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EC number: 606-467-2 | CAS number: 202189-76-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
In vitro mutagenicity in bacteria. Key study: OECD Guideline 471. GLP study. The test substance was determined to be mutagenic under test conditions.
Genetic toxicity in vitro Mammalian Chromosome Aberration. Key study: The 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:
- May 16, 2002 - July 5, 2002
- 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
- Code: W-02-7046-A1
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: DMSO was used as a vehicle to prepare the test item concentrations. A stock concentration of 100 mg/ml was prepared from which 1:5 dilutions were carried out. The test item precipitates in contact with the phospate tampon in concentrations of 10 and 20mg/ml.
- 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:
- Due to the fact that during the initial tests the concentrations of 10 and 20 mg/ml, precipitated in contact with the phosphate tampon, the following concentrations were used in successive tests: 4; 0.8; 0.16; 0.032 and 0.0064 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 two serioes 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 one of the five concentrations) or the reference item (positive control). The tubes were place in a water bath at 37ºC for 45 minutes. Then 2ml of surface agar supplemented with histidine/biotine 0.5mM 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 37ºC 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. In cases where a positive may exist the assay has been duplicated which results in 4 replicates for some concentrations.
DETERMINATION OF CYTOTOXICITY
-Method: Visual observation of the colonies.
OTHER EXAMINATIONS:
Phenotype and sterility controls were also performed.
- OTHER:
Solutions preparation: DMSO was used as a vehicle to prepare the test item concentrations. In all cases, these concentrations were prepared on the day they were used. A stock concentration of 100mg/ml was prepared from which 1:5 dilutions were carried out.
Test system: Prior to the study, the master plates for each strain were prepared. The strains were plated out in minimum enriched agar plate with Biotin 0.5 mM and Histidine 0.1 M. In the case of strains TA98 and TA100 the plates also contained ampicilyne 8 mg/ml and in the case of strain TA102 they contained tetracycline 8 mg/ml, in addition to Histidine, Biotin and Ampicilyne. The plates were cultivated for 48 hours at 37 ºC. - Rationale for test conditions:
- Due to the fact that during the initial tests the concentrations of 10 and 20 mg/ml, precipitated in contact with the phosphate tampon, the following concentrations were used in successive tests: 4; 0.8; 0.16; 0.032 and 0.0064 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 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- positive
- 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 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
- Genotoxicity:
- positive
- 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:
- 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: The concentrations of 10 and 20 mg/ml, precipitated in contact with the phosphate tampon - Conclusions:
- The test item induce a dose-dependent increase in Salmonella typhimurium strain TA1535 (with and without S9) and TA100 (with S9). Therefore, it was 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 0.0064, 0.032, 0.16, 0.8 and 4 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 colonies 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 induce a dose-dependent increase in TA1535 (with and without S9) and TA100 (with S9). Therefore, the test item was determined to be 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: 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". - 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 deta for the targets and structural analogues and mechanistic interpretation of experimental data and modeling results. The DNA alkylating capability, the positive results in the Ames test and the reported positive in vitro micronucleus/chromosomal aberration test results for the analogues suggest positive in vitro chromosomal aberration (OECD 473) and in vitro microncleus (OECD 487) results in mammalian eukaryotic cells. The chemical can be regarded a 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 there is no toxicity on the concentration taken as a reference to evaluate the mutagenic power.
2. The number of colonies on the spontaneous mutation colonies 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 induce an increase of colonies with respect to non-treated plates, dependent on the concentration of strains TA1535 (with and without S9) and TA100 (with S9).
- The test item does not induce an increase in colonies in the rest of the strains used for this assay.
- The mutation index (MI) calculated from the average os the number of colonies counted on each plate, show values of 1.74 and 3.11 for the strain TA1535 (without and with S9) and 1.46 on the TA100 (with S9) strain.
