Registration Dossier
Registration Dossier
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EC number: 281-978-8 | CAS number: 84082-30-4
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Additional strain / cell type characteristics:
- not specified
- Species / strain / cell type:
- E. coli WP2 uvr A
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9
- Test concentrations with justification for top dose:
- 5000 , 2500, 1250, 625 ,313 and 156 µg/plate
- Vehicle / solvent:
- The substance was found to be sufficiently soluble in water for the highest concentration to be tested of 5000 μg/plate.
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- without S9, strains TA1535 and TA100
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- without S9, strain TA1537
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- without S9, strain TA98
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- methylmethanesulfonate
- Remarks:
- without S9, strain WP2
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: 2-Aminoantracene
- Remarks:
- with S9, all strains
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: In agar (plate incorporation) and preincubation
DURATION
- Preincubation period: 30minutes
- Exposure duration: 72 hours
SELECTION AGENT (mutation assays): Histidine requirement (S. thyphimurium) or tryptophan requirement (E. coli)
NUMBER OF REPLICATIONS: 3
DETERMINATION OF CYTOTOXICITY
- Method: Reduction in number of spontaneous revertants, thinning of background lawn or microcolony formation - Evaluation criteria:
- For a test to be considered valid, the mean of the vehicle control revertant colony numbers for each strain should lie within or close to the current historical control range of the laboratory unless otherwise justified by the Study Director. Also, the positive control compounds must induce an increase in mean revertant colony numbers of at least twice the concurrent vehicle controls.
For the tested substance to be considered mutagenic, two-fold (or more) increases in mean revertant numbers must be observed at two consecutive dose levels or at the highest practicable dose level only. In addition, there must be evidence of a dose-response relationship showing increasing numbers of mutant colonies with increasing dose levels. - Statistics:
- The mean number and standard deviation of revertant colonies were calculated for all groups. The “fold-increases” relative to the vehicle controls were calculated in order to compare the means for all treatment groups with those obtained for the vehicle control groups.
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: No
- Effects of osmolality: No
- Precipitation: No
- Other confounding effects: None
RANGE-FINDING/SCREENING STUDIES: Toxicity screening at concentration range of 50.0 - 5000 microgram/plate showed no toxicity
COMPARISON WITH HISTORICAL CONTROL DATA: Results show that mean plate counts for untreated and positive control plates fell within the test laboratory's acceptance criteria based on historical control data. - Remarks on result:
- other: all strains/cell types tested
- Conclusions:
- Interpretation of results (migrated information): negative
It is concluded that the substance showed no evidence of mutagenic activity in this bacterial system under the test conditions employed. - Executive summary:
Gene mutation has been investigated in bacteria using strains of Salmonella typhimurium and Escherichia coli, in accordance with OECD/EU test methods. Five tester strains TA1535, TA1537, TA98, TA100 and WP2uvrA were used and experiments were performed both in the absence and presence of metabolic activation, using liver S9 fraction from rats pre-treated with phenobarbital and 5,6-benzoflavone. The tested substance did not induce reverse mutation in the tester strains, neither in the absence nor presence of S9 metabolism.
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.17 (Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- mammalian cell gene mutation assay
- Species / strain / cell type:
- mouse lymphoma L5178Y cells
- Details on mammalian cell type (if applicable):
- - Type and identity of media:were obtained from American Type culture Collection
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically "cleansed" against high spontaneous background: Yes - Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9
- Test concentrations with justification for top dose:
- Experiment 1 (3 hours treatment): in the absence of S9 - 201, 241, 289, 347, 417, 500 and 600 µg/ml
Experiment 1 (3 hours treatment): in the presence of S9 - 201, 241, 289, 347, 417, 500 and 600 µg/ml
Experiment 2 (24 hours treatment): in the absence of S9 - 240, 276, 318, 365, 420 and 483 µg/ml
Experiment 2 (3 hours treatment): in the presence of S9 - 209, 240, 276, 318, 365 and 420 µg/ml - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: Sterile distilled water
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- benzo(a)pyrene
- Remarks:
- as positive control with S9 presence
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- methylmethanesulfonate
- Remarks:
- as positive control without S9 presence.
