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EC number: - | CAS number: -
- 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
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- Water solubility
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- Ecotoxicological Summary
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- Short-term toxicity to fish
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- 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
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Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
For the test substance registered no Ames test is available. Read across to a structural analogue substance is made. Due to structural similarities it is assumed that both substances reveal almost the same metabolism and thus are of similar toxicity. Read across justification for this approach is attached to section 13 of this IUCLID. In conclusion, it can be stated that during the described mutagenicity test (AMES 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, both in the presence and absence of metabolic activation.
Further, two in vitro genetic toxicity studies with the test item registered are available, i.e. a mammalian chromosomal aberration test in human lymphocytes and an HPRT test using CHO AA8 cells.
Based on the results obtained with a mammalian chromosomal aberration test in human lymphocytes, Dodicor V 5654 is considered as non-clastogenic both in the presence and absence of metabolic activation under the presented test conditions.
Dodicor V 5654 is considered as non-mutagenic at and up to the concentration of 0.125 µL/mL, both in the presence and absence of metabolic activation under the tested laboratory conditions in the HPRT Test.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Remarks:
- In vitro Mammalian Cell Gene Mutation Tests using the Hprt and xprt genes
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 October 2019 TO 09 April 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Version / remarks:
- adopted on 29th July 2016
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- other: In vitro Mammalian Cell Gene Mutation Tests using the Hprt and xprt genes
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Clariant Ibérica Producción,S.A.
- Batch: ESD0033040
- Expiration date of the batch: August 2021
- Purity : UVCB substance; purity ca 97%
STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (21 to 29°C)
- Solubility of the test substance in the solvent/vehicle: miscible in DMSO - Target gene:
- HPRT gene
- Species / strain / cell type:
- Chinese hamster Ovary (CHO)
- Details on mammalian cell type (if applicable):
- The derivative of the CHO-K1, CHO AA8 Cells
- Metabolic activation:
- with and without
- Metabolic activation system:
- induced rat liver S9 homogenate
- Test concentrations with justification for top dose:
- moderate precipitation was observed at 0.25 µL/mL and the Relative Survival was greater than 10%. Therefore 0.125 µL/mL was selected as the highest concentration for testing in gene mutation test.
(four concentrations i.e. 0.015625, 0.03125, 0.0625 and 0.125 µL/mL were selected for gene mutation test) - Vehicle / solvent:
- dimethyl sulphoxide
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Details on test system and experimental conditions:
- CHO AA8 cells, Batch No.5000062 procured from American Type Culture Collection (ATCC).
- Evaluation criteria:
- • The concurrent vehicle control is considered acceptable for addition to the laboratory historical vehicle control database
• Concurrent positive controls should induce responses that are compatible with those generated in the historical positive control data base and produce a statistically significant increase compared with the concurrent negative/vehicle control
A test chemical is considered to be clearly positive if, in any of the experimental conditions examined:
• At least one of the test concentrations exhibits a statistically significant increase compared with the concurrent negative control.
• The increase is concentration-related when evaluated with an appropriate trend test.
• Any of the results are outside the distribution of the historical negative/vehicle control data.
When all of these criteria are met, the test chemical is then considered able to induce gene mutations in cultured mammalian cells in this test system.
• A test chemical is considered clearly negative if, in all experimental conditions examined:
• None of the test concentrations exhibits a statistically significant increase compared with the concurrent negative control.
• There is no concentration-related increase when evaluated with an appropriate trend test.
• All results are inside the distribution of the historical negative/vehicle control data. - Statistics:
- Data of mutant frequencies were analyzed for differences among vehicle control, treatment and positive control groups by performing power transformation procedure by Snee and Irr (1981) with which, the observed mutant frequency was transformed using the formula:
Y=〖(X+A)〗^B
Where,
Y = transformed mutant frequency, X = observed mutant frequency
[Where X=(No. of mutant colonies per replicate)/(ACE value)×100
and A, B = constants (viz. A = 1 and B = 0.15)]
Statistical analysis of the experimental data was carried out using SPSS Statistical package version 22.0. - Key result
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity, but tested up to precipitating concentrations
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: No change in pH was observed in any of the test concentrations.
- Water solubility: No
- Precipitation: No change in precipitation was observed at the tested concentrations 0.03125 and 0.0625 µL/mL, slight precipitation was observed at 0.125 µL/mL, moderate precipitation was observed at 0.25 µL/mL and heavy precipitation was observed at 0.50, 1 and 2 µL/mL.
RANGE-FINDING STUDIES: Pre study conducted to select highest test concentration.
