2-{4-[2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)propan-2-yl]phenyl}ethyl 4-methylbenzenesulfonate

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

(Q)SAR

Adequacy of study:

key study

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 adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
OASIS TIMES 2.27.19

2. MODEL
In vivo Micronucleus formation v.08.08

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: Cc1ccc(S(=O)(=O)OCCc2ccc(C(C)(C)C3=NC(C)(C)CO3)cc2)cc1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
The QMRF is available in "Attached justification".

5. APPLICABILITY DOMAIN
The QPRF is available in "Attached justification".

6. ADEQUACY OF THE RESULT
The QPRF is available in "Attached justification".

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSAR R.6

Principles of method if other than guideline:

- Software tool(s) used including version:
OASIST TIMES 2.27.19

- Model(s) used:
In vivo Micronucleus formation v.08.08

- Model description: see field 'Attached justification'

- Justification of QSAR prediction: see field 'Attached justification'

GLP compliance:

no

Type of assay:

mammalian germ cell cytogenetic assay

Test material

Test material information

Constituent 1

Reference substance name:

2-{4-[2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)propan-2-yl]phenyl}ethyl 4-methylbenzene-1-sulfonate

EC Number:

606-467-2

Cas Number:

202189-76-2

Molecular formula:

C23H29NO4S

IUPAC Name:

2-{4-[2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)propan-2-yl]phenyl}ethyl 4-methylbenzene-1-sulfonate

Test material form:

solid

Results and discussion

Test results

Key result

Remarks on result:

other: Mutagenic potential (based on QSAR/QSPR prediction)

Additional information on results:

The substance is predicted to be positive for in-vivo micronucleus.

Any other information on results incl. tables

In vivo Micronucleus. Application of TIMES in vivo Micronucleus model:

TIMES prediction for in vivo Micronucleus model was positive, belonging to model domain in 58%.

Experimental genotoxicity data of the targets and the analogues:

No experimental data has been reported for the in vitro CA (OECD TG 473) and in vivo bone marrow micronucleus (OECD TG 474) tests.

Mechanistic interpretation of the experimental data and the modelling results:

The target chemical belongs to Tosylate esters chemical class and have, approximately, the same reactivity as the corresponding alkyl bromides in the nucleophilic subtitution (SN2) reactions. The reason for this similarity is that sulfonate anions, like bromide anions, are good leaving groups, since they are weak bases. Tosylate esters are capable of alkylating organic bases. This could be also applied to nucleophilic nitrogen-containing fragments of biological macromolecules such as DNA and proteins.

Hydrolysis of sulfonate esters vs. induction of micronuclei based on experimental data:

Some experimental data have shown that highly hydrophoboc sulfonate esters exhibit SN1-type hydrolisis rate in aqueous medium. The more hydrophobic sulfonate esters with very low hydrolysis rates may act more efficiently as genotoxins by reaching the target biopolymer as intact chemicals. It has been reported that intestinal flora can hydrolyse sulfonate esters. Unique phosphonate monoester hydrolase (PMH) was characterized as sulfonate ester hydrolytic enzyme (sulfonate monoesterase), which belongs to the alkaline phosphatase superfamily. It was shown that alkaline phosphatase enzymes are predominantly located in the intestinal microflora, however, they are also present in kidney and liver tissues.

The hydrolysis detoxification of target chemical is assumed to be much less efficient, and the parent chemical is more likely to reach the bone marrow tissue intact, eliciting in vivo genotoxic effects.

For further details, please refer to the attached report.

Applicant's summary and conclusion

Conclusions:

The substance is predicted to be positive for in-vivo micronucleus test.

Executive summary:

Prediction in-vivo micronucleus of the test item was performed using: TIMES model (model version: In vivo Micronucleus formation v.08.08, Platform version: OASIS TIMES 2.27.19), available experimental data for the targets and structural analogues and mechanistic interpretation of experimental data and modeling results. The substance is assummed to be genotoxic in vivo, i.e., positive in the in vivo bone marrow micronucleus test (OECD 474) since:

- In vivo enzymatic hidrolysis to the non-genotoxic p-toluenesulfonic acid is very slow due to the bulky, brunched and hydrophobic structure of the target chemical. Thus, the metabolic hydrolysis could be hampered by steric hindrance effects in the formation of enzyme-substrate complex.

- The in vivo hydrolytic metabolic detoxification of test item is assumed to be much less efficient, and the parent chemical is more likely to reach the bone marrow tissue intact, eliciting in vivo genotoxic effects.