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EC number: 606-946-6 | CAS number: 221640-14-8
- 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
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- from March to April 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 21 July 1997
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- n.a.
- Molecular formula:
- n.a.
- IUPAC Name:
- n.a.
- Reference substance name:
- Carbamic acid [(1S)-,2-[(2-aminoethyl)amino]-1-[(4-ethoxyphenyl)methyl]ethyl]-,phenylmethyl ester, dihydrochloride (9Cl)
- IUPAC Name:
- Carbamic acid [(1S)-,2-[(2-aminoethyl)amino]-1-[(4-ethoxyphenyl)methyl]ethyl]-,phenylmethyl ester, dihydrochloride (9Cl)
- Reference substance name:
- benzyl[(2S)-1-[(2-aminoethyl)amino]-3-(4-ethoxyphenyl)propan-2-yl]carbamate dihydrochlorid
- EC Number:
- 606-946-6
- Cas Number:
- 221640-14-8
- Molecular formula:
- C21 H29 N3 O3 . 2 Cl H
- IUPAC Name:
- benzyl[(2S)-1-[(2-aminoethyl)amino]-3-(4-ethoxyphenyl)propan-2-yl]carbamate dihydrochlorid
- Test material form:
- solid
impurity 1
impurity 2
impurity 3
Constituent 1
Method
- Target gene:
- Histidine gene locus
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1537
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 1535
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 102
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 100
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 98
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced male rat liver S9 mix
- Test concentrations with justification for top dose:
- 0, 1.6, 5, 16, 50, 160, 500, 1600, 5000 µg/plate (first test = plate incorporation test; +/-S9 mix, all strains)
0, 1.6 (TA 1537, TA 102), 5, 16, 50, 160, 500 (TA 1535, TA 100, , TA 98; ) µg/plate (repeat test = Preincubation test, +/-S9 mix) - Vehicle / solvent:
- DMSO
Controls
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- Remarks:
- No solvent control was used since sufficient evidence was available in the literature and from testing laboratory experience, indicating that the solvents used had no influence on the spontaneous mutant counts of the used strains.
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- sodium azide
- mitomycin C
- other: 4-nitro-1,2-phenylene diamine (TA 1537), 2-aminoanthracene (all strains), cumene hydroperoxide (all strains)
- Remarks:
- The positive controls sodium azide, nitrofluorene, 4-nitro-1,2-phenylene diamine and mitomycin C were only used without S9 mix; the positive control 2-aminoanthracene was only used with S9 mix.
- Details on test system and experimental conditions:
- NUMBER OF REPLICATIONS:
- Number of cultures per concentration: triplicate
- Number of independent experiments: two experiments
METHOD OF TREATMENT/ EXPOSURE:
- Cell density at seeding (if applicable): The titel in the plate incorporation experiment ranged from 7.6E+08 to 20.6E+08 per mL and in the preincubation experiment from 4.9E+08 to 20.8E+08 per mL
- Test substance added in medium; in agar (plate incorporation); preincubation
METHODS FOR MEASUREMENT OF CYTOTOXICITY
- Method, e.g.: background growth inhibition; other: The toxicity of the substance was assessed by gross appraisal of background growth on the plates for mutant determination. Moreover, a toxic effect of the substance was assumed when there was a marked and dose-dependent reduction in the mutant count per plate, compared to the solvent controls. - Rationale for test conditions:
- As recommended by the OECD test guideline
- Evaluation criteria:
- A reproducible and dose-related increase in mutant counts of at least one strain is considered to be a positive result. For TA1535, TA100, TA1537 and TA98 this increase should be about twice that of solvent controls. For TA102 an increase of about 100 mutants should be reached. Otherwise, the result is evaluated as negative. However, these criteria may be overruled by good scientific judgment. In case of questionable results, investigations should continue, possibly with modifications, until a final evaluation is possible.
