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EC number: 640-454-2 | CAS number: 17318-08-0
- 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
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- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
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- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 5-bromo-1,3-dichloro-2-fluorobenzene
- EC Number:
- 640-454-2
- Cas Number:
- 17318-08-0
- Molecular formula:
- C6H2 BrCl2F
- IUPAC Name:
- 5-bromo-1,3-dichloro-2-fluorobenzene
- Test material form:
- liquid
Constituent 1
Method
Species / strain
- 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:
- Phenobarbital/ß-naphthoflavone induced rat liver S9 was used as the metabolic activation system. The S9 was prepared from male Wistar rats (RjHan:WI; weight approx. 220 – 320 g, Janvier Labs, 53941 Saint-Berthevin Cedex, France) induced by peroral administration of 80 mg/kg b.w. phenobarbital (Sigma-Aldrich Chemie GmbH, 82024 Taufkirchen, Germany) and by peroral administrations of ß-naphthoflavone (Acros Organics, 2440 Geel, Belgium) each, on three consecutive days. The livers were prepared 24 hours after the last treatment. The S9 fractions were produced by dilution of the liver homogenate with a KCl solution (1+3 parts) followed by centrifugation at 9000 g. Aliquots of the supernatant were frozen and stored in ampoules at –80 °C. Small numbers of the ampoules can be kept at –20 °C for up to one week. Each batch of S9 mix is routinely tested with 2-aminoanthracene as well as benzo[a]pyrene (Appendix 3).
The protein concentration in the S9 preparation was 32.6 mg/mL (lot no. 010617E) in the pre-experiment / Experiment I and 30.4 mg/mL (lot no. 261017K) in Experiment II.
Before the experiment an appropriate quantity of S9 supernatant was thawed and mixed with S9 cofactor solution. The amount of S9 supernatant was 10% v/v in the S9 mix. Cofactors are added to the S9 mix to reach the following concentrations in the S9 mix:
8 mM MgCl2 33 mM KCl 5 mM Glucose-6-phosphate 4 mM NADP
in 100 mM sodium-ortho-phosphate-buffer, pH 7.4.
During the experiment the S9 mix was stored in an ice bath. The S9 mix preparation was performed according to Ames et al.. - Test concentrations with justification for top dose:
- Pre-experiment / Experiment I: 3; 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate
Experiment II:
Strains TA 100 and WP2 pKM101: 0.3; 1, 3, 10; 33; 100; 333; and 1000 µg/plate
The remaining strains: 3; 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate
Based on the observed cytotoxicity the maximal concentration was 5000 μg/plate for strains TA 1535, TA 1537, TA 98, and WP2 uvrA pKM101, respectively 1000 μg/plate for strains TA 100 and WP2 pKM101. - Vehicle / solvent:
- dimethylsulfoxide (DMSO, purity 99%)
Controls
- 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:
- The thawed bacterial suspension was transferred into 250 mL Erlenmeyer flasks containing nutrient medium (50 mL). A solution of ampicillin (50 μL, 25 μg/mL) was added to the strains TA 98, TA 100, WP2 uvrA pKM101, and WP2 pKM101. This nutrient medium contains per liter:
8 g Nutrient Broth (MERCK, 64293 Darmstadt, Germany) 5 g NaCl (MERCK, 64293 Darmstadt, Germany)
The bacterial cultures were incubated in a shaking water bath for 4 hours at 37 °C. The optical density of the bacteria was determined by absorption measurement and the obtained values indicated that the bacteria were harvested at the late exponential or early stationary phase (10^8-10^9 cells/mL).
Plates with selective agar (without Histidine/Tryptophan) were used.
The overlay agar contained per litre:
for Salmonella strains:
7.0 g Agar Agar*
6.0 g NaCl*
10.5 mg L-Histidine×HCl×H2O*
12.2 mg Biotin*
for Escherichia coli strains:
7.0 g Agar Agar*
6.0 g NaCl*
10.2 mg Tryptophan*
* (MERCK, 64293 Darmstadt, Germany)
Sterilisations were performed at 121 °C in an autoclave.
