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EC number: 210-498-3 | CAS number: 616-91-1
- 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
In an in vitro bacterial reverse mutation assay (Ames test) according to OECD TG 471, the test item did not induce gene mutations in the tester strains used (reference 7.6.1-1). In addition, in several other bacterial reverse mutation assays, the test item did not show genotoxic properties (reference 7.6.1 -2 to 7.6.1 -4).
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:
- February 5, 2018 - March 15, 2018
- 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:
- 21 July 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
- Qualifier:
- according to guideline
- Guideline:
- JAPAN: Guidelines for Screening Mutagenicity Testing Of Chemicals
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9-mix from beta-Naphthoflavone and Phenobarbital pretreated Wistar rats
- Test concentrations with justification for top dose:
- The test material concentrations used were selected according to the EEC, OECD and Japanese guidelines for this test system. 5000 µg/plate was chosen as the appropriate maximum concentration.
+/- S9-Mix: 5.00;15.8; 50.0; 158; 500; 1580; 5000 µg/plate (1st Experiment)
+/- S9-Mix: 50.0; 158; 500; 1580; 5000 µg/plate (2nd Experiment) - Vehicle / solvent:
- - Solvent used: ultrapure water
- Justification for choice of solvent: The selection of the solvent for this assay was based on the available information from a preliminary solubility test. Ultrapure water showed best performance and was thus used for this experiment at a maximum concentration of 100 µL/plate. - Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: Daunomycin
- Remarks:
- without S9 Mix, TA 98
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- without S9 Mix, E.coli WP2 uvrA
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- without S9 Mix, TA 100, TA 1535
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- without S9 Mix, TA 1537
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Aminoanthracene
- Remarks:
- with S9 Mix, all tester strains
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Exposure duration: 72 h at 37°C
NUMBER OF REPLICATIONS: 2 - Evaluation criteria:
- A test material was to be defined as positive or mutagenic in the assay if
- the assay is considered valid and
- a biologically relevant increase in the mean number of revertants above a threshold of 2-fold (TA98,TA 100, WP2 uvrA) or 3-fold (TA 1535, TA 1537) as compared to the concurrent negative controls is observed
- an increase exceeding the threshold at only one concentration is considered as biologically meaningful if reproduced in a second independent experiment
- a concentration-dependent increase is considered biologically meaningful if the threshold is exceeded at more than one concentration
A test material is defined as negative or non-mutagenic in this assay if
- the assay is considered valid and
- none of the above-mentioned criteria are met - Statistics:
- None
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not applicable
- 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:
- not specified
- Vehicle controls validity:
- not applicable
- 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:
- not specified
- Vehicle controls validity:
- not applicable
- 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:
- not specified
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- valid
- 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:
- not applicable
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Conclusions:
- The substance was not mutagenic under the described experimental conditions.
- Executive summary:
A study according to OECD TG 471 was conducted to examine the mutagenic potential in an in vitro bacterial reverse mutation test employing Salmonella typhimurium TA 98, TA 100. TA 1535 and TA 1537 and Escherichia coli WP2 uvrA as indicator organisms.
The plate incorporation test with and without addition of liver S9 mix from Phenobarbital/p-Naphthoflavone-pretreated rats was used. In this study, two experimental series were performed. In the experiments with S9 mix, 10% and 20% S9 in the S9 mix were used.Treatments of all tester strains were performed using test item formulations prepared in ultrapure water in the absence and in the presence of S9 mix using final concentrations between 5 and 5000 µg/plate, plus vehicle and positive controls. The mean numbers of revertant colonies of the current negative controls were within the range of historical negative control values. The strain-specific positive controls, namely daunomycin, sodium azide, 4-nitroquinolin-N-oxide and 9-aminoacridine in the absence of S9 mix yielded the expected mutant frequencies that were greatly exceeding the negative controls. The genotype of the tester strains used was thus confirmed. 2-Aminoanthracene which requires metabolic activation, was strongly mutagenic. This indicates that the exogenous metabolizing system used in the present investigation (S9 mix) was active. Following treatment with the substance, neither precipitation of the test material, nor toxicity to the bacteria was observed. Under the conditions described, there were no relevant increases in revertant numbers observed after exposure to the test item in the absence and presence of S9 mix. According to the criteria for negative and positive results predetermined in the study, the substance was not mutagenic under the described experimental conditions.