- Statistics:
- not specified
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Data on pH: not reported
- Precipitation and time of the determination: no precipitates occurred
RANGE-FINDING/SCREENING STUDIES (if applicable): Due to the substance´s toxicity in the plate incorporation tests, doses ranging from 1.6 µg to 500 µg per plate were chosen for the independent repeat test (preincubation) and doses ranging from 1.6 µg to 16 µg per pakte were chosen in addition to the plate incorporation test. The plate first incorporation test was performed with 0, 50, 160, 500, 1600, 5000 µg/plate as recommended by the OECD test guideline.
STUDY RESULTS
- Concurrent vehicle negative and positive control data: yes, please refer to the 'Additional information on results incl. tables' section.
Ames test:
- Signs of toxicity: yes, in the plate incorporation experiment toxicity occurred from 160 µg onwards to the top dose, thus the experiment was repeated with lower concentrations
- Mean number of revertant colonies per plate and standard deviation: yes, please refer to the 'Additional information on results incl. tables' section.
HISTORICAL CONTROL DATA (with ranges, means and standard deviation, and 95% control limits for the distribution as well as the number of data)
- Positive historical control data: yes, please refer to the 'Additional information on results incl. tables' section.
- Negative (solvent/vehicle) historical control data: yes, please refer to the 'Additional information on results incl. tables' section. - Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
Any other information on results incl. tables
Table 1.1: Summary of results from the Salmonella mutagenicity assay (plate incorporation) with Z-Triamin-Dihydrochlorid (mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
0 |
8 |
156 |
7 |
17 |
202 |
50 |
7 |
135 |
7 |
24 |
184 |
160 |
7 |
95 |
4 |
17 |
47 |
500 |
0 |
43 |
0 |
7 |
0 |
1600 |
0 |
0 |
0 |
0 |
0 |
5000 |
0 |
0 |
0 |
0 |
0 |
Positive control |
622* |
1222* |
76* |
1260* |
933* |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
0 |
11 |
228 |
11 |
32 |
299 |
50 |
9 |
208 |
10 |
29 |
276 |
160 |
8 |
170 |
11 |
29 |
265 |
500 |
5 |
100 |
3 |
12 |
0 |
1600 |
0 |
0 |
0 |
0 |
0 |
5000 |
0 | 0 | 0 | 0 | 0 |
Positive control |
79* |
2083* |
136* |
1989* |
856* |
* = mutagenic effect
Table 1.2: Summary of results from the Salmonella mutagenicity assay (plate incorporation) with additional concentrations of Z-Triamin-Dihydrochlorid (mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
0 |
8 |
68 |
5 |
13 |
203 |
1.6 |
7 |
70 |
5 |
14 |
182 |
5 |
8 |
81 |
5 |
14 |
168 |
16 |
7 |
78 |
5 |
12 |
198 |
Positive control |
549* |
908* |
67* |
726* |
671* |
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
0 |
9 |
142 |
7 |
24 |
301 |
1.6 |
10 |
155 |
6 |
25 |
307 |
5 |
9 |
134 |
6 |
29 |
312 |
16 |
10 |
124 |
6 |
24 |
290 |
Positive control |
82* |
1204* |
58* |
1350* |
668* |
Table 2: Summary of results from the Salmonella mutagenicity assay (Pre-Incubation) with Z-Triamin-Dihydrochlorid
(mean values of revertants per plate)
Dose (µg per plate) |
Without metabolic activation |
||||||
|
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
||
0 |
9 |
113 |
6 |
16 |
217 |
||
1.6 |
- |
- |
5 |
- |
235 |
||
5 |
10 |
124 |
7 |
14 |
237 |
||
16 |
7 |
120 |
5 |
12 |
209 |
||
50 |
6 |
93 |
2 |
16 |
184 |
||
160 |
3 |
25 |
0 |
5 |
0 |
||
500 |
0 |
0 |
- |
0 |
- |
||
positive control |
1088 |
1306 | 73 | 1257 | 434 |
||
Dose ( µg per plate ) |
With metabolic activation (liver S9 mix) |
||||||
TA 1535 |
TA 100 |
TA 1537 |
TA 98 |
TA 102 |
|||
0 |
8 |
123 |
10 |
22 |
309 |
||
1.6 |
- |
- |
- |
- |
- |
||
5 |
8 |
112 |
9 |
24 |
312 |
||
16 |
9 |
144 |
9 |
17 |
320 |
||
50 |
9 |
103 |
8 |
22 |
318 |
||
160 |
7 |
99 |
7 |
18 |
222 |
||
500 |
3 | 49 | 0 | 0 | 0 | ||
Positive control |
134 |
1649 |
176 |
1194 |
550 |
* = mutagenic effect
The plate incorporation test, employing doses of up to 5000¿g per plate, showed the test item to produce strain-specific bacteriotoxic effects starting already at 160¿g/ plate. Therefore three additional concentrations (1.6, 5 and 16 µg/plate) were applied .The Salmonella/microsome test, using preincubation employing doses of up to 500¿g per plate, showed the test item to produce strain-specific bacteriotoxic effects at 50¿g per plate and above. Substance precipitation did not occur. Evidence of mutagenic activity of the test item was not seen. No biologically relevant increase in the mutant count, in comparison to the solvent controls, was observed in any of the strains tested, without and with S9 mix, in the plate incorporation as well in the preincubation modification, under the experimental conditions applied.
