of metabolic activity either with or without metabolic activation with S-9 mix. Adequate positive and negative control substances were included in the test system. In conclusion, up to and including concentrations of 5000 µg/plate the test substance did not increase the mutation frequency of the 5 tested strains and is therefore considered to be non-.mutagenic. The test substance was the carboxylic acid component of the registered substance. Read-across between the tosyl salt carboxylic acid (6 -[(p-tosyl)amino]hexanoic acid) and the registered substance is considered justified as the registered substance is manufactured directly from 6-[methyl(phenylsulphonyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). 6-[methyl(phenylsulphonyl)amino]hexanoic acid and 6-[(p-tosyl)amino]hexanoic acid are structural isomers. They are the same molecular weight and differ only in the position of a single methyl group. In the former, the methyl group is bound to the nitrogen atom of the sulphonamide linkage whereas in the latter, it resides on the aromatic ring. Other than ionization of the carboxylic acid group, the 6-[methyl(phenylsulphonyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrilotriethanol (1:1) dissociate completely and behave essentially as independent substances. Since TEA can be considered non-hazardous, it is the acid component of the salt that will have a more significant impact on the outcome of any (eco)toxicological or environmental tests.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

Studies were conducted on the carboxylic acid component of a structurally similar substance (tosyl salt). The substance was found to be negative for genetic toxicity, with and without metabolic activation, in the Ames test (OECD 471), gene cell mutation test (OECD 476) and the micronucleus test (OECD 487).


Justification for selection of genetic toxicity endpoint
A study was conducted on the carboxylic acid component of a structurally similar substance (tosyl salt) by a GLP accredited laboratory using OECD Testing Guideline 471.

Justification for classification or non-classification

The carboxylic acid component of a structurally similar substance (tosyl salt) was found to be negative for genetic toxicity, with and without metabolic activation, in the Ames test (OECD 471), gene cell mutation test (OECD 476) and the micronucleus test (OECD 487). Read-across between the tosyl salt carboxylic acid (6 -[(p-tosyl)amino]hexanoic acid) and the registered substance is considered justified as the registered substance is manufactured directly from 6-[methyl(phenylsulphonyl)amino]hexanoic acid by simple neutralisation with triethanolamine (TEA). 6-[methyl(phenylsulphonyl)amino]hexanoic acid and 6-[(p-tosyl)amino]hexanoic acid are structural isomers. They are the same molecular weight and differ only in the position of a single methyl group. In the former, the methyl group is bound to the nitrogen atom of the sulphonamide linkage whereas in the latter, it resides on the aromatic ring. Other than ionization of the carboxylic acid group, the 6-[methyl(phenylsulphonyl)amino]hexanoic acid remains chemically unchanged upon salt formation. In water, the acid and amine components of 6-[methyl(phenylsulphonyl)amino]hexanoic acid, compound with 2,2’,2’’-nitrilotriethanol (1:1) dissociate completely and behave essentially as independent substances. Since TEA can be considered non-hazardous, it is the acid component of the salt that will have a more significant impact on the outcome of any (eco)toxicological or environmental tests.