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration:3 h (without S9) , 24 hours (without S9) and 3 hours with S9
SELECTION AGENT (mutation assays): 5-trifluorothymidine resistance
NUMBER OF CELLS EVALUATED: cell suspension= 1E6 cells/ml
TREATMENT MEDIA PREPARATION:
Without S9 metabolism 3-hour treatment time:
Cell suspension (2E6 cells/ml in complete medium 5%) 5.0 mL
Complete medium (5%) 13.0 mL
Control or Test item solution 2.0 mL
20.0 mL
Without S9 metabolism 24-hour treatment time
Cell suspension (1E6 cells/ml in complete medium l0%) 3.0 mL
Complete medium(l0%) 15.0 mL
Control or Test item solution 2.0 mL
20.0 mL
With S9 metabolism - 3-hour treatment time
Cell suspension (2E6 cells/ml in complete medium 5%) 5.0 mL
S9 mix 9.8 mL
Control or Test item solution 2.0 mL
Complete medium (5%) 3.2 mL
20.0 mL - Evaluation criteria:
- The assay was considered valid if the following criteria were met:
(i) The cloning efficiencies at Day 2 in the untreated control cultures in the absence of S9 metabolic activation fell within the range of 65 -120%.
(ii) The untreated control growth factor in the absence of S9 metabolic activation over 2 days fell within the range of 8-32.
(iii) The mutant frequencies in the untreated control cultures fell within the range of 50-200 E6 viable cells.
(iv) The positive control chemicals induced a clear increase in mutant frequency (the difference between the positive and negative control mutant frequencies was greater than half the historical mean value). - Statistics:
- According to UKEMS guidelines
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: No
- Effects of osmolality: No
- Water solubility: No
- Precipitation: Yes - Remarks on result:
- other: all strains/cell types tested
- Conclusions:
- Interpretation of results (migrated information): negative
lt is concluded that the tested substance does not induce mutation at the TK locus of L5178Y mouse lymphoma cells in vitro in the absence or presence of S9 metabolic activation, under the reported experimental conditions. - Executive summary:
Mutagenic activity has been examined by assaying for the induction mutants in mouse lymphoma L5178Y cells after in vitro treatment, in the absence and presence of S9 metabolic activation, using a fluctuation method according to OECD/EU test methods. No relevant increases in mutant frequencies were observed following treatment.
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 487 (In vitro Mammalian Cell Micronucleus Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- Chinese hamster lung fibroblasts (V79)
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9
- Test concentrations with justification for top dose:
- First test:
In the absence and presence of S9 mix: 156, 313, 625, 1250, 2500 and 5000 µg/mL.
Second test:
In the absence of S9 mix: 97.5, 146, 219, 329, 494, 741, 1110, 1670 and 2500 µg/mL.
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: Sterile water
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- mitomycin C
- Remarks:
- Final concentration: 0.5 µg/mL (3 hour treatment) 0.1 µg/mL (26 hour continuous treatment) Migrated to IUCLID6: without S9
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: Colchicine without S9
- Remarks:
- Final concentration: 2.5 µg/mL (3 hour treatment) 0.25µg/mL (26 hour continuous treatment)
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- Final concentration: 7.5 µg/mL (3 hour treatment) Migrated to IUCLID6: with S9
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Preincubation period: 20 hours
- Exposure duration: 3 hours and 26 hours
- Expression time (cells in growth medium): 23 hours
- Selection time (if incubation with a selection agent):
- Fixation time (start of exposure up to fixation or harvest of cells):
SPINDLE INHIBITOR (cytogenetic assays): Cytochalasin B
STAIN (for cytogenetic assays): Acridine Orange
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 1000 cells/culture
DETERMINATION OF CYTOTOXICITY
- Method: cytokinesis-block proliferation index - Evaluation criteria:
- An assay is considered to be acceptable if the negative and positive control values lie within the current historical control range.