The results described indicate that:
- The test item is not mutagenic for the strains TA98, TA102 and TA1537
- The test item is mutagenic for the strains TA1535 and TA100
Calculation of the mutation index (MI)
MI = nº. of mut. in a dose / nº. of mut. in the control
Strain TA1535 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
20/28 |
24.00 |
|
19/25/18/25 |
21.75 |
|
0.00 (mg/ml) |
17/20/23/27 |
21.75 |
|
23/23/17/20 |
20.75 |
|
0.0064 (mg/ml) |
16/22 |
19.00 |
0.874 |
23/20/22 |
21.67 |
1.044 |
0.032 (mg/ml) |
16/13 |
14.50 |
0.667 |
22/23/13/19 |
19.25 |
0.928 |
0.16 (mg/ml) |
17/19 |
18.00 |
0.828 |
25/14/18/24 |
20.25 |
0.976 |
0.8 (mg/ml) |
28/22/25/32 |
26.75 |
1.230 |
47/35/30/32 |
36.00 |
1.735 |
4 (mg/ml) |
28/39/45/42 |
38.50 |
1.770 |
66/65/62/65 |
64.50 |
3.108 |
Control + |
480/470 |
475.00 |
21.839 |
134/172 |
153.00 |
7.373 |
Strain TA1000 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
110/116 |
113.00 |
|
95/108 |
101.50 |
|
0.00 (mg/ml) |
89/90 |
89.50 |
|
100/138/146/80 |
116.00 |
|
0.0064 (mg/ml) |
108/99 |
103.50 |
1.156 |
132/135/134/129 |
132.50 |
1.142 |
0.032 (mg/ml) |
88/106 |
97.00 |
1.084 |
138/111/134/117 |
125.00 |
1.078 |
0.16 (mg/ml) |
102/95 |
98.50 |
1.101 |
127/124/149/132 |
133.00 |
1.147 |
0.8 (mg/ml) |
112/106 |
109.00 |
1.218 |
138/125/161/160 |
146.00 |
1.259 |
4 (mg/ml) |
124/100 |
112.00 |
1.251 |
168/144/183/182 |
169.25 |
1.459 |
Control + |
505/487 |
496.00 |
5.542 |
952/946/940/1108 |
986.50 |
8.504 |
Strain TA98 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
28/28 |
28.00 |
|
36/38 |
37.00 |
|
0.00 (mg/ml) |
20/29 |
24.50 |
|
33/33 |
33.00 |
|
0.0064 (mg/ml) |
21/23 |
22.00 |
0.898 |
34/26 |
30.00 |
0.909 |
0.032 (mg/ml) |
20/27 |
23.50 |
0.959 |
33/34 |
33.50 |
1.015 |
0.16 (mg/ml) |
22/30 |
26.00 |
1.061 |
28/29 |
28.50 |
0.864 |
0.8 (mg/ml) |
28/30 |
29.00 |
1.184 |
32/29 |
30.50 |
0.924 |
4 (mg/ml) |
30/23 |
26.50 |
1082 |
38/26 |
32.00 |
0.970 |
Control + |
>1000/>1000 |
>1000 |
>40.816 |
973/965 |
969.00 |
29.364 |
Strain TA1537 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
23/23 |
23.00 |
|
28/40 |
34.00 |
|
0.00 (mg/ml) |
21/18 |
19.50 |
|
26/24 |
25.00 |
|
0.0064 (mg/ml) |
20/22 |
21.00 |
1.077 |
28/24 |
26.00 |
1.040 |
0.032 (mg/ml) |
21/21 |
21.00 |
1.077 |
29/29 |
29.00 |
1.160 |
0.16 (mg/ml) |
21/21 |
21.00 |
1.077 |
30/25 |
27.50 |
1.100 |
0.8 (mg/ml) |
23/21 |
22.00 |
1.128 |
28/26 |
27.00 |
1.080 |
4 (mg/ml) |
25/19 |
22.00 |
1.128 |
28/30 |
29.00 |
1.160 |
Control + |
941/786 |
863.50 |
44.282 |
112/92 |
102.00 |
4.080 |
Strain TA102 |
||||||
|
-S9 |
+S9 |
||||
|
No. Col. |
Average |
MI |
No. Col. |
Average |
MI |
Sp. Mut. |
270/-- |
270.00 |
|
355/316 |
335.50 |
|
0.00 (mg/ml) |
261/260 |
260.50 |
|
315/295 |
305.00 |
|
0.0064 (mg/ml) |
228/239 |
233.50 |
0.896 |
250/240 |
245.00 |
0.803 |
0.032 (mg/ml) |
256/244 |
250.00 |
0.960 |
222/227 |
224.50 |
0.736 |
0.16 (mg/ml) |
200/231 |
215.50 |
0.827 |
282/286 |
284.00 |
0.931 |
0.8 (mg/ml) |
229/268 |
248.50 |
0.954 |
320/284 |
302.00 |
0.990 |
4 (mg/ml) |
250/254 |
252.00 |
0.967 |
321/282 |
301.50 |
0.989 |
Control + |
512/568 |
540.00 |
2.069 |
>1000/>1000 |
>1000 |
>3.279 |
--: 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 |
- |
- |
- |
- |
Resistant |
In vitro Chromosomal aberration. Aplication of TIMES in vitro CA model:
The target chemical is predicted in vitro positive as parents by TIMES Chromosomal aberrations model. The target belong 100% in model applicability domain. The DNA binding alert causing genotoxicity is Sulfonates and Sulfates.
