Registration Dossier
Registration Dossier
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EC number: 813-963-4 | CAS number: 202189-77-3
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
Genetic toxicity in vitro Mammalian Chromosome Aberration. Key study: The test substance is predicted to be non-mutagenic in mammalian cells.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- August 29, 2006 - September 30, 2006
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: sponsor
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature in darkness.
- Solubility and stability of the test substance in the solvent/vehicle: Sodium phosphate buffer, 200mM, pH=7.4, was used as diluent to prepare the item concentrations. A stock concentration of 100 mg/ml was prepared in DMSO from which 1:5 dilutions were made.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no - Target gene:
- Histidine
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9
- Test concentrations with justification for top dose:
- The top concentration of the test item was toxic for strain TA100 so, the following concentrations were assayed on the rest of the strains: 20; 4; 0.8; 0.16; and 0.032 mg/ml corresponding to 1; 0.2; 0.04; 0.008 and 0.002 mg/plate.
- Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Justification for choice of solvent/vehicle: Solvent is compatible with the survival of the bacteria and the S9 activity. - 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
- cumene hydroperoxide
- other: 2-aminoantracene
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: Preincubation
Each point of the two series of tubes (with and without S9) was tested in duplicate and with the following composition: phosphate buffer (or S9 mixture), 2E9 cell/ml
DURATION
- Preincubation period: 45 minutes
- Exposure duration:48 -72 hours
SELECTION AGENT (mutation assays): The lack of amino-acid in the medium. Only the mutants can grow due to their capability to synthesize an essential amino acid.
NUMBER OF REPLICATIONS: 2.
DETERMINATION OF CYTOTOXICITY
- Method: Visual observation of the colonies.
OTHER EXAMINATIONS:
Phenotype and sterility controls were also performed.
- OTHER:
Solutions preparation: Sodium phosphate buffer, 200mM, pH=7.4, was used as the vehicle to prepare the item concentrations. In all cases, these concentrations were prepared on the day they were used. A stock concentration of 100mg/ml was prepared in DMSO from which 1:5 dilutions were carried out.
Test system: Prior to the study, the master plates of each strain were prepared. The strains were plated out in minimal agar plates enriched with 0.5 mM Biotin and 0.1 M Histidine. In the case of strains TA98 and TA100 the plates also contained ampicillin 8 mg/mL and for strain TA102 they contained, in addition to Histidine, Biotin and Ampicillin, Tetracycline 8mg/mL. The seeded plates were grown for 48 hours at 37 ºC. - Rationale for test conditions:
- The top concentration of the test item, 100 mg/ml, was toxic for TA100 strain so, the following concentrations were tested on the rest of the strains: 20; 4; 0.8; 0.16 and 0.032 mg/ml corresponding to 1; 0.2; 0.04; 0.008 and 0.002 mg/plate.
- Evaluation criteria:
- Criteria conclusion: the result of the test is considered as positive if the test item induce an increase of colonies with respect to non-treated plates, dependent on the concentration of one, or several of the 5 strains, without and/or with metabolic activation.
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: No - Conclusions:
- The test item does not induce an dose-dependent increase in Salmonella typhimurium strains. Therefore, it was not considered as mutagenic under test conditions.
- Executive summary:
A Bacterial reverse mutation test was performed according OECD guideline 471 with GLP. Based on a previous toxicity test, 1-2E9 cell/mL of Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA102 were exposed to 0.032, 0.16, 0.8, 4 and 20 mg/mL test item, solvent and positive controls with and without metabolic activation (two replicates each). The incubation mixtures were pre-incubated at 37 ºC for 45 minutes and incubated at 37 ºC for 48 -72 hours. Then, the revertant colonies were counted. Phenotype and sterility controls were also performed. The plates showed a firm, uniform lawn, which demonstrates that there was no toxicity. The number of colonies in the spontaneous mutation plates was within the normal range for each strain. The positive controls induced a clear increase in the number of revertants in all cases and the phenotype control plates show the expected results for each strain. The test item does not induce a dose-dependent increase in Salmonella typhimurium strains. Therefore, the test item was determined to be non-mutagenic under test conditions.