HISTORICAL CONTROL DATA (with ranges, means and standard deviation and confidence interval (e.g. 95%)
- Positive historical control data:
Positive Control- Benzo(a)pyrene and 4- Nitroquinoline N-oxide
With Metabolic Activation
(3 to 6 hours)
[Benzo(a)pyrene] Without Metabolic Activation
(3 to 6 hours)
[4 Nitroquinoline N-oxide]
Mean Data of Mutant Frequency/2x106 Cells 261.94 264.60
Standard
Deviation 27.28 18.52
Margin of Error 17.82 12.10
Upper bound 279.76 276.70
Lower bound 244.12 252.50
- Negative (solvent/vehicle) historical control data:
Vehicle-DMSO
With Metabolic Activation
(3 to 6 hours) Without Metabolic Activation
(3 to 6 hours)
Mean Data of Mutant Frequency/2x106 Cells 24.51 25.43
Standard
Deviation 2.81 1.89
Margin of Error 1.95 1.31
Upper bound 26.46 26.74
Lower bound 22.56 24.12
ADDITIONAL INFORMATION ON CYTOTOXICITY:
- Measurement of cytotoxicity used: Yes - Remarks on result:
- other:
- Remarks:
- Non mutagenic
- Conclusions:
- Based on the results obtained, the test item, Dodicor V 5654 is considered as non-mutagenic at and upto the concentration of 0.125 µL/mL, both in the presence and absence of metabolic activation under the tested laboratory conditions.
- Executive summary:
The test itemDodicor V 5654was evaluated for gene mutation test in CHO AA8 cells.
The test item was found miscible in DMSO at 200 µL/mL. Precipitation test was conducted at 0.03125, 0.0625, 0.125, 0.25, 0.50, 1 and 2 µL/mL. Post 3 hours and
3 minutes of incubation, no change in precipitation was observed at the tested concentrations of 0.03125 and 0.0625 µL/mL, slight precipitation was observed at
0.125 µL/mL, moderate precipitation was observed at 0.25 µL/mL and heavy precipitation was observed at 0.50, 1 and 2 µL/mL. No change in pH was observed in any of the test concentrations.On the basis of precipitation results, 0.125 µL/mL was selected as the highest concentration for the initial cytotoxicity test. Initial cytotoxicity test was conducted at the concentrations of 0.0078125, 0.015625, 0.03125, 0.0625 and 0.125 µL/mL using DMSO as a vehicle in tetra plates/group in the presence and absence of metabolic activation (3 to 6 hours). Cytotoxicity was assessed by determining the Adjusted Cloning Efficiency and Relative Survival in the test.
The results of the initial cytotoxicity test indicated that the Relative Survival was greater than 10% (26.50% in presence of metabolic activation and24.55% in absence of metabolic activation) at 0.125 µL/mL when compared with the respective vehicle control, both in the presence and absence of metabolic activation. Based on these results, 0.125 µL/mL was selected as highest concentration for gene mutation test.
The gene mutation test was conducted at the concentrations of 0.015625, 0.03125, 0.0625 and 0.125 µL/mLusing DMSO as a vehicle in four plates/group in the presence and absence of metabolic activation (3 to 6 hours).
Benzo(a) pyrene and4 Nitroquinoline N-oxidewere used asPositive controlsfor the gene mutation test.
Cytotoxicity as Relative Survival was 27.19% in presence of metabolic activation and28.44% in absence of metabolic activation) at the highest tested concentration of 0.125 µL/mL.
There was no statistically significant increase in mutant frequencies at any of the concentrations tested when compared with the vehicle control. Moreover, treatment withDodicor V 5654resulted in mutant frequencies which fell within acceptable ranges with regard to historical controls.
There was statistically significant increase in mutant frequenciesfor positive controlswhen compared with the vehicle controlin both the phases of the experiment.- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 08 November 2019 to 09 July 2020
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- adopted on 29th July 2016.
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- other: In vitro Mammalian Chromosomal Aberration Test
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: Clariant Ibérica Producción,S.A.
- Batch No.of test material: ESD0033040
- Expiration date of the batch: August 2021
- Purity : UVCB substance; purity ca 97%
STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (21 to 29°C)
- Solubility of the test substance in the solvent/vehicle:
Test item was soluble in DMSO at 500 mg/mL. - Target gene:
- Human Peripheral Blood Lymphocytes
- Species / strain / cell type:
- lymphocytes:
- Details on mammalian cell type (if applicable):
- Human peripheral lymphocytes from the blood of healthy, young, non-smoking donors [22 (Female), 28 (Male) and 29 (Male) years of age] with no known recent exposure to genotoxic chemicals or radiation were used
- Test concentrations with justification for top dose:
- Based on the results of initial cytotoxicity test 0.01953 mg/mL was selected has highest testing concentration.
