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Genetic toxicity in vitro
Description of key information
Ames test (OECD 471): negative with S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 and E. coli WP2 uvrA with and without metabolic activation
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:
- 02 - 23 Nov 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- adopted 21 Jul 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Version / remarks:
- 30 May 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Hess. Ministerium für Umwelt, Klimaschutz, Landwirtschaft und Verbraucherschutz, Wiesbaden, Germany
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- his operon (for S. typhimurium strains)
trp operon (for E. coli strain) - Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Metabolic activation system:
- cofactor supplemented post-mitochondrial fraction (S9 mix), prepared from the livers of rats treated with phenobarbital/β-naphthoflavone
- Test concentrations with justification for top dose:
- Pre-experiment: 3, 10, 33, 100, 333, 1000, 2500 and 5000 µg/plate with and without metabolic activation
The pre-experiment is reported as Experiment 1.
Experiment 2:
1, 3, 10, 33, 100, 333 and 1000 µg/plate with and without metabolic activation for TA 98 and TA 100
10, 33, 100, 333, 1000, 2500 and 5000 µg/plate with and without metabolic activation for TA 1535, TA 1537 and WP2 uvr A - Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Justification for choice of solvent/vehicle: The solvent was chosen because of its solubility properties and its relative nontoxicity to bacteria. - Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- methylmethanesulfonate
- other: 4-nitro-o-phenylene-diamine (4-NOPD); 2-aminoanthracene (2-AA)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation; Experiment 1); preincubation (Experiment 2)
DURATION
- Preincubation period: 1 h
- Exposure duration: at least 48 h
NUMBER OF REPLICATIONS: 3 replications each in 2 independent experiment
DETERMINATION OF CYTOTOXICITY
- Method: reduction in the number of spontaneous revertants or a clearing of the bacterial background lawn - Evaluation criteria:
- A test substance is considered as a mutagenic if a biologically relevant increase in the number of revertants exceeding the threshold of twice (strains TA 98, TA 100 and WP2 uvrA) or thrice (strains TA 1535 and TA 1537) the colony count of the corresponding solvent control is observed.
A dose-dependent increase is considered biologically relevant if the threshold is exceeded at more than one concentration.
An increase exceeding the threshold at only one concentration is judged as biologically relevant if reproduced in an independent second experiment.
A dose-dependent increase in the number of revertant colonies below the threshold is regarded as an indication of a mutagenic potential if reproduced in an independent second experiment. However, whenever the colony counts remain within the historical range of negative and solvent controls such an increase is not considered biologically relevant. - Statistics:
- Mean values and standard deviations were calculated.
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Experiment I: -S9: starting at 2500 µg/plate; +S9: starting at 1000 µg/plate Experiment II: -S9: -; +S9: at 5000 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Experiment I: -S9 and +S9: starting at 2500 µg/plate Experiment II: -S9: starting at 1000 µg/plate; +S9: starting at 2500 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Experiment I: -S9 and +S9: starting at 333 µg/plate Experiment II: -S9 and +S9: at 1000 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Experiment I: -S9 and +S9: starting at 333 µg/plate Experiment II: -S9: at 33µg/plate; +S9: at 333 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- Experiment I: -S9: - ;+S9: starting at 2500 µg/plate Experiment II: -S9 and +S9: starting at 2500 µg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: The test item precipitated in the overlay agar in the test tubes from 1000 up to 5000 μg/plate. No precipitation of the test item was observed in the overlay agar on the incubated agar plates.
RANGE-FINDING/SCREENING STUDIES: The pre-experiment is reported as Experiment I (all strains were tested in the pre-experiment).
HISTORICAL CONTROL DATA (with ranges, means and standard deviation and confidence interval (e.g. 95%): Please refer to table 1 in "Any other information on results incl. tables".
ADDITIONAL INFORMATION ON CYTOTOXICITY: The plates incubated with the test substance showed reduced background growth in all tester strains used. Toxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5), occurred in all tester strains used. - Conclusions:
- Under the conditions of the conducted test the substance was not mutagenic in any of the five bacterial strains (TA 1535, TA 1537, TA 98, TA 100 and WP2 uvrA) tested with and without metabolic activation.
- Executive summary:
This study was performed to investigate the potential of test substance to induce gene mutations according to the plate incorporation test (experiment I) and the preincubation test (experiment II) using the Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100, and the Escherichia coli strain WP2 uvrA. The assay was performed in two independent experiments both with and without liver microsomal activation. The test item was tested at the following concentrations:
Pre-Experiment/Experiment I: 3; 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate
Experiment II:
Strains TA 98 and TA 100: 1; 3; 10; 33; 100; 333; and 1000 µg/plate
Strains TA 1535, TA 1537, and WP2 uvrA: 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate
No Precipitation of the test item was observed in the overlay agar on the incubated agar plates. Toxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5), occurred in all strains with and without metabolic activation.
No substantial increase in revertant colony numbers of any of the five tester strains was observed at any dose level, neither in the presence nor absence of metabolic activation (S9 mix). There was also no tendency of higher mutation rates with increasing concentrations in the range below the generally acknowledged border of biological relevance. Appropriate reference mutagens were used as positive controls and showed a distinct increase of induced revertant colonies.