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: gene mutation
- 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 (incl. version number)
In vitro Chromosomal Aberrations v.12.12
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
SMILES: CCOCCN1c2ccccc2N=C1C1CCN(CCc2ccc(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". - 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:
OASIS TIMES 2.27.19
- Model(s) used:
In vitro Chromosomal Aberrations v.12.12
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification' - GLP compliance:
- no
- Type of assay:
- other: In-vitro chromosomal aberrations in mammalian cells
- Key result
- Additional information on results:
- The substance is predicted to be negative for in-vitro chromosomal aberration.
- Remarks on result:
- no mutagenic potential (based on QSAR/QSPR prediction)
- Conclusions:
- The substance is predicted to be negative for in-vitro chromosomal aberration.
- Executive summary:
Prediction in-vitro chromosomal aberrations of the test item was performed using: TIMES models (Model version: In vitro Chromosomal Aberrations v.12.12, 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. No quinone imine matabolites can formed, due to the lack of H-atoms bount to nitrogen and the concomitant presence of subtituent at the N-atom of benzimidazole ring. The chemical cannot be regarded as in vitro genotoxic.
Referenceopen allclose all
The conditions listed below indicate that the tests are acceptable:
1. The plates show a firm and uniform lawn which demonstrates that there is no toxicity in the concentrations that were taken as a reference to evaluate the mutagenic power.
2. The number of colonies in the spontaneous mutation plates is within the normal range for each strain.
3. The positive controls induce a clear increase in the number of revertants in all cases.
4. The phenotype control plates show the expected results for each strain.
From the results expressed on the tables below it can be deduced that the test item does not induce an increase in colonies in any of the strains used in this study, either in the presence or absence of S9.
Calculation of the mutation index (MI)
MI = No. of mut. at one dose / No. of mut. in the control
Strain TA98 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
33/31 |
32.0 |
-- |
42/40 |
41.0 |
-- |
0.000 mg/plate |
34/31 |
32.5 |
-- |
44/46 |
45.0 |
-- |
0.002 mg/plate |
n.t. |
n.t. |
-- |
32/29 |
30.5 |
0.678 |
0.008 mg/plate |
28/26 |
27.0 |
0.831 |
26/34 |
30.0 |
0.667 |
0.040 mg/plate |
30/32 |
31.0 |
0.954 |
35/31 |
33.0 |
0.733 |
0.200 mg/plate |
26/30 |
28.0 |
0.862 |
22/35 |
28.5 |
0.633 |
1.000 mg/plate |
30/25 |
27.5 |
0.846 |
32/38 |
35.0 |
0.778 |
5.000 mg/plate |
32/27 |
29.5 |
0.908 |
n.t. |
n.t. |
-- |
Control + |
>3000/>3000 |
>3000 |
>92.308 |
>3000/>3000 |
>3000 |
>66.67 |
Strain TA100 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
109/102 |
105.0 |
-- |
146/139 |
142.5 |
-- |
0.000 mg/plate |
122/116 |
119.0 |
-- |
148/152 |
150.0 |
-- |
0.002 mg/plate |