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: Test item was soluble in DMSO at 500 mg/mL. - Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- mitomycin C
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: 3 to 6 hours and 20 to 24 hours
- Expression time (cells in growth medium): 44 to 48 hours
- Selection time (if incubation with a selection agent): 44 to 48 hours
- Fixation time (start of exposure up to fixation or harvest of cells): 27 hours
STAIN (for cytogenetic assays): 5% Giemsa stain
NUMBER OF REPLICATIONS: 02
METHODS OF SLIDE PREPARATION AND STAINING TECHNIQUE USED: Pellets were mixed with 4 mL of freshly prepared warm 0.56% Potassium chloride. Cell suspension was incubated for 10 minutes at room temperature and later it was centrifuged at 1800 rpm for 10 minutes. Supernatant was discarded and cell pellet was mixed with 3 to 4 mL of freshly prepared cold acetic acid:methanol fixative (1:3). Cell suspension was incubated for 10 minutes at room temperature and later suspension was centrifuged at 2200 rpm for 10 minutes. The procedure was repeated twice by adding 4 mL of cold acetic acid: methanol fixative (1:3). Clean slides were stored in a beaker with distilled water and kept in the refrigerator for 1 hour before use. The cell suspension was mixed using a pipette and few drops of the suspension were aspirated and dropped onto the chilled slide pre labeled with study number, with (+S9) or without metabolic activation(-S9), treatment/group and slide number. The slides was air dried. Minimum of 3 slides were prepared for each treatment replicate. Slides were stained using 5% Giemsa stain for 15 minutes.
NUMBER OF CELLS EVALUATED: 500 cells were scored for initial cytotoxicity and 150 metaphases for chromosomal abbrevation test.
NUMBER OF METAPHASE SPREADS ANALYSED PER DOSE (if in vitro cytogenicity study in mammalian cells): 150 metaphases
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index
OTHER EXAMINATIONS:
- Determination of polyploidy:Yes
- Determination of endoreplication: Yes - Rationale for test conditions:
- The following set of criteria was followed for the selection of concentrations for chromosomal aberration test.
• Three analyzable concentrations were used for chromosomal aberration test.
• The percentage reduction in Mitotic Index was in the range of 7.62% to 45.42% at 0.00488, 0.00977 and 0.01953 mg/mL. As the percentage reduction in MI was not more than 45±5% at 0.01953 mg/mL, same was selected as the highest concentration for the chromosomal aberration test. Other concentrations tested were 0.00488 and 0.00977 mg/mL. - Evaluation criteria:
- • All slides including vehicle control, Negative control, treatment and positive controls of chromosomal aberration test were coded before evaluation.
• Cytotoxicity was determined by calculating percentage reduction in mitotic index (%).
• Concurrent measures of mitotic index for all treated and vehicle control cultures were determined.
• The cells were evaluated for structural aberrations in 150 metaphase plates for each replicate and 300 (per concentration), the metaphases with aberrations were recorded in raw data.
•Gaps were recorded separately and reported but not included in the total aberration frequency. - Statistics:
- Yes
- Key result
- Species / strain:
- lymphocytes: Human blood
- 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 change in pH was observed in any of the concentrations tested upto 5 mg/mL
- Water solubility: Insoluble
- Precipitation: Milld and moderate precipitation was observed at 1.25 and 2.5 mg/mL respectively
RANGE-FINDING/SCREENING STUDIES: Yes, Initial cytotoxicity
HISTORICAL CONTROL DATA (with ranges, means and standard deviation and confidence interval (e.g. 95%)
- Positive historical control data: 95% Confidence level
With S9 - cyclophosphamide monohydrate
(3 to 6 hours) Without S9 - Mitomycin C (3 to 6 hours) Without S9 - Mitomycin C (20 to 24 hours)
Average (% of Aberrated cells) 9.88 9.90 10.42
Standard Deviation 1.12 1.26 1.89
Sample size 16.00 16.00 16.00
Margin of error 0.55 0.62 0.93
Upper bound 10.43 10.52 11.34
Lower bound 9.33 9.28 9.49
95% Confidence level 1.96 1.96 1.96
Max 12.00 13.35 16.00
Min 8.67 8.67 8.67
- Negative (solvent/vehicle) historical control data:
95% Confidence level
With S9
(3-6 hours) Without S9 (3-6 hours) Without S9 (20-24 hours)
Average (% of Aberrated cells) 0.76 0.90 0.81
Standard Deviation 0.24 0.24 0.29
Sample size 12.00 12.00 12.00
Margin of error 0.14 0.14 0.16
Upper bound 0.90 1.04 0.97
Lower bound 0.62 0.76 0.65
95% Confidence level 1.96 1.96 1.96
Max 1.00 1.33 1.30
Min 0.35 0.67 0.34
ADDITIONAL INFORMATION ON CYTOTOXICITY:
- Measurement of cytotoxicity used: Mitotic index
- Other observations when applicable: metaphase counting - Conclusions:
- Based on the results obtained, the test item, Dodicor V 5654 is considered as non-clastogenic both in the presence and absence of metabolic activation under the presented test conditions.