Reference
Table 1: Summery of Results (1st Run)
Metabolic Activation |
Test material |
Concentration [µg/plate] |
Revertants per plate (mean ± SD) |
||||
|
|
|
TA 98 |
TA100 |
TA1535 |
TA1537 |
WP2 uvrA |
Without Activation |
H20 |
|
36 ±14 |
115 ± 9 |
18 ± 4 |
5 ± 3 |
28 ± 4 |
|
|
|
|
|
|
|
|
|
Test item |
5.00 |
40 ± 2 |
107 ±6 |
18 ± 6 |
5 ± 4 |
31 ± 7 |
|
|
15.8 |
37 ± 3 |
104 ± 16 |
18 ± 6 |
7 ± 3 |
25 ± 10 |
|
|
50.0 |
37 ± 2 |
115 ± 10 |
19 ± 4 |
5 ± 3 |
30 ± 6 |
|
|
158 |
39 ± 7 |
121 ± 10 |
23 ± 2 |
4 ± 3 |
26 ± 14 |
|
|
500 |
36 ± 9 |
122 ± 17 |
17 ± 3 |
8 ± 4 |
27 ± 4 |
|
|
1580 |
361± 10 |
121 ± 9 |
20 ± 12 |
3 ± 2 |
31 ± 9 |
|
|
5000 |
32 ± 8 |
112 ± 9 |
14 ± 3 |
5 ± 4 |
28 ± 7 |
|
DAUN |
2.00 |
1130 ±115 |
|
|
|
|
|
NaN3 |
2.00 |
|
1386 ± 47 |
891 ± 21 |
|
|
|
9-AA |
50.0 |
|
|
|
1331 ± 341 |
|
|
NQO |
2.00 |
|
|
|
|
2038 ± 69 |
With Activation |
H20 |
|
48 ± 14 |
127 ±5 |
21 ± 2 |
7 ± 3 |
34 ± 6 |
|
|
|
|
|
|
|
|
|
Test item |
5.00 |
38 ±7 |
125 ± 11 |
17 ± 4 |
7 ± 2 |
35 ± 5 |
|
|
15.8 |
33 ± 2 |
138 ± 11 |
18 ± 9 |
8 ± 7 |
39 ± 5 |
|
|
50.0 |
42 ± 8 |
130 ± 22 |
26 ± 10 |
6 ± 4 |
35 ± 8 |
|
|
158 |
43 ± 10 |
129 ± 22 |
19 ± 2 |
10 ± 5 |
33 ± 9 |
|
|
500 |
42 ± 2 |
110 ± 14 |
13 ± 4 |
6 ± 2 |
28 ± 9 |
|
|
1580 |
46 ± 5 |
132 ± 34 |
15 ± 2 |
6 ± 3 |
30 ± 6 |
|
|
5000 |
32 ± 3 |
130 ± 15 |
17 ± 3 |
7 ± 4 |
29 ± 6 |
|
2-AA |
2.00 |
1154 ± 122 |
2219 ± 392 |
|
|
|
|
2-AA |
5.00 |
|
|
100 ± 28 |
180 ±25 |
|
|
2-AA |
10.0 |
|
|
|
|
396 ±52 |
NaN3 = Sodium azide 2-AA = 2-Aminoanthracene 9-AA = 9-Aminoacridine DAUN = Daunomycin NQO = 4-Nitroquinoline-N-oxide
Table 2: Summery of Results (2nd Run)
Metabolic Activation |
Test material |
Concentration [µg/plate] |
Revertants per plate (mean ± SD) |
||||
|
|
|
TA 98 |
TA100 |
TA1535 |
TA1537 |
WP2 uvrA |
Without Activation |
H20 |
|
39 ±5 |
127 ± 9 |
16 ± 3 |
6 ± 4 |
37 ± 8 |
|
|
|
|
|
|
|
|
|
Test item |
50.00 |
39 ± 9 |
120 ± 3 |
19 ± 4 |
5 ± 2 |
31 ± 10 |
|
|
158 |
30 ± 2 |
116 ± 10 |
19 ± 4 |
6 ± 3 |
36 ± 5 |
|
|
500 |
34 ± 4 |
128 ± 9 |
15 ±3 |
7 ± 3 |
40 ± 10 |
|
|
1580 |
35 ± 7 |
106 ± 10 |
21 ± 7 |
6 ± 2 |
32 ± 10 |
|
|
5000 |
34 ± 3 |
118 ± 0 |
18 ± 2 |
7 ± 2 |
31 ± 6 |
|
DAUN |
2.00 |
670 ± 26 |
|
|
|
|
|
NaN3 |
2.00 |
|
1590 ± 37 |
922 ± 117 |
|
|
|
9-AA |
50.0 |
|
|
|
2681 ± 576 |
|
|
NQO |
2.00 |
|
|
|
|
1814 ± 141 |
With Activation |
H20 |
|
42 ± 6 |
124 ±15 |
16 ± 7 |
10 ± 4 |
39 ± 9 |
|
|
|
|
|
|
|
|
|
Test item |
50.00 |
37 ± 6 |
111 ± 16 |
15 ± 8 |
13 ± 5 |
44 ± 4 |
|
|
158 |
46 ± 4 |
111± 10 |
16 ± 6 |
6 ±1 |
36 ± 12 |
|
|
500 |
42 ± 10 |
104 ± 16 |
10 ± 4 |
11± 5 |
30 ± 6 |
|
|
1580 |
45 ± 11 |
108 ± 6 |
14 ± 5 |
8 ± 2 |
41 ± 6 |
|
|
5000 |
43 ± 2 |
136 ± 21 |
10 ± 3 |
9 ± 1 |
25 ± 3 |
|
2-AA |
2.00 |
430 ± 20 |
698 ± 79 |
|
|
|
|
2-AA |
5.00 |
|
|
228 ± 96 |
200 ± 22 |
|
|
2-AA |
10.0 |
|
|
|
|
252 ± 22 |
NaN3 = Sodium azide2-AA = 2-Aminoanthracene9-AA = 9-AminoacridineDAUN = DaunomycinNQO = 4-Nitroquinoline-N-oxide
The historical data have been obtained in experiments between 01/2017 and 12/2017.
Table 3: Historical data - Negative Controls
Strain |
TA 98 |
TA 100 |
|
|
||
S9 Mix |
Without |
With |
Without |
With |
|
|
Compound |
Solvent |
Solvent |
Solvent |
Solvent |
|
|
Total Plates |