n.t. |
n.t. |
-- |
170/168 |
169.0 |
1.127 |
0.008 mg/plate |
106/112 |
109.0 |
0.916 |
156/162 |
159.0 |
1.060 |
0.040 mg/plate |
131/117 |
124.0 |
1.042 |
168/180 |
174.0 |
1.160 |
0.200 mg/plate |
124/100 |
112.0 |
0.941 |
197/173 |
185.0 |
1.233 |
1.000 mg/plate |
114/-- |
114.0 |
0.958 |
150/148 |
149.0 |
0.993 |
5.000 mg/plate |
tox/tox |
|
|
n.t. |
n.t. |
-- |
Control + |
1840/1680 |
1760 |
14.790 |
1600/1750 |
1675 |
11.167 |
Strain TA102 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
310/322 |
316.0 |
-- |
458/471 |
464.5 |
-- |
0.000 mg/plate |
346/339 |
342.0 |
-- |
482/495 |
488.5 |
-- |
0.002 mg/plate |
264/271 |
267.5 |
0.781 |
462/479 |
470.5 |
0.963 |
0.008 mg/plate |
252/301 |
276.5 |
0.807 |
480/473 |
476.5 |
0.975 |
0.040 mg/plate |
264/278 |
271.0 |
0.791 |
493/475 |
484.0 |
0.991 |
0.200 mg/plate |
280/263 |
271.5 |
0.793 |
472/487 |
479.5 |
0.982 |
1.000 mg/plate |
268/275 |
271.5 |
0.793 |
464/481 |
472.5 |
0.967 |
Control + |
>3000/>3000 |
>3000 |
>8.759 |
2600/2500 |
2550 |
5.220 |
Strain TA1535 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
17/20 |
18.5 |
-- |
23/19 |
21.0 |
-- |
0.000 mg/plate |
19/22 |
20.5 |
-- |
22/24 |
23.0 |
-- |
0.002 mg/plate |
23/22 |
22.5 |
1.098 |
22/25 |
23.5 |
1.022 |
0.008 mg/plate |
21/20 |
20.5 |
1.000 |
20/28 |
24.0 |
1.043 |
0.040 mg/plate |
20/16 |
18.0 |
0.878 |
20/17 |
18.5 |
0.804 |
0.200 mg/plate |
19/18 |
18.5 |
0.902 |
19/23 |
21.0 |
0.913 |
1.000 mg/plate |
20/20 |
20.0 |
0.976 |
19/21 |
20.0 |
0.870 |
Control + |
334/362 |
348.0 |
16.976 |
329/356 |
342.5 |
14.891 |
Strain TA1537 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
18/13 |
15.5 |
-- |
8/11 |
9.5 |
-- |
0.000 mg/plate |
11/11 |
11.0 |
-- |
10/7 |
8.5 |
-- |
0.002 mg/plate |
9/12 |
10.5 |
0.955 |
9/13 |
11.0 |
1.294 |
0.008 mg/plate |
10/9 |
9.5 |
0.864 |
10/10 |
10.0 |
1.176 |
0.040 mg/plate |
9/9 |
9.0 |
0.818 |
10/12 |
11.0 |
1.294 |
0.200 mg/plate |
12/11 |
11.5 |
1.045 |
13/9 |
11.0 |
1.294 |
1.000 mg/plate |
8/9 |
8.5 |
0.773 |
10/13 |
11.5 |
1.353 |
Control + |
269/274 |
271.5 |
24.682 |
297/285 |
291.0 |
34.235 |
--: The colonies could not be counted. The plate is not uniform
tox: The colonies could not be counted. There is evidence of toxicity.
n.t.: The indicated concentrations have not been tested.
Results of the phenotype control
|
TA98 |
TA100 |
TA1535 |
TA1537 |
TA102 |
Ampicilyne |
Resistant |
Resistant |
Sensitive |
Sensitive |
Resistant |
Violet Crystal |
Sensitive |
Sensitive |
Sensitive |
Sensitive |
Sensitive |
UV light |
Sensitive |
Sensitive |
Sensitive |
Sensitive |
Sensitive |
Tetracycline |
- |
- |
- |
- |
Resistant |
In vitro Chromosomal aberration. Application of TIMES in vitro CA model:
The target chemical is predicted in vitro negative by TIMES Chromosomal aberrations model. It belongs 79% in model applicability domain. No alerts damaging DNA are identified. Fragments that could cause chromosomal aberrations are identified, but they lack additional structural requirements needed to bring about the positive effect.