- Executive summary:
The test item,Dodicor V 5654was evaluated for chromosomal aberrations test in human lymphocytes.Test item was soluble in DMSO at 500 mg/mL. Precipitation test was conducted at 0.3125, 0.625, 1.25, 2.5 and 5 mg/mL. Post 23 hours and 37 minutes of incubation, mild and moderate precipitation was observed at 2.5 and 5 mg/mL respectively. No precipitation was observed at any of the other concentrations tested. No change in pH was observed in any of the concentrations tested upto 5 mg/mL. Hence, 5 mg/mL was selected as highest concentration for testing in the initial cytotoxicity test. The other concentrations selected were0.3125, 0.625, 1.25 and 2.5 mg/mL of test item. In initial cytotoxicity test, complete cytotoxicity was observed down to 0.3125 mg/mL both in short and long term treatments.Hence a follow up initial cytotoxicity test was performed to select concentrations for the chromosomal aberration test.
Follow up initial cytotoxicity testwas conducted with the cocentrations of 0.00488, 0.00977, 0.01953, 0.03906 and 0.07812 mg/mL.The percentage reduction in Mitotic Index was in the range of 7.62% to 45.42% at 0.00480, 0.00977 and 0.01953 mg/mL. As the percentage reduction in MI was not more than 45±5% at 0.01953 mg/mL, same was selected as the highest concentration for the chromosomal aberration test. Other concentrations tested were 0.00488 and 0.00977 mg/mL.
In the chromosomal aberration test, the cells were treated with test item at the concentrations of 0.00488, 0.00977 and 0.01953 mg/mL using DMSO as the vehicle. The treatment was carried out in duplicates for the short term period (3 to 6 hours) both in the presence and absence of metabolic activation and for the long term period (20 to 24 hours) in the absence of metabolic activation. Cyclophosphamide Monohydrate (+S9 for short term) at the concentration of 10 µg/mL and Mitomycin-C at the concentration of 0.05 µg/mL (-S9 both for short term and long term) were used as positive controls.
The treated cells were harvested at about 1.5 normal cell cycle length after treatment. During harvesting of cultures, thecells were treated with a metaphase-arresting substance (colchicine), harvested, stained and metaphase cells were analysed microscopically for the structural chromosomal aberrations.There was no statistically significant increase in the number of aberrated cells when compared with vehicle control at any of the concentration levels tested.The cultures treated with positive controlsfor the short-term period (3 to 6 hours) both in the presence and absence of metabolic activation, and for the long-term period (20 to 24 hours) in the absence of metabolic activation induced aberrated cells which was statistically significant compared with the respective vehicle control. This demonstrated sensitivity of the test system towards positive controls and confirmed that the test conditions were adequate. The concurrent vehicle control values were within the 95% control limits of the distribution of the laboratory’s historical vehicle control database.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2008
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: According to the OECD Guideline, under GLP
- Justification for type of information:
- Justification for Read across to analogue substance is attached (refer to Read across statement Section 13 of this IUCLID)
- Reason / purpose for cross-reference:
- read-across source
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Batch No. of test material: ESD0003028:
- Purity: 25 %
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: Stable in water for days at room temperature (not quantified)
- Solubility: Solvent water was chosen because of its solubility properties
OTHER SPECIFICS
- Other relevant information needed for characterising the tested material, e.g. if radiolabelled, adjustment of pH, osmolality and precipitate in the culture medium to which the test chemical is added:
No precipitation of the test item occurred up to the highest investigated dose of 5000 µg/plate. - Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- E. coli WP2 uvr A
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- induced rat liver S9-mix
- Test concentrations with justification for top dose:
- 3, 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate / pre-experiment/experiment I and experiment II
- Vehicle / solvent:
- Deionised water
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: sodium azide; 4-nitro-o-phenylene-diamine; methyl methane sulfonate, 2-aminoanthracene
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
in agar plate incorporation; preincubation
DURATION
- Preincubation period: 1 hour
- Exposure duration: 72 hours
NUMBER OF REPLICATIONS: 3 plates - Evaluation criteria:
- A test item is considered as a mutagen 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:
- According to the OECD guideline 471, a statistical analysis of the data is not mandatory.
