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EC number: 206-169-9 | CAS number: 305-84-0
- 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
- Nanomaterial dustiness
- Nanomaterial porosity
- 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
Data waiving, Ames test, OECD 471: Test technically not feasible, as the substance is a dipeptide of histidine and alanine and interferes with the test system.
Supporting study, QSAR for genetic toxicity in bacteria (OECD Toolbox v4.1, 2018 and VEGA software v1.1.4, 2018 and Danish (Q)SAR Database 2018): non-mutagenic in bacteria
Supporting study, Ames test: negative in S. typhimurium SD100, TM677 and Eschrichia coli WP2uvrA (histidine independent strains) with and without metabolic activation. (RA from source substance catena-(S)[µ-[Na-(3-Aminopropionyl)histidinato(2-)-N1,N2,0:N' ]-zinc], (CAS 107667 -60 -7))
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Data waiving:
- study technically not feasible
- Justification for data waiving:
- other:
- Endpoint:
- genetic toxicity in vitro, other
- Remarks:
- : QSAR profiling
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting 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
OECD QSAR Toolbox: a Quantitative Structure-Activity Relationship model that was developed by the Laboratory of Mathematical Chemistry, Burgas, Bulgaria (http://toolbox.oasis-lmc.org).
2. MODEL (incl. version number)
OECD QSAR Toolbox version 4.1
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See "Any other information of materials and methods incl. tables"
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See description of profilers in attached document.
5. APPLICABILITY DOMAIN
General mechanistic profilers with relevance for mutagenicity were selected.
See description of profilers in attached document.
6. ADEQUACY OF THE RESULT
The results may be used in a weight-of-evidence approach together with other information to reach a conclusion regarding the in vitro mutagenicity potential in bacteria of the test substance. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: REACH Guidance on QSARs
- GLP compliance:
- no
- Type of assay:
- other: QSAR profiling
- Key result
- Species / strain:
- other: QSAR in vitro mutagenicity
- Genotoxicity:
- negative
- Additional information on results:
- No general mechanistic DNA binding alert was found. Within the selected endpoint specific profilers, no alerts were found for in vitro mutagenicity, DNA alerts for AMES, CA and MNT by OASIS and Protein binding alerts for Chromosomal aberration by OASIS.
The in vivo mutagenicity (Micronucleus) alerts by ISS identified the “H-acceptor-path3-H-acceptor” alert; this structural alert is triggered by a multitude of different substances, and it was therefore considered as negligible.
The Carcinogenicity (genotox and nongenotox) alerts by ISS identified the structural alert “Imidazole, benzimidazole (Nongenotox)”. This is however related to non-genotoxic carcinogenicity effects of chemicals acting via a variety of modes of action that give rise to hormonal imbalance and subsequent overproduction of trophic hormones. As this alert is not related to genotoxicity, it is not considered for further evaluation. - Remarks on result:
- other: no mutagenic potential based on QSAR profiling
- Conclusions:
- OECD QSAR toolbox v4.1 profiling did not identify structural alerts for the test substance and the results support the evaluation of the substance as non-mutagenic.
- Executive summary:
Two carcinogenicity (genotox and nongenotox) alerts were identified (ISS). The structural alert “Imidazole, benzimidazole (Nongenotox)” is however related to non-genotoxic carcinogenicity effects of chemicals acting via a variety of modes of action that give rise to hormonal imbalance and subsequent overproduction of trophic hormones. As this alert is not related to genotoxicity, it was not considered relevant for evaluation.
- Endpoint:
- genetic toxicity in vitro, other
- Remarks:
- : QSAR prediction
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting 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
Vega, v1.1.4, a freely available software
2. MODEL (incl. version number)
Mutagenicity (Ames test) model (CAESAR) 2.1.13
Mutagenicity (Ames test) model (SarPy/IRFMN) 1.0.7
Mutagenicity (Ames test) model (ISS) 1.0.2
Mutagenicity (Ames test) model (KNN/Read-Across) 1.0.0
Mutagenicity (Ames test) CONSENSUS model 1.0.2
Carcinogenicity model (CAESAR) 2.1.9
Carcinogenicity model (ISS) 1.0.2
Carcinogenicity model (IRFMN/Antares) 1.0.0
Carcinogenicity model (IRFMN/ISSCAN-CGX) 1.0.0
Results in all VEGA models are presented qualitatively: positive or negative.
