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Registration Dossier
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EC number: 813-966-0 | CAS number: 202189-81-9
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
Genetic toxicity in vitro mutagenicity in bacteria. Key study: OECD Guideline 471. GLP study. The test substance was determined to be non-mutagenic under test conditions.
Genetic toxicity in vitro Mammalian Chromosome Aberration. Key study: The test substance is predicted to be 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:
- October 22, 2007 - December 21, 2007
- 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
- Lot: 5BM
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 the vehicle 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 Salmonella typhimurium so, the following concentrations were tested: 20; 4; 0.8; 0.16; and 0.032 mg/ml.
- 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 bacterial culture and the solvent (negative control), the test item (each of the five concentrations) or the reference item (positive controls). The tubes were placed in a water bath at 37 ºC for 45 minutes. Then 2 mL of surface agar supplemented with histidine/biotin 0.5 mM was added to each tube and poured out onto a minimum agar plate. The plates were left to set for 1 hour and they were then placed in the incubator at 37 ºC for 48-72 hours.
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 minimum agar plates enriched with Biotin 0.5 mM and Histidine 0.1 M. In the case of strains TA98 and TA100 the plates also contained ampicillin 8 mg/ml and in the case of strain TA102 they contaided tetracycline 8 mg/ml, in addition to Histidine, Biotin and Ampicillin. The plates were cultivated for 48 hous at 37 ºC. - Rationale for test conditions:
- The top concentration of the test item, 100 mg/ml, was toxic for Salmonella typhimurium so, the following concentrations were tested: 20; 4; 0.8; 0.16 and 0.032 mg/ml.
- 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 a dose-dependent increase in Salmonella typhimurium strains. Therefore, it was considered as non-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 any of the Salmonella typhimurium. 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: CC1(C)COC(C(C)(C)c2ccc(CCN3CCC(C4Nc5ccccc5N=4)CC3)cc2)=N1
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 positive for in-vitro chromosomal aberration.
- Remarks on result:
- mutagenic potential (based on QSAR/QSPR prediction)
- Conclusions:
- The substance is predicted to be positive for in-vitro chromosomal aberration.
- Executive summary:
Prediction in-vitro chromosomal aberrations of the test item was performed using: TIMES model (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. The capability of forming protein-reactive quinone imine metabolites suggest to cause positive in vitro chromosomal aberration (OECD 473) effects with eukaryotic mammalian CHO and CHL cells (i.e. to damage the proteins). The chemical can 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, 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, neither in the presence of S9 nor in its absence.
Calculation of the mutation index (MI)
MI = nº. of mut. in a dose / nº. of mut. in the control
Strain TA98 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
22/20 |
21.0 |
-- |
20/17 |
18.5 |
-- |
0mg/ml |
18/20 |
19.0 |
-- |
15/16 |
15.5 |
-- |
32mg/ml |
17/17 |
17.0 |
0.895 |
18/14 |
16.0 |
1.032 |
160mg/ml |
27/25 |
26.0 |
1.368 |
20/13 |
16.5 |
1.065 |
800mg/ml |
16/22 |
19.0 |
1.000 |
24/15 |
19.5 |
1.258 |
4000mg/ml |
16/19 |
17.5 |
0.921 |
18/24 |
21.0 |
1.355 |
2000mg/ml |
26/24 |
25.0 |
1.316 |
27/15 |
21.0 |
1.355 |
Control + |
>2000/>2000 |
>2000 |
>105.263 |
>2000/>2000 |
>2000 |
129.032 |
Strain TA100 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
173/179 |
176.0 |
-- |
200/184 |
192.0 |
-- |
0mg/ml |
180/176 |
178.0 |
-- |
191/197 |
194.0 |
-- |
32mg/ml |
172/174 |
173.0 |
0.972 |
182/175 |
178.5 |
0.920 |
160mg/ml |
181/173 |
177.0 |
0.994 |
190/194 |
192.0 |
0.990 |
800mg/ml |
168/174 |
171.0 |
0.961 |
181/176 |
178.5 |
0.920 |
400mg/ml |
190/176 |
183.0 |
1.028 |
198/179 |
188.5 |
0.972 |
20000mg/ml |
184/191 |
187.5 |
1.053 |
207/210 |
208.5 |
1.075 |
Control + |
>2000/>2000 |
>2000 |
>11.236 |
>2000/>2000 |
>2000 |
>10.309 |
Strain TA102 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
330/324 |
327.0 |
-- |
420/416 |
418.0 |
-- |
0mg/ml |
321/324 |
322.5 |
-- |
380/410 |
395.0 |
-- |
32mg/ml |
330/326 |
328.0 |
1.017 |
426/430 |
428.0 |
1.084 |
160mg/ml |
321/337 |
329.0 |
1.020 |
412/400 |
406.0 |
1.028 |
800mg/ml |
320/326 |
323.0 |
1.002 |
430/422 |
426.0 |
1.078 |
4000mg/ml |
329/334 |
331.5 |
1.028 |
416/420 |
418.0 |
1.058 |