- Key result
- Species / strain:
- other: TA 1535, TA 1537, TA 98, TA 100, WP2 uvrA
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- stains affected: see additional information on results.
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):
negative with and without metabolic activation
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. - Executive summary:
The test item Hostapon SG was assessed for its potential to induce gene mutations in the plate incorporation test (experiment I) and the pre-incubation test (experiment II) using Salmonella typhimurium strains TA 1535, TA 1537, TA 98, and TA 100, and the Escherichia coli strain WP2 uvrA.
The assay was performed in two independent experiments both with and without liver microsomal activation. Due to irregular background growth in strain TA 98 in experiment II no data were evaluated. This part was repeated under identical conditions and is reported as part of experiment II. Each concentration, including the controls, was tested in triplicate. The test item was tested at the following concentrations:
Pre-Experiment/Experiment I and II: 3; 10; 33; 100; 333; 1000; 2500; and 5000 µg/plate
The 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
2500 - 5000
2500 - 5000
1000 - 5000
1000 - 5000
TA 1537
2500 - 5000
2500 - 5000
1000 - 5000
1000 - 5000
TA 98
2500 - 5000
2500 - 5000
1000 - 5000
1000 - 5000
TA 100
2500 - 5000
2500 - 5000
100 - 5000
333 - 5000
WP2 uvrA
/
/
/
/
/ = no reduced background growth
Toxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5), occurred in the test groups 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
2500 - 5000
2500 - 5000
1000 - 5000
5000
TA 1537
2500 - 5000
2500 - 5000
1000 - 5000
5000
TA 98
5000
5000
1000 - 5000
1000 - 5000
TA 100
2500 - 5000
2500 - 5000
1000 - 5000
2500 - 5000
WP2 uvrA
/
/
/
/
/ = no toxic effects, evident as a reduction in the number of revertants (below the indication factor of 0.5)
No substantial increase in revertant colony numbers of any of the five tester strains was observed following treatment with Hostapon SG 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. They showed a distinct increase of induced revertant colonies.
Referenceopen allclose all
TABLE 1. SUMMARY OF INITIAL CYTOTOXICITY TEST
Refer: Appendix 1
Set No. |
Treatment |
Concentration (µL/mL) |
Average Colony Count± SD |
Cloning Efficiency (CE) |
Adjusted Cloning Efficiency (ACE) |
Relative Survival (RS) (%) |
|||||||||||
Set 1 +S9 |
Vehicle Control (DMSO) |
- |
183.33 |
± |
7.57 |
0.92 |
1.17 |
- |
|||||||||
Dodicor V 5654 |
0.0078125 |
172.00 |
± |
3.00 |
0.86 |
1.07 |
91.45 |
||||||||||
0.015625 |
163.00 |
± |
8.19 |
0.82 |
0.99 |
84.62 |
|||||||||||
0.03125 |
143.00 |
± |
4.36 |
0.72 |
0.85 |
72.65 |
|||||||||||
0.0625 |
103.00 |
± |
4.58 |
0.52 |
0.50 |
42.74 |
|||||||||||
0.125 |
76.67 |
± |
5.13 |
0.38 |
0.31 |
26.50 |
|||||||||||
Set 2 -S9 |
Vehicle Control (DMSO) |
- |
179.00 |
± |
6.56 |
0.90 |
1.10 |
- |
|||||||||
Dodicor V 5654 |
0.0078125 |
162.67 |
± |
4.04 |
0.81 |
0.97 |
88.18 |
||||||||||
0.015625 |
152.33 |
± |
7.51 |
0.76 |
0.90 |
81.82 |
|||||||||||
0.03125 |
136.00 |
± |
7.21 |
0.68 |
0.73 |
66.36 |
|||||||||||
0.0625 |
101.33 |
± |
3.51 |
0.51 |
0.48 |
43.64 |
|||||||||||
0.125 |
62.33 |
± |
4.93 |
0.31 |
0.27 |
24.55 |
+S9: with metabolic activation; -S9: without metabolic activation;
Adjusted CE = CE × Number of cells at the end of treatment/number of cells at the beginning of treatment.
RS = Adjusted CE in treated culture/Adjusted CE in the vehicle control × 100.