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See "Any other information of materials and methods incl. tables"
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See "Any other information of materials and methods incl. tables"
5. APPLICABILITY DOMAIN
See "Any other information of materials and methods incl. tables"
6. ADEQUACY OF THE RESULT
The results may be used in a weight-of-evidence approach together with other information to reach a conclusion regarding the in vitro mutagenicity potential in bacteria of the test substance. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: REACH Guidance on QSARs
- Deviations:
- not applicable
- GLP compliance:
- no
- Type of assay:
- other: QSAR modelling
- Key result
- Species / strain:
- other: QSAR in vitro mutagenicity
- Additional information on results:
- Overall, the test substance is predicted as non-mutagenic by the CONSENSUS model 1.0.2, which uses the prediction and related reliability of the four models. However, the reliability score (Applicability Domain Index) for non-mutagenic was just slightly higher compared to the mutagenic outcome (0.3 and 0.2, respectively). The scores lower than 0.6 reflect a low reliability of the results obtained by the four considered (Q)SAR models.
No structural alerts related to mutagenic effect have been identified by two models including knowledge-based rules (ISS) or statistically identified rules (SarPy/IRFMN). A structural alert for mutagenicity was identified by CAESAR. However, compared to the other predictions with medium reliability, the prediction was of low reliability and therefore not considered relevant for the overall prediction. The Read-Across model based its mutagenic prediction on the four most similar compounds identified within the internal dataset; the similarity index associated to this model reflects however only a moderate similarity of the read-across analogues to the evaluated molecule.
Carcinogenicity is for this evaluation not relevant per se, but was investigated to check for possible genotoxic structural alerts, not included in the mutagenicity models. Only two structural alerts have been identified:
- The “SA49 Imidazole and benzimidazole” (Carcinogenicity model (ISS) 1.0.2)
This is however related to non-genotoxic carcinogenicity effects of chemicals acting via a variety of modes of action that give rise to hormonal imbalance and subsequent overproduction of trophic hormones (Woo, 2003). As this alert is not related to genotoxicity, it is not considered for further evaluation.
- The “Structural alert for carcinogenity defined by the SMARTS: NCCCN” (Carcinogenicity model (IRFMN/ISSCAN-CGX) 1.0.0), no information is however provided on the mechanism (genotoxic or non-genotoxic).
Reference
Woo Y.T., 2003, Mechanisms of action of chemical carcinogens, and their role in Structure-Activity Relationships (SAR) analysis and risk assessment., in R Benigni (ed), Quantitative Structure-Activity Relationship (QSAR) models of mutagens and carcinogens.: Boca Raton, CRC Press, p. 41-80. - Remarks on result:
- no mutagenic potential (based on QSAR/QSPR prediction)
- Conclusions:
- VEGA QSAR prediction did not provide indications for mutagenic potential of the test substance.
- Executive summary:
Absence of mutagenic potential was also supported by the findings of the VEGA software. Overall, the test substance was predicted as non-mutagenic by the CONSENSUS model 1.0.2. However, the reliability score for non-mutagenic was just slightly higher compared to the mutagenic outcome (0.3 and 0.2, respectively). Scores lower than 0.6 reflect a low reliability of the results.
- Endpoint:
- genetic toxicity in vitro, other
- Remarks:
- : mutagenicity prediction with Danish (Q)SAR
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting 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
See description of software in attached document.
2. MODEL
See description in attached document.
The genotoxicity results reported by the Danish (Q)SAR Database are qualitative and include information on the prediction and the applicability domain of the models.
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See "Any other information of materials and methods incl. tables"
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See "Any other information of materials and methods incl. tables"
5. APPLICABILITY DOMAIN
See "Any other information of materials and methods incl. tables" an “Overall remarks, attachments”
6. ADEQUACY OF THE RESULT
The results may be used in a weight-of-evidence approach together with other information to reach a conclusion regarding the in vitro mutagenicity potential in bacteria of the test substance. - Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- other: REACH Guidance on QSARs
- Deviations:
- not applicable
- GLP compliance:
- no
- Type of assay:
- other: QSAR modelling
- Key result
- Species / strain:
- other: QSAR in vitro mutagenicity
- Genotoxicity:
- negative
- Additional information on results:
- No structural alerts from the Ashby collection (Ashby 1985, Ashby and Tennant 1988) were identified by the three models, leading to negative (non-mutagenic) predictions. The molecule was also evaluated as within the applicability domain of Leadscope and SciQSAR, increasing the reliability of the results.