In conclusion, it can be stated that during the described mutagenicity test and under the experimental conditions reported, the test item did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used and is considered to be non-mutagenic.
Reference
Table 1: Historical control data
Strain |
|
|
without S9 mix
|
with S9 mix |
|
||||
Mean |
SD |
Min |
Max |
Mean |
SD |
Min |
Max |
||
TA 1535 |
Solvent control |
12 |
2.5 |
6 |
25 |
12 |
2.5 |
7 |
26 |
Untreated control |
12 |
3.1 |
6 |
28 |
12 |
2.9 |
7 |
26 |
|
Positive control |
1130 |
143.1 |
334 |
1816 |
388 |
58.2 |
176 |
668 |
|
TA1537 |
Solvent control |
10 |
2.2 |
6 |
19 |
13 |
3.5 |
7 |
30 |
Untreated control |
11 |
2.7 |
5 |
21 |
14 |
4 |
7 |
31 |
|
Positive control |
82 |
12.7 |
43 |
157 |
191 |
60.8 |
83 |
434 |
|
TA 98 |
Solvent control |
25 |
4.4 |
13 |
43 |
34 |
6.2 |
15 |
58 |
Untreated control |
27 |
4.9 |
12 |
43 |
37 |
6.5 |
11 |
57 |
|
Positive control |
378 |
73.7 |
211 |
627 |
3949 |
771.8 |
360 |
6586 |
|
TA 100 |
Solvent control |
156 |
26 |
78 |
209 |
148 |
32.3 |
73 |
208 |
Untreated control |
176 |
23.6 |
79 |
217 |
172 |
25.4 |
85 |
218 |
|
Positive control |
1966 |
293.2 |
498 |
2767 |
3798 |
830.4 |
536 |
6076 |
|
WP2uvrA |
Solvent control |
41 |
5.6 |
27 |
63 |
50 |
6.8 |
28 |
72 |
Untreated control |
42 |
5.8 |
30 |
63 |
52 |
6.8 |
36 |
88 |
|
Positive control |
798 |
362.7 |
319 |
4732 |
378 |
112.6 |
167 |
1265 |
Mean = mean value of revertants/plate
SD = standard deviation
Min = minimal value/Max = maximal value
Data from November 2014 until November 2016 representing approx. 600 experiments (WP2 uvrA the historical data are based on approx. 350 experiments).
Table 2: Test results of Experiment I (plate incorporation).
|
Number of revertant colonies per plate |
||||
S9-Mix |
Without |
||||
Test substance (µg/plate) |
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 uvr A |
Solvent control (DMSO) |
18 ± 3 |
13 ± 1 |
25 ± 4 |
134 ± 12 |
36 ± 8 |
Negative control (untreated) |
15 ± 1 |
11 ± 6 |
26 ± 8 |
162 ± 15 |
38 ± 11 |
3 |
16 ± 5 |
9 ± 5 |
26 ± 7 |
125 ± 10 |
38 ± 4 |
10 |
17 ± 3 |
12 ± 2 |
24 ± 8 |
104 ± 6 |
41 ± 2 |
33 |
17 ± 2 |
12 ± 2 |
30 ± 6 |
83 ± 4 |
29 ± 7 |
100 |
22 ± 10 |
17 ± 3 |
29 ± 3 |
62 ± 6 r |
40 ± 2 |
333 |
14 ± 3 rm |
13 ± 2 |
7 ± 2 rm |
2 ± 1 r |
30 ± 2 |
1000 |
9 ± 1 rm |
7 ± 2 rm |
0 ± 1 rm |
0 ± 0 r |
30 ± 5 |
2500 |
8 ± 2 rm |
2 ± 1 rm |
0 ± 0 rm |
1 ± 1 r |
32 ±1 r |
5000 |
4 ± 2 rm |
0 ± 0 rm |
0 ± 0 rm |
0 ± 1 r |
21 ± 6 r |
Positive Control |
NaN3 |
4-NOPD |
4-NOPD |
NaN3 |
MMS |
Dose (µg/plate) |
10 |
50 |
10 |
10 |
2 |
Number of revertant colonies/plate |
1607 ± 89 |
100 ± 9 |
426 ± 35 |
2404 ± 194 |
1013 ± 144 |
S9-Mix |
With |
||||
Test substance (µg/plate) |
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 uvr A |
Solvent control (DMSO) |
16 ± 3 |
15 ± 6 |
35 ± 6 |
105 ± 8 |
53 ± 10 |
Negative control (untreated) |
11 ± 5 |
15 ± 3 |
43 ± 6 |
136 ± 11 |
48 ± 1 |
3 |
17 ± 5 |
18 ± 8 |
43 ± 1 |
94 ± 13 |
50 ± 8 |
10 |
16 ± 2 |
21 ± 4 |
30 ± 3 |
107 ± 8 |
51 ± 3 |
33 |
16 ± 6 |
12 ± 3 |
29 ± 2 |
83 ± 18 |
44 ± 16 |
100 |
14 ± 2 |
16 ± 6 |
32 ± 7 |
60 ± 7 |
41 ± 14 |
333 |
11 ± 5 |
17 ± 2 |
15 ± 5 rm |
15 ± 3 rm |