To evaluate the cytotoxicity of the test substance a pre-experiment was performed with all strains. Eight concentrations were tested for cytotoxicity and mutation induction each with three replicate plates. The experimental conditions in this pre-experiment are described in section 3.7 (plate incorporation test).
Cytotoxicity of the test substance results in a reduction in the number of spontaneous revertants (below a factor of 0.5) or a clearing of the bacterial background lawn.
The pre-experiment is reported as the Main Experiment I since the criteria mentioned in Section 3.8.2: Acceptability of the Assay were met.
For each strain and concentration including the controls, three plates were used.
The following materials were mixed in a test tube and poured onto the selective agar plates:
100 μL Test solution at each concentration, solvent (negative control) or reference mutagen solution (positive control),
500 μL S9 mix (for test with metabolic activation) or S9 mix substitution buffer* (for test without metabolic activation),
100 μL Bacteria suspension (cf. test system, pre-culture of the strains; OD = 0.9 - 1.2; wavelength = 500 nm; approx. 8x108 cells/mL),
2000 μL Overlay agar
For the pre-incubation method test solution (100 μL) (solvent or reference mutagen solution (positive control)), S9 mix / S9 mix substitution buffer* (500 μL) and bacteria suspension (100 μL) were mixed in a test tube and incubated at 37 °C for 60 minutes. After pre-incubation overlay agar (2.0 mL, 45 °C) was added to each tube. The mixture was poured on selective agar plates.
After solidification the plates were incubated upside down for 72 hours at 37°C in the dark, plates were then stored at 4°C until counted. (6).
In parallel to each test a sterile control of the test substance was performed and documented in the raw data. Therefore, stock solution (100 μL) and S9 mix / S9 mix substitution buffer* (500 μL) were mixed with overlay agar (2.0 mL) and poured on minimal agar plates.
* Substitution buffer: 7 parts of the 100 mM sodium-ortho-phosphate-buffer pH 7.4 with 3 parts of KCl solution 0.15 M - Evaluation criteria:
- The Salmonella typhimurium and Escherichia coli reverse mutation assay is considered acceptable if it meets the following criteria:
- regular background growth in the negative and solvent control
- the spontaneous reversion rates in the negative and solvent control are in the range of the historical data
- the positive control substances should produce a significant increase in mutant colony frequencies
- a minimum of five analysable concentrations should be present with at least four showing no signs of toxic effects, evident as a reduction in the number of revertants below the indication factor of 0.5.
A test substance is considered as a mutagen if a biologically relevant increase in the number of revertants of twice or above the spontaneous mutation rate of the corresponding solvent control is observed (1).
A concentration dependent increase is considered biologically relevant if the threshold is reached or exceeded at more than one concentration (6).
An increase of revertant colonies equal or above the threshold at only one concentration is judged as biologically relevant if reproduced in an independent second experiment.
A concentration 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:
- According to the OECD guideline 471, a statistical analysis of the data is not mandatory.
