2-(piperidin-4-yl)-1H-1,3-benzodiazole

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
C1CC(C2Nc3ccccc3N=2)CCN1

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-(piperidin-4-yl)-1H-1,3-benzodiazole

EC Number:

609-547-5

Cas Number:

38385-95-4

Molecular formula:

C12H15N3

IUPAC Name:

2-(piperidin-4-yl)-1H-1,3-benzodiazole

Results and discussion

Test results

Key result

Remarks on result:

other: Non-mutagenic (based on QSAR/QSPR prediction)

Additional information on results:

The substance is predicted to be negative 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 negative, belonging to model domain in 50%.

Experimental data and mechanistic interpretation od the results:

The target chemical contains benzimidazole fragment bound to piperidine ring in its molecular structure. No experimental data for in vivo metabolism of the target chemical has been observed. No data on the in vivo genotoxicity as indicated by the in vivo rodent bone marrow micronucleus test is provided for the target chemical. Due to the lack of relevant data for target chemical, examples of some selected organic chemicals with benzimidazole structural fragment and existing metabolism and in vivo genotoxicity data are selected. Additionally, due to the commonly more extended in vivo xenobiotic metabolism, other example chemicals containing piperidine ring only have been discussed with respect to metabolic transformations affecting the piperidine structural motif.

The target chemical is assumed to undergo in vivo metabolic transformations, affecting both the benzimidazole ring (aromatic ring hydroxylation) and piperidine rings (aliphatic oxidation).

- Formation of protein-reactive quinone imine, following the aromatic hydroxylation is possible, due to the presence of non-substituted nitrogen atoms (-NH) in benzimidazole ring. However, the highly-reactive quinone imine, if formed in vivo, can be rapidly detoxified before reaching the bone marrow tissue, due to its high protein/glutathione reactivity;

- Oxidation of piperidine ring without its cleavage produces in vivo non-genotoxic metabolites, which are then eliminated by phase II transformations.

Therefore the target chemical is regarded as non-genotoxic in vivo, with expected negative BM-MNT results.

For further details, please refer to the attached report.

Applicant's summary and conclusion

Conclusions:

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

Executive summary:

Prediction in-vivo micronucleus of the test item was performed using: TIMES models (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 assumed to be non-genotoxic in vivo, i.e., negative in the in vivo micronucleus test (OECD 474). The formation of protein-reactive Quinoneimine is possible due to the presence of non-substituted nitrogen atoms (-NH) in benzimidazole ring. However, the highly-reactive Quinoneimine, if formed in vivo, can be rapidly detoxified before reaching the bone marrow tissue, due to its high protein/glutathione reactivity.

Hence, in vivo metabolism patterns of the target chemical do not suggest the formation of any active genotoxic metabolites, capable of reaching the rodent bone marrow tissue.