Experimental data and mechanistic interpretion of the results:
The chemical contains benzimidazole fragment bound to piperidine ring in its molecular structure. No
experimental data has been reported for in vitro metabolism of the target chemical with microsomal/S9
activation. No data on the in vitro cytogenetics (chromosomal aberrations) has been provided. The target
chemical is negative in the in vitro Ames test for bacterial mutagenecity. Due to the lack of relevant data
for the target chemical, examples of some selected organic chemicals with benzimidazole structural
fragment and existing metabolism and in vitro genotoxicity data have been selected.
The lack of hydrogen atoms bound to the cyclic nitrogens, and the presence of large subtituents at both the N-atoms of benzimidazole and piperidine rings would wignificantly restrict the occurrence of in vitro metabolism. The lack of metabolic activation with quinone imine formation should contribute to negative with respect to in vitro Chromosomal aberration.
For further details, please refer to the attached report.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Description of key information
Genetic toxicity in vivo Micronucleus formation. Key study: The test substance is predicted to be non-genotoxic in mammalian cells.
Link to relevant study records
- 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: CCOCCN1c2ccccc2N=C1C1CCN(CCc2ccc(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" - 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
- 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.
- 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) since:
- The lack of hydrogen atoms bound to the cyclic nitrogens, and the concomitant presence of large subtituents at both the N-atoms of benzimidazole and piperidine rings restrict the ocurrence of any significant in vivo metabolism.
- The lack of metabolic activation of benzimidazole ring to quinone imine and the poor metabolism with formation of non-genotoxic metabolites are then subjected to phase II conjugations.
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.
Reference
In vivo Micronucleus. Application of TIMES in vivo Micronucleus model:
TIMES prediction for in vivo Micronucleus model was negative, belonging to model domain in 79%.
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 lack of hydrogen atoms bound to the cyclic nitrogens, and the concomitant presence of large subtituents at both the N-atoms of benzimidazole and piperidine rings restrict the ocurrence of any significant in vivo metabolism. The lack of metabolic activation of benzimidazole ring to quinone imine, the poor metabolism with formation of non-genotoxic metabolites only, which are the subjected to phase II conjugations probably contribute to negative in vivo micronucleus.
For further details, please refer to the attached report.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Genetic toxicity in vitro Ames: Key study: A Bacterial reverse mutation test was performed according OECD guideline 471 with GLP. Based on previous results, 1-2E9 cell/ml of Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA102 were exposed up to 20 mg/ml test item with and without metabolic activation. The test item does not induce an increase in colonies in any of the strains used in this study, neither in the presence of S9 nor in its absence, so it was classified as negative in the Ames test.
Genetic toxicity in vitro Mammalian Chromosome Aberration: Key study. Prediction in-vitro chromosomal aberrations of the test item was performed using: TIMES models (Model version: In vitro Chromosomal Aberrations v.12.12, 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. No quinone imine matabolites can formed, due to the lack of H-atoms bount to nitrogen and the concomitant presence of subtituent at the N-atom of benzimidazole ring. The chemical cannot be regarded as in vitro genotoxic.
Genetic toxicity in vivo Micronucleus formation. Key study. 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) since:
- The lack of hydrogen atoms bound to the cyclic nitrogens, and the concomitant presence of large subtituents at both the N-atoms of benzimidazole and piperidine rings restrict the ocurrence of any significant in vivo metabolism.
- The lack of metabolic activation of benzimidazole ring to quinone imine and the poor metabolism with formation of non-genotoxic metabolites are then subjected to phase II conjugations.
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.
Justification for classification or non-classification
Based on the available information, i.e. a negative Ames test, a negative in-vitro chromosome aberration prediction, and a negative in-vivo micronucleus prediction, the substance is determined not to be classified for genotoxicity according to CLP Regulation (EC) no. 1272/2008.
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