Results and discussion
Test results
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not applicable
- Positive controls validity:
- valid
Any other information on results incl. tables
Table 1: Plates incubated with the test item showed reduced background growth at the following concentrations (μg/plate)
Strain |
Experiment I |
Experiment II |
||
|
without S9 mix |
with S9 mix |
without S9 mix |
with S9 mix |
TA 1535 |
1000 – 5000 |
1000 – 5000 |
1000 – 5000 |
1000 – 5000 |
TA 1537 |
1000 – 5000 |
1000 – 5000 |
100 – 5000 |
333 – 5000 |
TA 98 |
1000 – 5000 |
2500 – 5000 |
333 – 5000 |
1000 – 5000 |
TA 100 |
2500 – 5000 |
333 – 5000 |
1000 |
333 – 1000 |
WP2 pKM101 |
333 – 5000 |
1000 – 5000 |
/ |
1000 |
WP2 uvrA pKM101 |
2500 – 5000 |
1000 – 5000 |
2500 – 5000 |
1000 – 5000 |
/ = normal background growth
Table 2: Cytotoxic effects, evident as a reduction in the number of revertants (below the induction factor of 0.5), were observed at the following concentrations (µg/plate)
Strain |
Experiment I |
Experiment II |
||
|
without S9 mix |
with S9 mix |
without S9 mix |
with S9 mix |
TA 1535 |
/ |
/ |
/ |
/ |
TA 1537 |
5000 |
2500 – 5000 |
2500 – 5000 |
2500 – 5000 |
TA 98 |
2500 – 5000 |
/ |
1000 – 5000 |
2500 |
TA 100 |
333 – 5000 |
333 – 5000 |
100 – 1000 |
333 – 1000 |
WP2 pKM101 |
333 – 5000 |
2500 – 5000 |
100 – 1000 |
1000 |
WP2uvrApKM101 |
/ |
5000 |
333 – 5000 |
1000 – 5000 |
/ = no cytotoxic effects, evident as a reduction in the number of revertants (below the induction factor of 0.5)
Table 3: Summary of results of pre-experiment/experiment I
Metabolic Activation |
Test Group |
Concen-tration (per plate) |
|
Revertant Colony Counts (Mean ±SD) |
|||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 pKM101 |
WP2 uvrA pKM101 |
|
|
|
|
|
|
|
|
|
|
Without Activation |
DMSO |
|
|
12 ± 2 |
8 ± 3 |
26 ± 6 |
168 ± 8 |
233 ± 12 |
249 ± 7 |
Untreated |
|
|
14 ± 3 |
12 ± 5 |
23 ± 3 |
190 ± 6 |
232 ± 27 |
290 ± 14 |
|
CA5528 |
3 µg |
|
15 ± 5 |
9 ± 3 |
22 ± 2 |
151 ± 19 |
213 ± 15 |
239 ± 19 |
|
tech. |
10 µg |
|
13 ± 4 |
11 ± 1 |
31 ± 3 |
152 ± 4 |
216 ± 5 |
252 ± 13 |
|
|
33 µg |
|
11 ± 1 |
10 ± 2 |
33 ± 7 |
145 ± 20 |
223 ± 13 |
250 ± 5 |
|
|
100 µg |
|
11 ± 1 |
10 ± 1 |
22 ± 5 |
85 ± 6 |
172 ± 13 |
215 ± 30 |
|
|
333 µg |
|
12 ± 4 |
8 ± 2 |
25 ± 5 |
52 ± 9 |
68 ± 8R |
147 ± 6 |
|
|
1000 µg |
|
8 ± 3R |
7 ± 2M R |
15 ± 1M R |
41 ± 6 |
61 ± 4R |
136 ± 10 |
|
|
2500 µg |
|
10 ± 1R |
5 ± 2M R |
12 ± 3M R |
44 ± 7R |
58 ± 2R |
134 ± 3R |
|
|
5000 µg |
|
14 ± 3R |
3 ± 1M R |
9 ± 2M R |
36 ± 6M R |
54 ± 7R |
123 ± 13R |
|
NaN3 |
10 µg |
|