Compounds, containing Sulfonates and Sulfates structural alert are considered to be alkylating agents (direct-acting mutagens), requiring no prior metabolism. Some of the structural preconditions in the Sulfonates and Sulfates structural alert (which are met in the target structures) are the presence of sulphonate group attached to an aromatic ring and carbon sp3 atoms followed by oxygen.
The reliability of Sulfonates and Sulfates alerting group is defined as Undetermined because the local training set of the model consist of six chemicals only. The threshold with respect to the size of the local training set is 10 chemicals. However, the alert performance is 100% - all six chemicals in the local training set are predicted correctly as CA positive. Hence, no matter of the undetermined reliability, all chemical from the local training set are causing CA effect.
Experimental genotoxicity data of the targets and the analogues:
The substance have been reported positive in the bacterial mutagenicity (Ames) test. No experimental data has been reported for the in vitro CA (OECD TG 473) and in vivo bone marrow micronucleus (OECD TG 474) tests. Due to the lack of available experimental data for in vitro CA and in vivo Micronucleus of the target chemical, structurally similar chemicals have been selected from public databases and web sources in order to collect weight of evidence with respect to the modeling results. The criteria of structural similarity are based on the presence of Tosylate or Mesylate ester functionalities which have been considered as critical for eliciting hazardous effects.
- All four analogues have positive experimental data at least in one in vitro test (in vitro Chromosomal aberration (OECD 473), in vitro Bacterial Reverse Mutation assay (OECD 471) or in vitro mammalian cell micronucleus test (OECD TG 487).
- The analogues have DNA alkylating capability and are direct-acting bacterial mutagens (positive in vitro Ames mutagenicity test results).
- The analogue chemicals are considered to elicit positive Chromosomal aberration given the available positive data for more reliable in vitro micronucleus test in mammalian cells (OECD TG 487) which is capable of detecting both clastogend and aneugens.
Mechanistic interpretation of the experimental data and the modelling results:
The target chemical belong to Tosylate esters chemical class and have, approximately, the same reactivity as the corresponding alkyl bromides in the nucleophilic substitution (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.
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 substance is predicted to be 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: 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". - 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: Mutagenic potential (based on QSAR/QSPR prediction)
- Additional information on results:
- The substance is predicted to be positive for in-vivo micronucleus.
- 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.
Reference
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.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
Additional information
Genetic toxicity in vitro: Key study: A Bacteria reverse mutation test was performed according OECD guideline 471 with GLP. Based on previous results, 1 -2E9 cell/ml os Salmonella typhimurium strains Ta98, TA100, TA1535, TA1537 and TA102 were exposed up to 4 mg/ml test item with and without metabolic activation. The test item induced a dose-dependent increase in TA1535 and TA100 in the presence of S9, so it was classified positive 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 deta for the targets and structural analogues and mechanistic interpretation of experimental data and modeling results. The DNA alkylating capability, the positive results in the Ames test and the reported positive in vitro micronucleus/chromosomal aberration test results for the analogues suggest positive in vitro chromosomal aberration (OECD 473) and in vitro microncleus (OECD 487) results in mammalian eukaryotic cells. The chemical can be regarded a in vitro genotoxic
Genetic toxicity in vivo Micronucleus formation. Key study. 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.
Justification for classification or non-classification
Based on the available information, i.e. a positive Ames test and a positive in-vitro chromosome aberration prediction, and a positive in-vivo micronucleus prediction, the substance is determined to be classified for genotoxicity Category 2 according to CLP Regulation (EC) no. 1272/2008.
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