According to the Danish (Q)SAR Database output: For the four Ames ”submodels” (Direct Acting Mutagens (without S9), Base-Pair Ames Mutagens, Frameshift Ames Mutagens, Potent Ames Mutagens) the predictions should only be used if the main Ames model (Ames test in S. typhimurium (in vitro)) is POS_IN.
The results of the main Ames model were always NEG_IN (non-mutagenic, in the applicability domain), therefore the results of the single submodels were not considered.
References:
Ashby J., Fundamental structural alerts to potential carcinogenicity or noncarcinogenicity, Environ Mutagen 1985;7:919-21.
Ashby J. and Tennant R.W., Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested by the U.S.NCI/NTP. Mutat Res 1988;204:17-115. - Remarks on result:
- other: no mutagenic potential based on QSAR prediction
- Conclusions:
- The Danish(Q)SAR Database did not identify structural alerts for the test substance and the predictions support the evaluation of the substance as non-mutagenic.
- Executive summary:
The Danish(Q)SAR Database did not identify structural alerts for the test substance.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1991
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- GLP compliance:
- no
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- trp operon for E. coli strain
Streptomycin dependent bacteria Salmonella typhimurium (SD100)
8 - azaguanine sensitive bacteria Salmonella typhimurium (TM677) - Species / strain / cell type:
- E. coli WP2 uvr A
- Species / strain / cell type:
- other: S. typhimurium SD100
- Details on mammalian cell type (if applicable):
- The SD100 strain was isolated from the strain TA100. (obtained from National Institute of Hygienic Sci ences, Tokyo, Japan). SD100 requires a small amount of streptomycin for its growth, and its mutation allows growth in the absence of streptomycin.
- Species / strain / cell type:
- other: S. typhimurium TM677
- Details on mammalian cell type (if applicable):
- The TM677 corresponds to His mutated strain TA100. TM677 mutants are able to growth even in the presence of 8 - azaguanine after treatment with mutagenic chemicals.
- Metabolic activation:
- with and without
- Metabolic activation system:
- cofactor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of rats treated with polychlorobiphenyl (PCB, Aroclor 1254, Monsanto)
- Test concentrations with justification for top dose:
- Experiment: 200, 500, 1000, 2000 or 5000 µg/mL with and without metabolic activation.
- Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-(2-furyl) - 3-(S-nitro -2-furyl)-acrylamide (AF-2), 2- aminoanthracene (2-AA)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: For SD100, TM677 pre-incubation, in agar; and WP2 uvrA, in agar
DURATION
- Preincubation period: For SD100 30 min; For TM677 3h
- Exposure duration: at least 48 h
NUMBER OF REPLICATIONS: single experiment
DETERMINATION OF CYTOTOXICITY
- Method: number of survival/ plate (10 -4 x 0.1 mL/plate) - Evaluation criteria:
- Induced mutation frequency was calculated: Control induced mutant - treated induced mutant
- Statistics:
- Mean values were given
- Key result
- Species / strain:
- other: S. typhimurium SD100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- other: S. typhimurium TM677
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- CHOICE OF TESTER STRAINS:
Since the test substance has histidine in its structure, bacteria requiring histidine for the detection of mutagenicity were not applicable. Therefore, the mutagenic acitivity of the test substance was examined in a streptomycin dependent strain SD100, an 8-azaguanine sensitive strain and a WP2 uvrA strain requiring tryptophan.
ADDITIONAL INFORMATION ON CYTOTOXICITY: No toxic effects of the test substance were observed. - Conclusions:
- Under the conditions of the conducted test, the substance was not mutagenic in any of the three strains (SD100, TM 677 and WP2 uvrA) tested with and without metabolic activation up to 5000 µg/mL.
- Executive summary:
A bacterial gene mutation assay with the read across substance catena-(S) [µ-[Nα-(3 Aminopropionyl)histidinato(2-)-N1,N2,0:Nτ]- zinc] (CAS 107667 -60 -7)) was performed. Since the test substance has histidine in its structure, bacteria requiring histidine for the detection of mutagenicity were not applicable. In this study, the mutagenic activity of the test substance was examined in a streptomycin dependent S. typhimurium strain SD100, an 8-azaguanine sensitive S. typhimurium strain and the E. coli WP2uvrA strain requiring tryptophan. In this study the RA substance (CAS 107667 -60 -7) was not mutagenic in any of the three strains
Referenceopen allclose all
Table1: Mutagenicity study of test substance using Salmonella typhimurium SD100.