1228 ± 25 |
|
|
2121 ± 130 |
|
|
|
4-NOPD |
10 µg |
|
|
|
323 ± 27 |
|
|
|
|
4-NOPD |
50 µg |
|
|
125 ± 9 |
|
|
|
|
|
MMS |
2.0 µL |
|
|
|
|
|
3741 ± 24 |
2926 ± 12 |
|
|
|
|
|
|
|
|
|
|
|
With Activation |
DMSO |
|
|
13 ± 4 |
11 ± 3 |
30 ± 2 |
143 ± 11 |
215 ± 31 |
277 ± 20 |
Untreated |
|
|
14 ± 2 |
15 ± 3 |
41 ± 7 |
166 ± 17 |
259 ± 38 |
338 ± 48 |
|
CA5528 |
3 µg |
|
11 ± 2 |
10 ± 1 |
38 ± 6 |
126 ± 10 |
229 ± 4 |
326 ± 25 |
|
tech. |
10 µg |
|
12 ± 2 |
14 ± 3 |
37 ± 3 |
148 ± 27 |
220 ± 7 |
261 ± 39 |
|
|
33 µg |
|
18 ± 3 |
10 ± 1 |
41 ± 7 |
160 ± 8 |
203 ± 28 |
240 ± 12 |
|
|
100 µg |
|
12 ± 4 |
12 ± 3 |
36 ± 9 |
159 ± 17 |
231 ± 13 |
265 ± 32 |
|
|
333 µg |
|
15 ± 4 |
15 ± 1 |
37 ± 9 |
47 ± 9R |
196 ± 26 |
296 ± 22 |
|
|
1000 µg |
|
12 ± 2R |
9 ± 2M R |
41 ± 5 |
46 ± 4R |
105 ± 18R |
157 ± 16R |
|
|
2500 µg |
|
11 ± 2M R |
5 ± 2M R |
33 ± 4M R |
31 ± 4M R |
76 ± 11R |
146 ± 16R |
|
|
5000 µg |
|
7 ± 2M R |
2 ± 1M R |
23 ± 5M R |
24 ± 4M R |
38 ± 11M R |
80 ± 10M R |
|
2-AA |
2.5 µg |
|
543 ± 28 |
106 ± 7 |
4009 ± 62 |
3596 ± 184 |
|
|
|
2-AA |
10.0 µg |
|
|
|
|
|
1212 ± 29 |
2025 ± 6 |
|
|
|
|
|
|
|
|
|
|
|
Table 4: Summary of results of experiment II
Metabolic Activation |
Test Group |
Concen-tration (per plate) |
|
Revertant Colony Counts (Mean ±SD) |
|||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 pKM101 |
WP2 uvrA pKM101 |
|
|
|
|
|
|
|
|
|
|
Without Activation |
DMSO |
|
|
8 ± 3 |
11 ± 1 |
39 ± 2 |
152 ± 18 |
230 ± 8 |
346 ± 28 |
Untreated |
|
|
8 ± 2 |
16 ± 5 |
37 ± 3 |
204 ± 19 |
286 ± 20 |
384 ± 35 |
|
CA5528 |
0.3 µg |
|
|
|
|
152 ± 14 |
206 ± 8 |
|
|
tech. |
1 µg |
|
|
|
|
162 ± 4 |
209 ± 2 |
|
|
|
3 µg |
|
6 ± 1 |
12 ± 4 |
32 ± 10 |
153 ± 12 |
228 ± 22 |
384 ± 7 |
|
|
10 µg |
|
8 ± 2 |
11 ± 3 |
35 ± 8 |
159 ± 17 |
223 ± 11 |
388 ± 36 |
|
|
33 µg |
|
6 ± 2 |
11 ± 4 |
27 ± 7 |
128 ± 22 |
207 ± 4 |
285 ± 34 |
|
|
100 µg |
|
10 ± 1 |
11 ± 1R |
19 ± 3 |
49 ± 6 |
95 ± 14 |
180 ± 2 |
|
|
333 µg |
|
8 ± 3 |
6 ± 2M R |
20 ± 6R |
37 ± 6 |
51 ± 7 |
124 ± 14 |
|
|
1000 µg |
|
9 ± 3R |
6 ± 2M R |
12 ± 4M R |
38 ± 8R |
48 ± 7 |
109 ± 17 |
|
|
2500 µg |
|
10 ± 2R |
5 ± 2M R |
9 ± 3M R |
|
|
101 ± 10R |
|
|
5000 µg |
|
6 ± 2M R |
3 ± 1M R |
1 ± 1M R |
|
|
90 ± 7R |
|
NaN3 |
10 µg |
|
1266 ± 5 |
|
|
2109 ± 114 |
|
|
|
4-NOPD |
10 µg |
|
|
|
351 ± 22 |
|
|
|
|
4-NOPD |
50 µg |
|
|
181 ± 13 |
|
|
|
|
|
MMS |
2.0 µL |
|
|
|
|
|
4237 ± 145 |
3630 ± 101 |
|
|
|
|
|
|
|
|
|
|
|
With Activation |
DMSO |
|
|
12 ± 3 |
16 ± 5 |
43 ± 6 |
132 ± 12 |
229 ± 4 |
467 ± 11 |
Untreated |
|
|
8 ± 2 |
17 ± 5 |
42 ± 1 |
195 ± 14 |
282 ± 13 |