CE = Number of colonies/Number of cells plated.
TABLE 2. SUMMARY OF PARALLEL CYTOTOXICITY TEST- GENE MUTATION TEST
Refer: Appendix 2
Set No. |
Treatment |
Concentration (µL/mL) |
Average Colony Count ± SD |
Cloning Efficiency (CE) |
Adjusted Cloning Efficiency (ACE) |
Relative Survival (RS) (%) |
||
Set 1 +S9 |
Vehicle Control (DMSO) |
- |
182.00 |
± |
3.61 |
0.91 |
1.14 |
- |
Dodicor V 5654 |
0.015625 |
174.00 |
± |
4.36 |
0.87 |
1.08 |
94.74 |
|
0.03125 |
173.00 |
± |
6.56 |
0.87 |
1.03 |
90.35 |
||
0.0625 |
95.67 |
± |
8.33 |
0.48 |
0.47 |
41.23 |
||
0.125 |
72.00 |
± |
4.36 |
0.36 |
0.31 |
27.19 |
||
Benzo(a)pyrene (Positive Control) |
3 µg/mL |
145.33 |
± |
10.02 |
0.73 |
0.77 |
67.54 |
|
Set 2 |
Vehicle Control (DMSO) |
- |
178.67 |
± |
10.02 |
0.89 |
1.09 |
- |
Dodicor V 5654 |
0.015625 |
172.00 |
± |
4.00 |
0.86 |
1.04 |
95.41 |
|
0.03125 |
166.33 |
± |
4.04 |
0.83 |
0.98 |
89.91 |
||
0.0625 |
102.67 |
± |
8.62 |
0.51 |
0.50 |
45.87 |
||
0.125 |
68.33 |
± |
14.05 |
0.34 |
0.31 |
28.44 |
||
4 Nitroquinoline N-oxide (Positive Control) |
1 µg/mL |
140.33 |
± |
8.50 |
0.70 |
0.71 |
65.14 |
+S9: with metabolic activation; -S9: without metabolic activation;
*Note: Cloning Efficiency = 200 cells plated for each replicate.
RS = Adjusted CE in treated culture/Adjusted CE in the vehicle control × 100.
CE = Number of colonies/Number of cells plated.
Adjusted CE = CE × Number of cells at the end of treatment/number of cells at the beginning of treatment.
Set No. |
Treatment |
Concentration (µL/mL) |
*Average Colony Count ± SD |
Cloning Efficiency in selective media |
Cloning Efficiency in non-selective media |
Total number of Mutant Colonies/ 2×106cells |
Mutant Frequency/ 2×106cells |
||
Set 1 +S9 |
Vehicle Control (DMSO) |
- |
188.00 |
± |
6.24 |
0.0000115 |
0.94 |
23 |
24.47 |
Dodicor V 5654 |
0.015625 |
175.00 |
± |
5.29 |
0.0000115 |
0.88 |
23 |
26.14 |
|
0.03125 |
181.33 |
± |
9.02 |
0.0000120 |
0.91 |
24 |
26.37 |
||
0.0625 |
168.33 |
± |
3.06 |
0.0000110 |
0.84 |
22 |
26.19 |
||
0.125 |
159.00 |
± |
4.58 |
0.0000100 |
0.80 |
20 |
25.00 |
||
Benzo(a)pyrene (Positive Control) |
3 µg/mL |
163.67 |
± |
8.50 |
0.0001060 |
0.82 |
212 |
258.54** |
|
Set 2 -S9 |
Vehicle Control (DMSO) |
- |
183.00 |
± |
7.21 |
0.0000120 |
0.92 |
24 |
26.09 |
Dodicor V 5654 |
0.015625 |
180.33 |
± |
1.53 |
0.0000115 |
0.90 |
23 |
25.56 |
|
0.03125 |
174.00 |
± |
7.00 |
0.0000105 |
0.87 |
21 |
24.14 |
||
0.0625 |
176.00 |
± |
8.54 |
0.0000115 |
0.88 |
23 |
26.14 |
||
0.125 |
164.33 |
± |
5.51 |
0.0000105 |
0.82 |
21 |
25.61 |
||
4 Nitroquinoline N-oxide (Positive Control) |
1 µg/mL |
152.67 |
± |
10.07 |
0.0001030 |
0.76 |
206 |
271.05** |
TABLE 3. SUMMARY OF GENE MUTATION TEST
Refer: Appendix 3
+S9: with metabolic activation; -S9: without metabolic activation; *Note: Cloning efficiency = 200 cells plated for each replicate.