37 ± 8 |
1000 |
7 ± 2 rm |
9 ± 2 rm |
1 ± 1 rm |
1 ± 1 r |
25 ± 5 |
2500 |
7 ± 2 rm |
5 ± 1 rm |
0 ± 0 rm |
0 ± 0 r |
18 ± 4 r |
5000 |
4 ± 2 rm |
4 ± 1 rm |
0 ± 0 rm |
0 ± 0 r |
6 ± 1r |
Positive Control |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
Dose (µg/plate) |
2.5 |
2.5 |
2.5 |
2.5 |
10 |
Number of revertant colonies/plate |
396 ± 51 |
121 ± 5 |
4563 ± 298 |
2777 ± 315 |
439 ± 51 |
NaN3: sodium acide; 2-AA: 2-Aminoanthracene; 4-NOPD: 4-nitro-o-phenylene-diamine; MMS: methyl methane sulfonate r: reduced background growth m: manual count
|
Table 2: Results of Experiment II (pre-incubation)
|
Number of revertant colonies per plate |
||||
S9-Mix |
Without |
||||
Test substance (µg/plate) |
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 uvr A |
Solvent control (DMSO) |
10 ± 2 |
11 ± 5 |
31 ± 5 |
169 ± 12 |
41 ± 2 |
Negative control (untreated) |
11 ± 1 |
16 ± 5 |
29 ± 3 |
203 ± 11 |
42 ± 6 |
1 |
|
|
27 ± 7 |
157± 20 |
|
3 |
|
|
24 ± 8 |
168 ± 6 |
|
10 |
9 ± 2 |
11 ± 4 |
36 ± 5 |
169 ± 15 |
37 ± 6 |
33 |
10 ± 1 |
8 ± 2 |
19 ±2 |
70 ± 10 |
38 ± 10 |
100 |
11 ± 4 |
8 ± 2 |
25 ± 3 |
69 ± 13 |
35 ± 3 |
333 |
7 ± 3 |
11 ± 2 |
16 ± 2 |
43 ± 6 r |
22 ± 3 |
1000 |
5 ± 1 rm |
3 ± 1 rm |
2 ± 1 |
1 ± 1 rm |
26 ± 5 |
2500 |
6 ± 2 rm |
1 ± 1 rm |
|
|
16 ± 4 rm |
5000 |
5 ± 1 rm |
0 ± 1 rm |
|
|
10 ± 2 rm |
Positive Control |
NaN3 |
4-NOPD |
4-NOPD |
NaN3 |
MMS |
Dose (µg/plate) |
10 |
50 |
10 |
10 |
2 |
Number of revertant colonies/plate |
1761 ± 16 |
93 ± 6 |
548 ± 32 |
2534 ± 43 |
1052 ± 96 |
S9-Mix |
With |
||||
Test substance (µg/plate) |
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 uvr A |
Solvent control (DMSO) |
13 ± 6 |
13 ± 3 |
33 ± 6 |
156 ± 11 |
52 ± 8 |
Negative control (untreated) |
13 ± 1 |
16 ± 4 |
47 ± 8 |
206 ± 6 |
54 ± 11 |
1 |
|
|
33 ± 13 |
167± 1 |
|
3 |
|
|
38 ± 6 |
149 ± 10 |
|
10 |
10 ± 4 |
14 ± 4 |
39 ± 10 |
161 ± 4 |
49 ± 10 |
33 |
14 ± 3 |
15 ± 4 |
44 ± 8 |
137 ± 18 |
48 ± 6 |
100 |
10 ± 4 |
17 ± 2 |
39 ± 9 |
85 ± 4 |
52 ± 10 |
333 |
9 ± 2 |
18 ± 2 |
25 ± 7 r |
28 ± 7 rm |
47 ± 9 |
1000 |
11 ± 1 |
18 ± 4 r |
1 ± 1 rm |
0 ± 1 rm |
28 ± 3 |
2500 |
7 ± 1 rm |
4 ± 1 rm |
|
|
17 ± 5 rm |
5000 |
6 ± 1 rm |
2 ± 1 rm |
|
|
11 ± 2 rm |
Positive Control |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
Dose (µg/plate) |
2.5 |
2.5 |
2.5 |
2.5 |
10 |
Number of revertant colonies/plate |
453 ± 31 |
109 ± 2 |
5475 ± 288 |
4801 ± 140 |
385 ± 10 |
NaN3: sodium acide; 2AA: 2-Aminoanthracene; 4-NOPD: 4-nitro-o-phenylene-diamine; MMS: methyl methane sulfonate r: reduced background growth m: manual count
|
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
A bacterial gene mutation assay with the test substance was performed in accordance with OECD Guideline 471 and in compliance with GLP (2017). In this study the substance was not mutagenic in any of the five bacterial strains (TA 1535, TA 1537, TA 98, TA 100 and WP2 uvr A) tested with and without metabolic activation up to 5000 µg/plate or cytotoxic concentrations.
Justification for classification or non-classification
The available data on genetic toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008.
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