Compounds |
Concentrations (µg/mL) |
S9 mix |
Number of survival/plate (10-4 x 0.1 mL/plate) |
Smind mutant/plate(0.1 mL/plate) |
Induced mutants/platec |
Induced mutation frequency(Smind/ 105)d |
Control |
|
- |
235.0a |
20.3a |
- |
- ( 0.86)e |
Test substance |
200 |
- |
223.5b |
17.5b |
0 |
0 |
500 |
- |
208.5 |
20.5 |
0.2 |
0.1 |
|
1000 |
- |
237.5 |
18.5 |
0 |
0 |
|
2000 |
- |
267.5 |
21.0 |
0.7 |
0.03 |
|
5000 |
- |
236.0 |
17.0 |
0 |
0 |
|
AF-2 |
0.2 |
- |
187.0 |
94.5 |
74 |
3.97 |
0.05 |
- |
195.0 |
218 |
197.7 |
10.14 |
|
Control |
|
+ |
200.5a |
25.5 |
- |
- (1.27)e |
Test substance |
200 |
+ |
146.5b |
15.5 |
0 |
0 |
500 |
+ |
122.0 |
15.5 |
0 |
0 |
|
1000 |
+ |
176.5 |
16.5 |
0 |
0 |
|
2000 |
+ |
191.0 |
28.5 |
3.0 |
0.16 |
|
5000 |
+ |
169.0 |
25.5 |
0 |
0 |
|
2-AA |
10 |
+ |
167.0 |
89.5 |
64 |
3.83 |
20 |
+ |
124.0 |
124.0 |
98.5 |
7.94 |
|
10 |
- |
236.0 |
18.5 |
0 |
0 |
|
20 |
- |
232.0 |
18.0 |
0 |
0 |
a mean of 4 plates
b mean of 2 plates
c (control Smind mutant) – (treated Smind mutant) if value is minus, the value is zero.
d induced mutants / number of survival
e spontaneous mutation frequency
Table 2: Mutagenicity study of test substance using Salmonella typhimurium TM677.
Compounds |
Concentrations (µg/mL) |
S9 mix |
Number of survival/plate (10-4 x 0.1 mL/plate) |
8-Agr mutant/plate (0.1 mL/105)c |
Induced mutants/plated |
Induced mutation frequency(8-Agr/105)e |
Control |
|
- |
78.0a |
41.0a |
- |
- ( 5.5)f |
Test substance |
200 |
- |
36.5b |
41.0b |
0 |
0 |
500 |
- |
24.5 |
51.0 |
9.0 |
0.1 |
|
1000 |
- |
28.5 |
58.5 |
16.5 |
0 |
|
2000 |
- |
26.5 |
49.0 |
7.0 |
0.03 |
|
5000 |
- |
40.0 |
37.5 |
|
0 |
|
AF-2 |
0.01 |
- |
64.5 |
146.0 |
104.0 |
3.97 |
0.02 |
- |
56.0 |
275.0 |
233.0 |
10.14 |
|
Control |
|
+ |
71.2a |
51.3a |
- |
- (7.2)f |
Test substance |
200 |
+ |
57.0b |
51.5b |
0.2 |
0 |
500 |
+ |
56.0 |
44.0 |
0 |
0 |
|
1000 |
+ |
67.0 |
45.0 |
0 |
0 |
|
2000 |
+ |
54.5 |
62.0 |
10.7 |
2.0 |
|
50000 |
+ |
38.5 |
43.5 |
0 |
0 |
|
2-AA |
2.5 |
+ |
58.5 |
856.0 |
804.7 |
137.6 |
5 |
+ |
33.0 |
817.5 |
766.2 |
232.2 |
|
2.5 |
- |
53.0 |
46.5 |
4.5 |
0.8 |
|
5 |
- |
67.0 |
42.0 |
0 |
0 |
a mean of 6 plates
b mean of 2 plates
c 8-AGrmutant / number of survival
d (control 8 -AGr mutant) – (treated 8 -AGr mutant) if value is minus, the value is zero.
e induced mutants / number of survival
f spontaneous mutation frequency
Table 3: Mutagenicity study of test substance using Escherichia coli WP2 uvrA.