In spite of the low doses used, positive controls increased the mutant counts to well over those of the solvent controls, and thus demonstrated the system's high sensitivity.
Applicant's summary and conclusion
- Conclusions:
- The mutagenic potential of Z-Triamin-Dihydrochlorid was evaluated in a Salmonella/microsome test with the S. typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 in the presence and absence of S9 mix according to OECD TG 471. Doses up to and including 5000 µg/plate were initially used. Due to strain-specific bacteriotoxic effects at concentrations >= 160 µg per plate the concentration range up to and including 500 µg/plate could only partly used for assessment purposes and the concentration range was supplemented by additional concentrations (1.6, 5 and 16 µg/plate). In an independent repeat using doses up to and including 500 µg/plate strain-specific bacteriotoxic effects occured at >=50 µg/plate. In both experiments, the employed positive controls had a marked mutagenic effect, as was seen by a biologically relevant increase in mutant colonies compared to the corresponding solvent controls. Evidence of mutagenic activity of the test substance was not seen. No biologically relevant increase in the mutant count compared to the corresponding solvent control was observed in any of the strains tested, without and with S9 mix. Therefore, the test item was considered to be non-mutagenic without and with S9 mix in the plate incorporation as well as in the preincubation modification of the Salmonella/mirosome test.
- Executive summary:
In a reverse gene mutation assay in bacteria according to OECD guideline 471 (adopted 21 July 1997), Salmonella typhimurium strains TA98, TA100, TA102, TA1535 and TA1537 were exposed to Z-Triamine Dihydrochloride in DMSO in concentrations of 0 (control), 50, 160, 500, 1600, and 5000 µg/plate in all strains in the absence and presence of mammalian metabolic activation (rat liver S9 mix). The assay was performed using the plate incorporation method.
The test substance was tested up to cytotoxic concentrations. Cytotoxic effects were noted in all strains from 160 µg/plate with/without metabolic activation on. Therefore a second experiment was conducted using the preincubation method with and without metabolic activation at the following concentrations: 0, 5, 16, 50, 160, 500 µg/plate for the tester srains TA98, TA100, TA1535 and TA1537. TA102 was treated with 0, 1.6, 5, 16, 50, 160, and 500 µg/plate in the presence and absence of S9 liver mix. Again, cytotoxicity occurred from 160 µg/plate onwards. Precipitation was not observed. The positive controls induced the appropriate responses in the corresponding strains. The mean numbers of revertant colonies in the negative controls were within the ranges of the historical control data.
There was no evidence of an increase in the number of revertant colonies that exceeded twice background in any of the five tester strains (TA98, TA 100, TA102, TA1535or TA1537) examined at dose levels up to 5000 µg/plate in the absence and presence of a metabolic activation source (S9). Therefore, test substance was considered to be non-genotoxic (non-mutagenic) in Salmonella tester strains TA98, TA100, TA102, TA1535 and TA 1537 under the conditions employed (plate incorporation assay and preincubation method).
There was no evidence of induced mutant colonies over background.
Under the conditions of the study, the test substance was negative for mutagenic potential.
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