20000mg/ml |
323/329 |
326.0 |
1.011 |
410/420 |
415.0 |
1.021 |
Control + |
>2000/>2000 |
>2000 |
>6.202 |
880/900 |
890.0 |
2.253 |
Strain TA1535 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
6/7 |
6.5 |
-- |
13/15 |
14.0 |
-- |
0mg/ml |
8/6 |
7.0 |
-- |
16/17 |
16.5 |
-- |
32mg/ml |
4/5 |
4.5 |
0.643 |
18/18 |
18.0 |
1.091 |
160mg/ml |
7/8 |
7.5 |
1.071 |
16/18 |
17.0 |
1.030 |
800mg/ml |
7/5 |
6.0 |
0.857 |
22/15 |
18.5 |
1.121 |
4000mg/ml |
6/5 |
5.5 |
0.786 |
24/17 |
20.5 |
1.242 |
20000mg/ml |
5/7 |
6.0 |
0.857 |
21/20 |
20.5 |
1.242 |
Control + |
>1500/>1500 |
>1500 |
>214.286 |
245/257 |
251.0 |
15.212 |
Strain TA1537 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
4/4 |
4.0 |
-- |
10/7 |
8.5 |
-- |
0mg/ml |
7/6 |
6.5 |
-- |
6/8 |
7.0 |
-- |
32mg/ml |
7/5 |
6.0 |
0.923 |
6/8 |
7.0 |
1.000 |
160mg/ml |
5/4 |
4.5 |
0.692 |
4/8 |
6.0 |
0.857 |
800mg/ml |
2/5 |
3.5 |
0.538 |
13/10 |
11.5 |
1.643 |
4000mg/ml |
5/4 |
4.5 |
0.692 |
12/7 |
9.5 |
1.357 |
20000mg/ml |
7/5 |
6.0 |
0.923 |
9/5 |
7.0 |
1.000 |
Control + |
164/171 |
167.5 |
25.769 |
180/191 |
185.5 |
26.500 |
--: It was not possible to count colonies
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 |
n.t |
n.t |
n.t |
n.t |
Resistant |
n.t.: not tested
In vitro Chromosomal aberration. Application of TIMES in vitro CA model:
The target chemical is predicted in vitro positive by TIMES Chromosomal aberrations model. It belongs 52% 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.
In the structure of its simulated phenolic metabolite there is available hydrogen atom at position 1 of the benzimidazole fragment which appears to be critical for eliciting protein damages.
The corresponding Quinoneimine is expected to be formed as a result of Quinone imine transformation reaction. The reactive Quinoneimine metabolites are able to form protein adducts.
Hence, the target chemical is able to form after S9 metabolic activation reactive metabolites able to damage the proteins.
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 target chemical is assumed to undergo in vitro metabolic transformations, affecting both the benzimidazole and piperidine ring, similarly to one of the selected examples. The potential for formation of quinone imine as active metabolite indicates possible positive in vitro Chromosomal aberration after metabolic activation.
The target chemical with non-substituted benzimidazole ring in position 1, i.e containing cyclic -NH group, is capable of forming protein-reactive quinone imine metabolites. Hence, it is predicted to cause positive in vitro chromosomal aberration effects with eukaryotic mammalian CHO and CHL cells (i.e. to damage the proteins).
For further details, please refer to the attached report.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
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: CC1(C)COC(C(C)(C)c2ccc(CCN3CCC(C4Nc5ccccc5N=4)CC3)cc2)=N1
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). 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. The substance is predicted to be negative for in-vivo micronucleus test.
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 52%.
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 may undergo in vivo metabolic transformations, affecting the benzimidazole ring (aromatic ring hydroxylation) and Oxidative N-dealkylation at the piperidine ring.
- Formation of protein-reactivo quinone imine, following the aromatic hydroxylation is possible. However, the highly-reactive quinone imine, if formed in vivo, is assumed to rapidly detoxified before reaching the bone marrow tissue;
- Oxidative N-dealkylation at the piperidine ring (without its cleavage) results in the formation of 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.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Genetic toxicity in vitro AMES: Key study: OECD Guideline 471. GLP 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 do not induce a dose-dependent increase in Salmonella typhymurium strains, 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 model (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. The capability of forming protein-reactive quinone imine metabolites suggest to cause positive in vitro chromosomal aberration (OECD 473) effects with
eukaryotic mammalian CHO and CHL cells (i.e. to damage the proteins). The chemical can 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). 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.
Justification for classification or non-classification
Based on the available information, i.e. a positive in-vitro chromosome aberration prediction, but a negative Ames test 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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