The test substance is considered to cause a positive response if the following conditions are met:
- Significant increases in the proportion of micronucleated cells over the concurrent controls occur at one or more concentrations.
- The proportion of micronucleated cells at such data points exceeds the normal range. If the increases fall within the range of values normally observed in the negative control cultures, the test cannot be classified as positive. Any significant increases over the concurrent negative controls were therefore compared with historical control values derived from recent studies.
- There is a significant dose-relationship. - Statistics:
- A modified chi-squared test was used to compare the number of cells bearing micronuclei in control and treated cultures.
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: None
- Effects of osmolality: Slight reduction in solvent controls (water)
- Evaporation from medium: No
- Water solubility: Good
- Precipitation: Opacity of test medium noted at higher test substance concentrations
- Other confounding effects: No
RANGE-FINDING/SCREENING STUDIES: Wide concentration range examined a part of main experiments
COMPARISON WITH HISTORICAL CONTROL DATA: Within test laboratory's acceptance limits
ADDITIONAL INFORMATION ON CYTOTOXICITY: Severe cytotoxicity was observed following treatment in the absence of S9 metabolism with the substance at a concentration of 5000 µg/mL where no cells were recovered at harvesting. Severe cytotoxicity was also observed at the next lower concentration of 2500 µg/mL (97%). No cytotoxicity was observed over the remaining dose range. In the presence of S9 metabolism, severe cytotoxicity was observed following treatment at the highest dose level where no cells were recovered at harvesting. Severe cytotoxicity was also observed at 2500 µg/mL (92%). Mild cytotoxicity (33%) was observed at 1250 µg/mL, no remarkable cytotoxicity was observed over the remaining dose range. Severe cytotoxicity was observed at the highest dose level of 2500 µg/mL following continuous treatment in the absence of S9 metabolism. Severe cytotoxicity was also observed at 1670 µg/mL (89%) and marked cytotoxicity was observed at 1110 µg/mL (77%). Moderate cytotoxicity was observed at 741 µg/mL (58%) and mild or no remarkable cytotoxicity was observed over the remaining dose range. The highest dose level for genotoxicity assessment was selected as a dose which produced a substantial cytotoxicity compared with the solvent control, ideally between 50% and 60%. - Remarks on result:
- other: all strains/cell types tested
- Conclusions:
- Interpretation of results (migrated information): negative
On the basis of the results obtained, it is concluded that the substance does not induce micronuclei in Chinese hamster V79 cells after in vitro treatment in the absence or presence of S9 metabolism, under the reported experimental conditions - Executive summary:
The ability of the substance to induce micronuclei in Chinese hamster V79 cells following in vitro treatment in the absence and presence of S9 metabolic activation has been investigated using methods in accordance with OECD test guidelines. The tested substance did not induce micronuclei in Chinese hamster V79 cells after in vitro treatment.