Compounds |
Concentrations (µg/mL) |
S9 mix |
Number of revertants/plate a |
Control |
|
- |
17 |
Test substance |
200 |
- |
25 |
500 |
- |
20 |
|
1000 |
- |
18 |
|
2000 |
- |
18 |
|
5000 |
- |
17 |
|
AF-2 |
0.04 |
- |
415 |
Control |
|
+ |
22 |
Test substance |
200 |
+ |
20 |
500 |
+ |
23 |
|
1000 |
+ |
23 |
|
2000 |
+ |
20 |
|
5000 |
+ |
29 |
|
2-AA |
40 |
+ |
1025 |
a mean of 2 plates
Endpoint conclusion
- Endpoint conclusion:
- no study available
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Data waiving, Ames, OECD 471:
The bacterial reverse mutation assay (OECD TG 471) is based on the principle that mutagens are detected which revert mutations present in the test strains and restore the functional capability of the bacteria to synthesize an essential amino acid. The revertant bacteria are detected by their ability to grow in the absence of the amino acid required by the parent deficient test strain. For the recommended S. typhimurium strains this amino acid is histidine. Since the test substance is a dipeptide of histidine and alanine it interferes with the principle of the bacterial reverse mutation test (OECD TG 471).
Supporting study, Genetic toxicity (mutagenicity) in bacteria QSAR profiling/prediction in silico:
As data waiving was applied for mutagenicity in bacteria, since the Ames test was technically not feasible, the test substance was further assessed for its mutagenicity potential by QSAR modelling (OECD Toolbox v4.1, 2018 and VEGA software v1.1.4, 2018 and Danish (Q)SAR Database 2018).The models, profilers or predictions included in OECD QSAR Toolbox, VEGA and Danish (Q)SAR Database were not able to identify structural alerts related to genotoxic effects in the evaluated substance.
Using OECD QSAR Toolbox profiling one alert (“H-acceptor-path3-H-acceptor”) was identified as possibly related to micronucleus mutagenicity. The H-acceptor-path3-H-acceptor is triggered by a multitude of different substances, and was therefore considered as negligible. In addition, there were two carcinogenicity (genotox and nongenotox) alerts identified (ISS). The structural alert “Imidazole, benzimidazole (Nongenotox)” is however related to non-genotoxic carcinogenicity effects of chemicals acting via a variety of modes of action that give rise to hormonal imbalance and subsequent overproduction of trophic hormones. As this alert is not related to genotoxicity, it was not considered relevant for evaluation.
Absence of mutagenic potential was also supported by the findings of the VEGA software. Overall, the test substance was predicted as non-mutagenic by the CONSENSUS model 1.0.2. However, the reliability score for non-mutagenic was just slightly higher compared to the mutagenic outcome (0.3 and 0.2, respectively). Scores lower than 0.6 reflect a low reliability of the results.
No structural alerts related to mutagenic effect have been identified by two models including knowledge-based rules (ISS) or statistically identified rules (SarPy/IRFMN). A structural alert for mutagenicity was identified by CAESAR. However, compared to the other predictions with medium reliability, the prediction was of low reliability and therefore not considered relevant for the overall prediction. The Read-Across model based its mutagenic prediction on the four most similar compounds identified within the internal dataset; the similarity index associated to this model reflects however only a moderate similarity of the read-across analogues to the evaluated molecule.This was in line with the negative (non-mutagenic) predictions of the Danish (Q)SAR, no structural alerts from the Ashby collection were identified by the three models. The molecule was also evaluated as within the applicability domain of Leadscope and SciQSAR, increasing the reliability of the results.
The obtained results support the evaluation of the test substance as not mutagenic in bacteria.
Supporting study, Ames test with RA substance catena-(S) [µ-[Nα-(3-Aminopropionyl)histidinato(2-)-N1,N2,0:Nτ]- zinc], (CAS 107667 -60 -7)):
A bacterial gene mutation assay with the read across substance catena-(S) [µ-[Nα-(3 Aminopropionyl)histidinato(2-)-N1,N2,0:Nτ]- zinc] (CAS 107667 -60 -7)) was performed. Since the test substance has histidine in its structure, bacteria requiring histidine for the detection of mutagenicity were not applicable. In this study, the mutagenic activity of the test substance was examined in a streptomycin dependent S. typhimurium strain SD100, an 8-azaguanine sensitive S. typhimurium strain and the E. coli WP2uvrA strain requiring tryptophan. In this study the RA substance (CAS 107667 -60 -7) was not mutagenic in any of the three strains (SD100, TM677 and WP2 uvrA) tested with and without metabolic activation up to concentrations of 5000 µg/mL.
Justification for classification or non-classification
The results of QSAR models (OECD QSAR Toolbox, VEGA and Danish (Q)SAR Database) were not able to identify structural alerts related to genotoxic effects for the test substance.
The available data do not meet the criteria for classification according to Regulation (EC) 1272/2008.
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