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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
The analogue substance is mutagenic in the Ames test.
Link to relevant study records
Reference
Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-compliant guideline study, available as unpublished report, Test itm purity less than 80%., fully adequate for assessment.
Qualifier:
according to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
yes
Remarks:
, only one positive control used to test efficacy of the S9-mix.
Qualifier:
according to guideline
Guideline:
EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
Deviations:
yes
Remarks:
, only one positive control used to test efficacy of the S9-mix.
GLP compliance:
yes (incl. QA statement)
Remarks:
Experimental Toxicology and Ecology, BASF Aktiengesellschaft, 67056 Ludwigshafen/Rhein, Germany
Type of assay:
bacterial reverse mutation assay
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Species / strain / cell type:
E. coli WP2 uvr A
Metabolic activation:
with and without
Metabolic activation system:
Male S.D. rats liver S9, induced by Aroclor 1254
Test concentrations with justification for top dose:
- 1st experiment: 0, 20, 100, 500, 2500 and 5000 µg/plate
- 2nd experiment (TA 1535): 0, 4, 20, 100, 500, and 1000 µg/plate
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: Due to the Iimited solubility of the test substance in water, DMSO was selected as the vehicle, which had been demonstrated to be suitable in bacterial reverse mutation tests and for which historical control data are available.
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Remarks:
2.5 µg/plate, dissolved in DMSO (60 µg/plate for Escherichia coli WP2 uvrA)
Positive control substance:
other: 2-aminoanthracene (2-AA)
Remarks:
With metabolic activation for all strains
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Remarks:
5 µg/plate, dissolved inDMSO
Positive control substance:
other: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)
Remarks:
Without metabolic activation for strains TA 1535 and TA 100
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Remarks:
10 µg/plate, dissolved in DMSO
Positive control substance:
other: 4-nitro-o-phenylendiamine (NOPD)
Remarks:
Without metabolic activation for strain TA 98
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Remarks:
100 µg/plate, dissolved in DMSO
Positive control substance:
9-aminoacridine
Remarks:
Without metabolic activation for strain TA 1537
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Remarks:
5 µg/plate, dissolved in DMSO
Positive control substance:
4-nitroquinoline-N-oxide
Remarks:
Without metabolic activation for strain E. coli WP2 uvrA
Details on test system and experimental conditions:
EXPERIMENT 1 (TA 1535, TA 100, TA 1537, TA 98, E. coli WP2 uvrA) and 2 (TA 1535)
- METHOD OF APPLICATION: in agar (plate incorporation)
- DURATION: Exposure duration: 48 -72 h
- NUMBER OF REPLICATIONS: 3 test plates per dose or per control
- DETERMINATION OF CYTOTOXICITY: reduced his- or trp- background growth, decrease in the number of revertants, reduction in the titer

Evaluation criteria:
The test chemical is considered positive in this assay if the following criteria are met:
- A dose-related and reproducible increase in the number of revertant colonies, i.e. about doubling of the spontaneous mutation rate in at least one tester strain either without S-9 mix or after adding a metabolizing system.
A test substance is generally considered nonmutagenic in this test if:
- The number of revertants for all tester strains were within the historical negative control range under all experimental conditions in two experiments carried out independently of each other.
Species / strain:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with
Genotoxicity:
positive
Remarks:
from about 20 µg/plate (factor 1.9 - 2.3) onward with an increase in the number of his+ revertants by a factor of 72.1 at 5000 µg/plate.
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with
Genotoxicity:
positive
Remarks:
Slight increase in the number of revertant colonies from about 100 - 500 µg (factor 1.5 - 4.5) onward with a maximum response at 2500 µg/plate (factor 8.8).
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
bacteria, other: S. typhimurium TA 1537, TA 98; E. coli WP2 uvra
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
TOXICITY:
- A bacterio-toxic effect (reduced his- or trp- background growth, decrease in the number of revertants, reduction in the titer) was observed depending on the strain and test conditions from about 2500 µg/plate onward.

SOLUBILITY
- No test substance precipitation was found
Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.
Conclusions:
Interpretation of results (migrated information):
positive with metabolic activation
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Additional information

Additional information from genetic toxicity in vitro:

The analogue was tested with a crude sample obtained during production and showed a clear dose-dependent increase in the number of revertants in a number of strains. In theory it is possible that this was caused by the major side product. However, there is a mechanistic alert for DNA binding reactivity for the main component.

Justification for classification or non-classification