Referenceopen allclose all
ASSAY I
With (+) or |
Dose (µg/plate) |
Number of revertants Mean (±SD) |
||||
without(-) |
Base-pair substitution type |
Frameshift type |
||||
S9 mix |
TA100 |
TA1535 |
WP2 uvrA |
TA98 |
TA1537 |
|
|
Untreated |
132 (±11.1) |
20 (±1.2) |
30 (±2.8) |
29 (±2.7) |
18 (±1.7) |
|
156 |
|
|
|
|
15 (±2.6) |
S9 mix |
313 |
168 (±4.9) |
22 (±3.0) |
30 (±1.5) |
32 (±0.9) |
20 (±1.5) |
(-) |
625 |
156 (±4.5) |
24 (±3.5) |
34 (±2.0) |
30 (±1.2) |
17 (±2.0) |
|
1250 |
145 (±9.6) |
27 (±1.0) |
31 (±2.1) |
31 (±2.9) |
17 (±1.9) |
|
2500 |
142 (±7.4) |
24 (±2.1) |
33 (±1.7) |
32 (±2.2) |
18 (±1.5) |
|
5000 |
128 (±5.5) |
17 (±1.0) |
30 (±2.2) |
26 (±0.6) |
18 (±1.7) |
|
Untreated |
162 (±4.2) |
19 (±0.3) |
33 (±1.9) |
45 (±2.3) |
25 (±0.9) |
|
313 |
176 (±8.1) |
21 (±2.7) |
34 (±0.7) |
46 (±2.2) |
22 (±1.5) |
S9 mix |
625 |
167 (±2.4) |
23 (±2.3) |
35 (±0.7) |
41 (±5.2) |
20 (±2.6) |
(+) |
1250 |
158 (±5.0) |
21 (±1.2) |
36 (±1.2) |
47 (±4.1) |
23 (±2.9) |
|
2500 |
158 (±7.4) |
21 (±0.9) |
35 (±2.0) |
42 (±2.8) |
24 (±2.0) |
|
5000 |
161 (±5.9) |
21 (±3.2) |
36 (±1.5) |
50 (±2.3) |
16 (±0.7) |
+ve control |
Chemical |
SA |
SA |
MMS |
2NF |
9-AA |
S9 mix(-) |
Doseµg/plate |
1.0 |
1.0 |
500 |
2.0 |
50 |
|
Colonies/plate |
617 (±21.9) |
494 (±10.1) |
173 (±7.9) |
138 (±4.1) |
215 (±12.5) |
+ve control |
Chemical |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
S9 mix(+) |
Doseµg/plate |
1.0 |
1.0 |
10 |
1.0 |
1.0 |
|
Colonies/plate |
1234 (±42.8) |
107 (±5.2) |
264 (±17.3) |
535 (±36.4) |
118(±4.1) |
SA = sodium azide; MMS = methylmethanesulphonate; 2NF = 2-nitrofluorene; 9-AA = 9-aminoacridine; 2-AA = 2-aminoanthracene
ASSAY II
With (+) or |
Dose (µg/plate) |
Number of revertants Mean (±SD) |
||||
without(-) |
Base-pair substitution type |
Frameshift type |
||||
S9 mix |
TA100 |
TA1535 |
WP2 uvrA |
TA98 |
TA1537 |
|
|
Untreated |
145 (±2.9) |
19 (±1.0) |
29(±1.2) |
30 (±0.9) |
21 (±0.9) |
|
156 |
140 (±9.8) |
19 (±1.7) |
27 (±1.5) |
26 (±2.6) |
19 (±1.7) |
S9 mix |
313 |
127 (±3.6) |
16 (±1.8) |
34 (±2.3) |
26 (±1.5) |
18 (±1.5) |
(-) |
625 |
123 (±7.1) |
16 (±2.1) |
27 (±2.7) |
30 (±2.9) |
16 (±0.9) |
|
1250 |
103 (±9.3) * |
17 (±1.5) |
34 (±2.4) |
30 (±0.9) |
12 (±1.8) * |
|
2500 |
107 (±4.3) * |
25 (±1.9) |
28 (±2.0) |
33 (±2.0) |
6 (±22.3 * |
|
5000 |
86 (±3.8) * |
17 (±1.5) |
30 (±0.3) |
30 (±3.5) |
6 (±1.8) * |
|
Untreated |
130 (±2.3) |
17 (±2.0) |
34 (±1.2) |
43 (±1.9) |
24 (±1.2) |
|
156 |
118 (±2.0) |
18 (±0.9) |
36 (±1.7) |
45 (±2.0) |
26 (±2.8) |
|
313 |
128 (±5.5) |
23 (±1.5) |
36 (±1.9) |
50 (±2.8) |
25 (±0.6) |
S9 mix |
625 |
126 (±8.2) |
19 (±2.1) |
37 (±0.6) |
45 (±2.6) |
26 (±1.5) |