**: Statistically significant (p˂0.05).
Mutant Frequency = Cloning efficiency of mutant colonies in selective medium/Cloning efficiency in non- selective medium.
TABLE 1. SUMMARY OF PERCENTAGE MITOTIC INDEX FOR INITIAL CYTOTOXICITY TEST
Set No. |
Treatment |
Concentrations (mg/mL) |
Average % Mitotic Index |
% Reduction of Mitotic Index |
|
Set 1 (+S9) (3 to 6 hours) |
Vehicle Control |
- |
6.98 |
- |
|
Dodicor V 5654 |
0.3125 |
0 |
100 |
||
0.625 |
0 |
100 |
|||
1.25 |
0 |
100 |
|||
2.5 |
0 |
100 |
|||
5 |
0 |
100 |
|||
Set 2 (-S9) (3 to 6 hours) |
Vehicle Control |
- |
6.67 |
- |
|
Dodicor V 5654 |
0.3125 |
0 |
100 |
||
0.625 |
0 |
100 |
|||
1.25 |
0 |
100 |
|||
2.5 |
0 |
100 |
|||
5 |
0 |
100 |
|||
Set 3 (-S9) (20 to 24 hours) |
Vehicle Control |
- |
6.46 |
- |
|
Dodicor V 5654 |
0.3125 |
0 |
100 |
||
0.625 |
0 |
100 |
|||
1.25 |
0 |
100 |
|||
2.5 |
0 |
100 |
|||
5 |
0 |
100 |
TABLE 1 (Contd…). SUMMARY OF PERCENTAGE MITOTIC INDEX FOR INITIAL CYTOTOXICITY TEST
Follow up Initial cytotoxicity test
Set No. |
Treatment |
Concentrations (mg/mL) |
Average % Mitotic Index |
% Reduction of Mitotic Index |
|
Set 1 (+S9) (3 to 6 hours) |
Vehicle Control |
- |
7.61 |
- |
|
Dodicor V 5654 |
0.00488 |
7.03 |
7.62 |
||
0.00977 |
5.77 |
24.18 |
|||
0.01953 |
4.43 |
41.79 |
|||
0.03906 |
2.05 |
73.06 |
|||
0.07812 |
0.67 |
91.20 |
|||
Set 2 (-S9) (3 to 6 hours) |
Vehicle Control |
- |
7.83 |
- |
|
Dodicor V 5654 |
0.00488 |
6.85 |
12.52 |
||
0.00977 |
6.10 |
22.09 |
|||
0.01953 |
4.51 |
42.40 |
|||
0.03906 |
2.56 |
67.31 |
|||
0.07812 |
0.29 |
96.30 |
|||
Set 3 (-S9) (20 to 24 hours) |
Vehicle Control |
- |
8.08 |
- |
|
Dodicor V 5654 |
0.00488 |
7.44 |
7.92 |
||
0.00977 |
6.34 |
21.53 |
|||
0.01953 |
4.41 |
45.42 |
|||
0.03906 |
2.47 |
69.43 |
|||
0.07812 |
0.68 |
91.58 |
TABLE 2. SUMMARY OFCHROMOSOMAL ABERRATIONS AND MITOTIC INDEX
Set No. |
Treatment |
Concentrations (mg/mL) |
Mean % MI |
Mean % Reduction in MI |
Mean of Total Aberrations with Gaps |
Mean of Total Aberrations without Gaps |
Mean of Total Aberrant cells without Gaps |
Mean of Percentage Aberrated Cells |
Set 1 (+S9) (3 to 6 hours) |
Vehicle Control |
- |
8.18 |
NA |
1.5 |
1.5 |
1.5 |
1.00 |
Positive Control (Cyclophosphamide monohydrate) |
10 µg/mL |
7.68 |
6.11 |
19.5 |
18.5 |
17.0 |
11.33* |
|
Dodicor V 5654 |
0.00488 |
7.40 |
9.54 |
1.5 |
1.5 |
1.5 |
1.00 |
|
0.00977 |
6.34 |
22.49 |
3.0 |
2.0 |
2.0 |
1.34 |
||
0.01953 |
4.76 |
41.81 |
2.5 |
2.5 |
2.5 |
1.68 |
Set No. |
Treatment |
Concentrations (mg/mL) |
Mean % MI |
Mean % Reduction in MI |
Mean of Total Aberrations with Gaps |