486 |
486 |
482 |
488 |
|
|
Number of values |
90 |
90 |
89 |
90 |
|
|
Minimum |
19 |
20 |
94 |
90 |
|
|
Maximum |
52 |
58 |
159 |
172 |
|
|
Mean |
36 |
42 |
118 |
123 |
|
|
Standard Deviation |
7.1 |
7.3 |
12.1 |
13.4 |
|
|
|
|
|
|
|
|
|
Strain |
TA1537 |
WP2 uvrA |
TA 1538 |
|||
S9Mix |
Without |
With |
Without |
With |
Without |
With |
Compound |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Solvent |
Total Plates |
394 |
394 |
434 |
433 |
44 |
44 |
Number of Values |
68 |
68 |
77 |
77 |
11 |
11 |
Minimum |
4 |
6 |
19 |
28 |
6 |
11 |
Maximum |
11 |
16 |
44 |
47 |
15 |
21 |
Mean |
8 |
10 |
30 |
37 |
12 |
15 |
Standard Deviation |
15 |
23 |
49 |
43 |
2.9 |
2.7 |
Table 4: Historical data - Positive Controls
Strain |
TA 98 |
TA100 |
|
|
|||
S9 Mix |
Without |
With |
Without |
With |
|
|
|
Compound |
DAUN |
2-AA |
NaN3 |
2-AA |
|
|
|
Total Plates |
243 |
243 |
242 |
244 |
|
|
|
Number of Values |
90 |
90 |
89 |
90 |
|
|
|
Minimum |
68 |
112 |
821 |
437 |
|
|
|
Maximum |
779 |
3015 |
2376 |
3429 |
|
|
|
Mean |
243 |
738 |
1550 |
1386 |
|
|
|
Standard Deviation |
134 2 |
508.4 |
213.6 |
724.3 |
|
|
|
|
|||||||
Strain |
TA 1537 |
WP2 uvrA |
TA 1538 |
||||
S9 Mix |
Without |
With |
Without |
With |
Without |
With |
|
Compound |
9-AA |
2-AA |
NQO |
2-AA |
2-NF |
2-AA |
|
Total Plates |
203 |
203 |
217 |
217 |
22 |
22 |
|
Number of Values |
70 |
70 |
77 |
77 |
11 |
11 |
|
Minimum |
247 |
72 |
317 |
154 |
1087 |
461 |
|
Maximum |
1485 |
705 |
2275 |
696 |
2511 |
1323 |
|
Mean |
736 |
293 |
1677 |
353 |
1909 |
1038 |
|
Standard Deviation |
284.9 |
161.7 |
381.9 |
129.2 |
470 3 |
285.3 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
In vitro
A study according to OECD TG 471 was conducted to examine the mutagenic potential in an in vitro bacterial reverse mutation test employing Salmonella typhimurium TA 98, TA 100. TA 1535 and TA 1537 and Escherichia coli WP2 uvrA as indicator organisms. The plate incorporation test with and without addition of liver S9 mix from Phenobarbital/p-Naphthoflavone-pretreated rats was used. In this study, two experimental series were performed. In the experiments with S9 mix, 10% and 20% S9 in the S9 mix were used. Treatments of all tester strains were performed using test item formulations prepared in ultrapure water in the absence and in the presence of S9 mix using final concentrations between 5 and 5000 µg/plate, plus vehicle and positive controls. The mean numbers of revertant colonies of the current negative controls were within the range of historical negative control values. The strain-specific positive controls, namely daunomycin, sodium azide, 4-nitroquinolin-N-oxide and 9-aminoacridine in the absence of S9 mix yielded the expected mutant frequencies that were greatly exceeding the negative controls. The genotype of the tester strains used was thus confirmed. 2-Aminoanthracene which requires metabolic activation, was strongly mutagenic. This indicates that the exogenous metabolizing system used in the present investigation (S9 mix) was active. Following treatment with the substance, neither precipitation of the test material, nor toxicity to the bacteria was observed. Under the conditions described, there were no relevant increases in revertant numbers observed after exposure to the test item in the absence and presence of S9 mix. According to the criteria for negative and positive results predetermined in the study, the substance was not mutagenic under the described experimental conditions (reference 7.6.1-1).