(+) |
1250 |
101 (±3.4) * |
18 (±1.5) |
35 (±2.1) |
38 (±2.3) |
23 (±2.3) |
|
2500 |
100 (±6.0) * |
18 (±1.7) |
29 (±2.8) |
38 (±0.9) |
21 (±1.9) |
|
5000 |
106 (±5.2) * |
21 (±0.7) |
34 (±0.7) |
42 (±1.8) |
14 (±0.7) * |
+ve control |
Chemical |
SA |
SA |
MMS |
2NF |
9-AA |
S9 mix(-) |
Doseµg/plate |
1.0 |
1.0 |
500 |
2.0 |
50 |
|
Colonies/plate |
662 (±32.1) |
492 (±41.1) |
197 (±12.2) |
147 (±4.2) |
167 (±53.8) |
+ve control |
Chemical |
2-AA |
2-AA |
2-AA |
2-AA |
2-AA |
S9 mix(+) |
Doseµg/plate |
2.0 |
1.0 |
20 |
2.0 |
1.0 |
|
Colonies/plate |
912 (±44.6) |
107 (±5.3) |
240 (±11.9) |
636 (±39.7) |
112 (±10.1) |
SA = sodium azide; MMS = methylmethanesulphonate; 2NF = 2-nitrofluorene; 9-AA = 9-aminoacridine; 2-AA = 2-aminoanthracene; * = thinning of background lawn
MAIN ASSAY 1 - TREATMENT: 3 HOURS - WITHOUT S9 |
||||||
Dose level (µg/ml) |
RTG |
MF § |
P |
IMF § |
Proportion small colony mutants |
Precipitation |
0.00 |
100% |
72.6 |
|
|
0.53 |
|
201 |
94% |
77.8 |
NS |
5.28 |
|
+ |
241 |
86% |
83.9 |
NS |
11.35 |
|
+ |
289 |
101% |
58.6 |
NS |
- |
|
+ |
347 |
66% |
53.1 |
NS |
- |
|
+ |
417 |
39% |
71.7 |
NS |
- |
|
+ |
500 |
3% |
86.5 |
$ |
13.98 |
|
+ |
600 |
0% |
- |
$ |
- |
|
+ |
MMS (10.0) |
68% |
403.9 |
|
331.3@ |
0.72 |
|
MAIN ASSAY 2 - TREATMENT: 24 HOURS - WITHOUT S9 |
||||||
Dose level (µg/ml) |
RTG |
MF § |
P |
IMF § |
Proportion small colony mutants |
Precipitation |
0.00 |
100% |
75.6 |
|
|
0.41 |
- |
240 |
101% |
60.1 |
NS |
- |
|
- |
276 |
97% |
58.3 |
NS |
- |
|
- |
318 |
90% |
79.4 |
NS |
3.78 |
|
- |
365 |
74% |
75.2 |
NS |
- |
|
- |
420 |
48% |
91.9 |
NS |
16.30 |
|
+ |
483 |
46% |
88.3 |
NS |
12.71 |
|
+ |
MMS (5.00) |
68% |
408.9 |
|
333.3@ |
0.36 |
|
MAIN ASSAY 1 - TREATMENT: 3 HOURS - WITH S9 |
||||||
Dose level (µg/ml) |
RTG |
MF § |
P |
IMF § |
Proportion small colony mutants |
Precipitation |
0.00 |
100% |
68.7 |
|
|
0.40 |
|
201 |
120% |
74.9 |
NS |
6.25 |
|
+ |
241 |
108% |
101.4 |
NS |
32.74 |
|
+ |
289 |
91% |
109.1 |
NS |
40.44 |
|
+ |
347 |
42% |
116.2 |
* |
47.56 |
|
+ |
417 |
21% |
113.5 |
* |
44.80 |
|
+ |
500 |
3% |
84.3 |
$ |
15.62 |
|
+ |
600 |
0% |
|
$ |
|
|
+ |
B(a)P (2.00) |
36% |
758.9 |
|
690.3@ |
0.44 |
|
MAIN ASSAY 2 - TREATMENT: 3 HOURS - WITH S9 |
||||||
Dose level (µg/ml) |
RTG |
MF § |
P |
IMF § |
Proportion small colony mutants |
Precipitation |
0.00 |
100% |
72.2 |
|
|
0.24 |
|
209 |
112% |
68.7 |
NS |
- |
|
- |
240 |
112% |
48.3 |
NS |
- |
|
- |
276 |
99% |
74.4 |
NS |
2.19 |
|
- |
318 |
83% |
84.1 |
NS |
11.88 |
|
+ |
365 |
89% |
53.5 |
NS |
- |
|
+ |
420 |
74% |
64.9 |
NS |
- |
|
+ |
B(a)P (2.00) |
43% |
643.9 |
- |
571.7@ |
0.47 |
|
§ = per 106viable cells
