7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

3 August 1995 to 2 October 1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Proprietary guideline compliant study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Ministry of Labor of Japan 1988

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

1

Reference substance name:

7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

EC Number:

219-207-4

EC Name:

7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Cas Number:

2386-87-0

Molecular formula:

C14H20O4

IUPAC Name:

7-oxabicyclo[4.1.0]hept-3-ylmethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate

Method

Target gene:

Histidine and tryptophan genes

Species / strain

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2

Metabolic activation:

with and without

Test concentrations with justification for top dose:

156, 313, 625, 1250, 2500 and 5000ug per plate were used.

Vehicle / solvent:

Vehicle/solvent used: DMSO

Controls

Controls 1

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

True negative controls:

not specified

Positive controls:

yes

Remarks:

0.01ug / plate

Positive control substance:

2-acetylaminofluorene

Remarks:

Positive control used without metabolic activation for TA 100 Migrated to IUCLID6: AF-2

Controls 2

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

True negative controls:

not specified

Positive controls:

yes

Remarks:

0.5ug / plate

Positive control substance:

sodium azide

Remarks:

Positive control used without metabolic activation for TA 1535

Controls 3

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

True negative controls:

not specified

Positive controls:

yes

Remarks:

80ug / plate

Positive control substance:

9-aminoacridine

Remarks:

Positive control used without metabolic activation for TA 1537

Controls 4

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

True negative controls:

not specified

Positive controls:

yes

Remarks:

2ug / plate

Positive control substance:

N-ethyl-N-nitro-N-nitrosoguanidine

Remarks:

Positive control used without metabolic activation for E coli. WP2 uvrA-

Controls 5

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

True negative controls:

not specified

Positive controls:

yes

Remarks:

0.5ug / plate (TA98), 1ug / plate (TA100), 2ug / plate (TA1535), 2ug / plate (TA1537), 10ug / plate (E.coli WP2 uvrA-)

Positive control substance:

other: 2-Aminoanthracene

Remarks:

Positive control used with metabolic activation for all strains of bacteria.

Details on test system and experimental conditions:

METHOD OF APPLICATION: preincubation

DURATION
- Preincubation period: 20 minutes
- Exposure duration: 2 days
- Expression time (cells in growth medium): Not documented
- Selection time (if incubation with a selection agent): Not documented
- Fixation time (start of exposure up to fixation or harvest of cells): Not documented

SELECTION AGENT (mutation assays): No information provided.
SPINDLE INHIBITOR (cytogenetic assays): Not relevant
STAIN (for cytogenetic assays): Not relevant

NUMBER OF REPLICATIONS: Three plates per dose level were used for each assay and the test was run twice.

NUMBER OF CELLS EVALUATED: Not documented

DETERMINATION OF CYTOTOXICITY
- Method: other: Number of revertants per plate.

OTHER EXAMINATIONS:
- Determination of polyploidy: Not documented
- Determination of endoreplication: Not documented
- Other: Not documented

OTHER: Not documented

Evaluation criteria:

The test substance was positive in this assay when the mean number of revertants was more than double the negative control value and when the increase was significantly dose-dependent.

Statistics:

No information provided

Results and discussion

Test results

Test results 1

Species / strain:

other: S. typhimurium TA100 and TA1535

Metabolic activation:

with

Genotoxicity:

positive

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Test results 2

Species / strain:

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

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Test results 3

Species / strain:

other: S. typhimurium TA 98 and TA1537

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Test results 4

Species / strain:

E. coli WP2 uvr A

Metabolic activation:

with and without

Genotoxicity:

positive

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

Untreated negative controls validity:

not specified

Positive controls validity:

valid

Additional information on results:

TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: Not documented
- Effects of osmolality: Not documented
- Evaporation from medium: Not documented
- Water solubility: Not documented
- Precipitation: Not documented
- Other confounding effects: Not documented

RANGE-FINDING/SCREENING STUDIES:
In the dose finding test, the numbers of revertants induced by the test substance were more than double of the solvent control value in S. typhimurium TA100 and TA1535 with S9 mix.

COMPARISON WITH HISTORICAL CONTROL DATA:
No information provided

ADDITIONAL INFORMATION ON CYTOTOXICITY:
The positive controls induced significant revertants. For the solvent control, the numbers of revertants of all the tester strains were within the normal range of our laboratory's background data respectively. These results assured that the tests were performed correctly.

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

Any other information on results incl. tables

Strain Gene affected Additional mutations Mutation type

Repair LPS R-factor

S. typhimuriurn

TA98 his D uvrB rfa pKM 101 Frameshift

TAlOO his G uvrB rfa pKM101 Base-pair change

TA1535 his G uvrB rfa - Base-pair change

TA1537 his C uvrB rf'a - Frameshift

E. coli

WP2 uvrA- trp E uvrA + - Base-pair change

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information):
positive with metabolic activation For TA 100 and TA 1535, all other strains with or without metabolic activation gave negative results

Under the conditions employed in this test, the test substance UVR-6110, was considered to be a mutagen in the presence of metabolic activation when tested in the Salmonella strains TA100 and TA1535 which indicated a base pair mutagenic response. Without S-9 there were no positive responses in the strains tested.

Executive summary:

In a study conducted by Machigaki (1991), the test substance, UVR-6110 was examined for its potential to be mutagenic when tested in a bacterial assay using 5 strains of bacteria, including Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 and the Escherichia coli WP2 uvrA- strain. The study was performed using the following concentrations, 156, 313, 625, 1250, 2500 and 5000ug per plate. Each concentration was tested in triplicate and each assay was conducted twice. Each strain was tested using the appropriate a suitable positive control, relevant for each bacterial strain. Each assay was done both in the presence and absence of metabolic activation in the form of S9 mix.

Based on the results of this study, UVR-6110 was considered to be mutagenic under the test conditions employed in this study in the presence of metabolic activation when tested in the Salmonella strains TA100 and TA1535 which indicated a base pair mutagenic response. Without S-9 there were no positive responses in the strains tested..