In a further bacterial reverse mutation assay (Ames), seven strains of S. typhimurium (TA98, TA 102, TA 104, TA 1535, TA1537, TA1538) were incubated for 48 h with 2 or 10 mg/plate test item with or without S9 mix (7.6.1 -2). For metabolic activation, liver S-9 fractions from Aroclor-treated Sprague-Dawley rats were prepared. Concurrent vehicle and positive controls were valid. No signs of cytotoxicity were observed. No biological relevant increase of the revertant number was observed. In a follow-up study (7.6.1 -4), six bacterial strains of S. typhimurium (TA98, TA 100, TA 102, TA 104, TA 1535, TA1538) were incubated with the test item without S9 mix. No biological relevant increase of the revertant number was observed. In another bacterial reverse mutation assay (Ames), six strains of S. typhimurium (TA98, TA 100, TA 104, 98/1, 98NR, 8DNPG) were incubated with 3.06 - 61.3 µmol/plate test item without S9 mix (7.6.1 -3). Signs of cytotoxicity were observed at concentrations of 22 µmol/plate and more. No biological relevant increase of the revertant number was observed. Although not all studies used the proposed bacterial strains or metabolic activation, the results of all three studies do not report an increased number of revertants. Especially the study of DeFlora et al. (7.6.1 -1) covers a broad spectrum of strains (with and without metabolic activation). Since no signs of increased number of revertants are reported, the test item is considered to be non-genotoxic.
In vivo
In a publication 25 mg/kg bw/day test item in saline was daily administered to Wistar rats (n = 10) for 21 days via gavage [1]. Isolated lymphocytes were examined by comet assay. No DNA damages were reported. Furthermore, induction of chromosomal abberrations + chromatid breaks were reported in mouse bone marrow cells after daily oral administration of 200 mg/kg bw/d for 15 d to male Swiss albino mice (n = 5) [2].
[1] Altinoz E. and Turkoz Y., The Protective Role Of N-Acetylcysteine Against Acrylamide-Induced Genotoxicity And Oxidative Stress In Rats, Gene Therapy and Molecular Biology, (2014) Vol. 16, No. 1, pp. 35-43. Refs: 50 ISSN: 1529-9120
[2] Podder et al., Fluoride-induced genotoxicity in mouse bone marrow cells: Effect of buthionine sulfoximine and N-acety- l-cysteine. Journal of Applied Toxicology, (October 2011) Vol. 31, No. 7, pp. 618-625. Refs: 53 ISSN: 0260-437X; E-ISSN: 1099-1263 CODEN: JJATDK
Justification for classification or non-classification
Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available information on the test item regarding genetic toxicity are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available experimental information, the test substance is not classified for genetic toxicity according to Regulation (EC) No 1272/2008 (CLP), as amended for the 11th time in Regulation (EU) No 2018/669.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.