466 ± 16 |
|
CA5528 |
0.3 µg |
|
|
|
|
126 ± 22 |
250 ± 15 |
|
|
tech. |
1 µg |
|
|
|
|
151 ± 16 |
257 ± 20 |
|
|
|
3 µg |
|
10 ± 1 |
16 ± 5 |
46 ± 5 |
143 ± 6 |
216 ± 7 |
504 ± 11 |
|
|
10 µg |
|
13 ± 2 |
19 ± 4 |
38 ± 5 |
146 ± 15 |
218 ± 17 |
488 ± 4 |
|
|
33 µg |
|
10 ± 1 |
19 ± 3 |
36 ± 6 |
111 ± 15 |
232 ± 36 |
448 ± 47 |
|
|
100 µg |
|
13 ± 2 |
19 ± 3 |
46 ± 6 |
109 ± 17 |
258 ± 16 |
404 ± 43 |
|
|
333 µg |
|
10 ± 3 |
21 ± 5R |
37 ± 0 |
32 ± 3R |
119 ± 17 |
226 ± 32 |
|
|
1000 µg |
|
9 ± 3R |
19 ± 2M R |
31 ± 7R |
25 ± 7R M |
58 ± 12R |
131 ± 5R |
|
|
2500 µg |
|
6 ± 2M R |
6 ± 2M R |
18 ± 3M R |
|
|
70 ± 4R M |
|
|
5000 µg |
|
19 ± 6M R |
1 ± 1M R |
34 ± 12M R |
|
|
53 ± 5M R |
|
2-AA |
2.5 µg |
|
440 ± 26 |
144 ± 26 |
4137 ± 266 |
3572 ± 33 |
|
|
|
2-AA |
10.0 µg |
|
|
|
|
|
1173 ± 117 |
1933 ± 96 |
|
|
|
|
|
|
|
|
|
|
|
Key to Positive Controls |
Key to Plate Postfix Codes |
||
|
|
||
NaN3 2-AA 4-NOPD MMS |
sodium azide 2-aminoanthracene 4-nitro-o-phenylene-diamine methyl methane sulfonate |
R M |
Reduced background growth Manual count |
Applicant's summary and conclusion
- Conclusions:
- In conclusion, it can be stated that during the described mutagenicity tests and under the experimental conditions reported, the substance did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used.
Therefore, the substance is considered to be non-mutagenic in the Salmonella typhimurium and Escherichia coli reverse mutation assay. - Executive summary:
This study was performed to investigate the potential of the substance to induce gene mutations in the plate incorporation test (Experiment I) and the pre-incubation test (Experiment II) using the Salmonella typhimurium (S. typhimurium) strains TA1535, TA1537, TA98, and TA100, and the Escherichia coli (E. coli) strains WP2 uvrA pKM101 and WP2 pKM101.
The plates incubated with the test item showed reduced background growth in all strains used with and without S9 mix.
Cytotoxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5), occurred in all strains, except of strain TA 1535.
No increase in revertant colony numbers of any of the six tester strains was observed following treatment with the substance at any concentration level, neither in the presence nor absence of metabolic activation (S9 mix). There was also no observed 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, which showed a distinct increase of induced revertant colonies demonstrating the correct performance of the assay.
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.
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