NS = Not statistically significant
* = Statistically significant at p < 5 %
@ = Induced mutant frequency (IMF) > global evaluation factor (GEF = 126E-6)
$ = Excluded from statistical analysis due to excessive toxicity
Induction of Micronuclei in Chinese Hamster V79 cells following 3 hours exposure
Treatment |
Concentration |
Presence of S9 metabolism |
Absence of S9 metabolism |
||
|
μg/mL |
% Micronucleated cells |
% Cytotoxicity |
% Micronucleated cells |
% Cytotoxicity |
Untreated |
|
0.95 |
-11 |
0.75 |
4 |
Solvent |
10% |
0.90 |
0 |
0.85 |
0 |
Test |
313 |
1.15 |
6 |
0.95 |
-18 |
substance |
625 |
1.00 |
16 |
0.75 |
-16 |
|
1250 |
0.90 |
33 |
0.90 |
11 |
Mitomycin-C |
0.500 |
- |
- |
6.35 *** |
33 |
Colchicine |
2.50 |
- |
- |
3.05 *** |
39 |
Cyclophosphamide |
7.50 |
5.05 *** |
53 |
- |
- |
*** = Statistically significant at p<0.001
Induction of Micronuclei in Chinese Hamster V79 cells following 26 hours continuous exposure
Treatment |
Concentration |
Absence of S9 metabolism |
|
|
μg/mL |
% Micronucleated cells |
% Cytotoxicity |
Untreated |
|
0.50 |
3 |
Solvent |
10% |
0.50 |
0 |
Test |
329 |
0.80 |
21 |
substance |
494 |
0.35 |
31 |
|
741 |
0.30 |
58 |
Mitomycin-C |
0.100 |
4.10 *** |
24 |
Colchicine |
0.250 |
5.60 *** |
92 |
*** = Statistically significant at p<0.001
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The substance or its structural analogues has been tested in bacterial reverse mutation assays (Ames test) which showed the substance(s) not to induce reverse mutation in Salmonella typhimurium or Escherichia coli, an in-vitro chromosome aberration test which showed the substance not to induce chromosomal aberrations; an assay for the induction of trifluorothymidine resistant mutants in mouse lymphoma L5178Y cells after in vitro treatment which was negative and an assay for the ability to induce micronuclei in Chinese hamster V79 cells following in vitro treatment which was negative.
REACH Regulation 1907/2006 (Annex VIII, 8.4 Column 2) states that appropriate in-vivo mutagenicity studies should be considered in those cases of a positive result in any of the in vitro genotoxicity studies. In vitro investigations with the substance were negative and in vivo studies are therefore regarded as inappropriate and not in line with current concerns regarding animal welfare and the use of animals in scientific experiments.
Endpoint Conclusion: No adverse effect observed (negative)
Justification for classification or non-classification
Non-classification is justified on the basis of negative findings in a number of in-vitro tests on the substance
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.
