Methanone, (2-chloro-5-iodophenyl)[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]-

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:

key study

Study period:

22 August - 5 October 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes (incl. QA statement)

Type of assay:

bacterial reverse mutation assay

Test material

Test material information

Constituent 1

Reference substance name:

(3S)-3-[4-(2-chloro-5-iodobenzoyl)phenoxy]oxolane

EC Number:

619-598-5

Cas Number:

915095-87-3

Molecular formula:

C17 H14 Cl I O3

IUPAC Name:

(3S)-3-[4-(2-chloro-5-iodobenzoyl)phenoxy]oxolane

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): IN 78281
- Physical state: White powder
- Analytical purity: 100.1 %
- Lot/batch No.: 7889-058-10
- Supplier: Boehringer Ingelheim Pharmaceuticals
- Expiration date of the lot/batch: Dec 2006
- Stability under test conditions: Stability data on bulk test material was not provided by the Sponsor
- Storage condition of test material: Room temperature

Method

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

Metabolic activation system:

S 9 mix

Test concentrations with justification for top dose:

1.5, 5.0, 15, 150, 500, 1500 µg/plate

Vehicle / solvent:

- Vehicle used: DMSO

Controls

Untreated negative controls:

yes

Negative solvent / vehicle controls:

yes

True negative controls:

no

Positive controls:

yes

Positive control substance:

9-aminoacridine

2-nitrofluorene

sodium azide

methylmethanesulfonate

other: 2-aminoanthracene

Details on test system and experimental conditions:

METHOD OF APPLICATION: in agar (plate incorporation);

DURATION
- Exposure duration: 48 hours

NUMBER OF REPLICATIONS: 3 each per concentration level and control

Evaluation criteria:

For each replicate plating, the mean and standard deviation of the number of revertants per plate were calculated and are reported.
For the test article to be evaluated positive, it must cause a dose-related increase in the mean revertants per plate of at least one tester strain over a minimum of two increasing concentrations of test article.
Data sets for tester strains TA 1535 and TA 1537 were judged positive if the increase in mean revertants at the peak of the dose response was equal to or greater than 3.0-times the mean vehicle control value. Data sets for tester strains TA98, TA100 and VP2 uvrA were judged positive if the increase in mean revertants at the peak of the dose response was equal to or greater than 2.0-times the mean vehicle control value.
An equivocal response is a biologically relevant increase in a revertant count that partially meets the criteria for evaluation as positive. This could be a dose-responsive increase that does not achieve the respective threshold cited above or a non-dose responsive increase that is equal to or greater than the respective threshold cited. A response will be evaluated as negative, it it is neither positive nor equivocal.

Statistics:

not regarded as neccessary according to the OECD guidelines.

Results and discussion

Test results

Species / strain:

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

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

no cytotoxicity, but tested up to precipitating concentrations

Vehicle controls validity:

valid

Untreated negative controls validity:

valid

Positive controls validity:

valid

Any other information on results incl. tables

Solubility Test

Dimethyl sulfoxide (DMSO) was selected as the solvent of choice based on the solubility of the test article and compatibility with the target cells. The test article formed workable suspensions in dimethyl sulfoxide (DMSO) from approximately 200 to 350 mg/mL and a soluble and clear solution at approximately 150 mg/mL.

Sterility Results

No contaminant colonies were observed on the sterility plates for the vehicle control, the test article dilutions and the S9 and Sham mixes.

Initial Toxicity-Mutation Assay

The results of the initial toxicity-mutation assay are presented in Tables 1 through 10 and summarized in Table 21. These data were generated in Experiment B1. In the initial toxicity-mutation assay, the maximum dose tested was 5000 μg per plate; this dose was achieved using a concentration of 100 mg/mL and a 50 μL plating aliquot. The dose levels tested were 1.5, 5.0, 15, 50, 150, 500, 1500 and 5000 μg per plate. Precipitate was observed beginning at 500 μg per plate. No appreciable toxicity was observed. Based on the findings of the initial toxicity-mutation assay, the maximum dose plated in the confirmatory mutagenicity assay was 5000 μg per plate.

In Experiment B1 (Initial Toxicity-Mutation Assay), no positive mutagenic responses were observed with any of the tester strains in either the presence or absence of S9 activation.

Confirmatory Mutagenicity Assay

The results of the confirmatory mutagenicity assay are presented in Tables 11 through 20 and summarized in Table 22. These data were generated in Experiment B2. The dose levels tested were 15, 50, 150, 500, 1500 and 5000 μg per plate. Precipitate was observed beginning at 500 or 1500 μg per plate. No appreciable toxicity was observed.

In Experiment B2 (Confirmatory Mutagenicity Assay), no positive mutagenic responses were observed with any of the tester strains in either the presence or absence of S9 activation.

Applicant's summary and conclusion

Conclusions:

All criteria for a valid study were met as described in the protocol. The results of the IN00078281-Bacterial Reverse Mutation Assay indicate that, under the conditions of this study, IN00078281 did not cause a positive response in either the presence or absence of Aroclor induced rat liver S9.