Mean of Total Aberrations without Gaps |
Mean of Total Aberrant cells without Gaps |
Mean of Percentage Aberrated Cells |
Set 2 (-S9) (3 to 6 hours) |
Vehicle Control |
- |
7.89 |
NA |
1.5 |
1.5 |
1 |
0.67 |
Positive Control (Mitomycin-C) |
0.05 µg/mL |
7.39 |
6.34 |
21.5 |
18.5 |
15.5 |
10.34* |
|
Dodicor V 5654 |
0.00488 |
7.27 |
7.86 |
1.5 |
1.5 |
1 |
0.67 |
|
0.00977 |
6.25 |
20.79 |
2 |
2 |
1.5 |
1.00 |
||
0.01953 |
4.51 |
42.84 |
2.5 |
2.5 |
2.5 |
1.67 |
Set No. |
Treatment |
Concentrations (mg/mL) |
Mean % MI |
Mean % Reduction in MI |
Mean of Total Aberrations with Gaps |
Mean of Total Aberrations without Gaps |
Mean of Total Aberrant cells without Gaps |
Mean of Percentage Aberrated Cells |
Set 3 (-S9) (20 to 24 hours) |
Vehicle Control |
- |
7.89 |
NA |
2 |
2 |
2 |
1.33 |
Positive Control (Mitomycin-C) |
0.05 µg/mL |
7.40 |
6.21 |
17 |
16 |
15 |
10.00* |
|
Dodicor V 5654 |
0.00488 |
7.08 |
10.27 |
1.5 |
1.5 |
1.5 |
1.00 |
|
0.00977 |
6.29 |
20.28 |
2.5 |
2.5 |
2 |
1.33 |
||
0.01953 |
4.49 |
43.09 |
2.5 |
2 |
2 |
1.34 |
Summary Tables:
Summary of Results Pre-Experiment and Experiment I
Study Name: 1211000 |
Study Code: Harlan CCR 1211000 |
Experiment: 1211000 VV Plate |
Date Plated: 17/09/2008 |
Assay Conditions: |
Date Counted: 24/09/2008 |
Metabolic Activation |
Test Group |
Dose Level (µg/plate) |
Revertant Colony Counts (Mean ±SD) |
|||||
TA 1535 |
TA 1537 |
TA 98 |
TA 100 |
WP2 uvrA |
||||
Without Activation |
Deionised water |
20 ± 3 |
11 ± 3 |
35 ± 2 |
137 ± 5 |
55 ± 4 |
||
Untreated |
18 ± 3 |
13 ± 3 |
37 ± 10 |
126 ± 4 |
47 ± 3 |
|||
Hostapon SG |
3 µg |
20 ± 3 |
11 ± 4 |
29 ± 1 |
134 ± 12 |
50 ± 4 |
||
10 µg |
19 ± 4 |
14 ± 2 |
33 ± 5 |
124 ± 8 |
52 ± 6 |
|||
33 µg |
18 ± 3 |
11 ± 4 |
35 ± 6 |
132 ± 10 |
55 ± 1 |
|||
100 µg |
19 ± 4 |
8 ± 0 |
37 ± 6 |
139 ± 16 |
52 ± 4 |
|||
333 µg |
13 ± 2 |
10 ± 4 |
32 ± 8 |
122 ± 15 |
63 ± 3 |
|||
1000 µg |
17 ± 2 |
7 ± 1 |
25 ± 5 |
84 ± 11 R |
62 ± 2 |
|||
2500 µg |
8 ± 2 M R |
2 ± 2 M R |
19 ± 2 M R |
36 ± 5 M R |
59 ± 2 |
|||
5000 µg |
2 ± 2 M R |
0 ± 1 M R |
5 ± 2 M R |
27 ± 3 M R |
58 ± 2 |
|||
NaN3 |
10 µg |
2009 ± 31 |
2369 ± 114 |
|||||
4-NOPD |
10 µg |
424 ± 9 |
||||||
4-NOPD |
50 µg |
83 ± 3 |
||||||
MMS |
3.0 µL |
1017 ± 33 |
||||||
With Activation |
Deionised water |
23 ± 3 |
20 ± 5 |
37 ± 4 |
148 ± 5 |
68 ± 4 |
||
Untreated |
24 ± 6 |
19 ± 7 |
42 ± 8 |
148 ± 14 |
64 ± 9 |
|||
Hostapon SG |
3 µg |
24 ± 3 |
19 ± 5 |
39 ± 5 |
129 ± 14 |
64 ± 4 |
||
10 µg |
21 ± 5 |
17 ± 5 |
44 ± 8 |
135 ± 3 |
71 ± 2 |
|||
33 µg |
25 ± 3 |
19 ± 3 |
43 ± 6 |
132 ± 9 |
60 ± 11 |
|||
100 µg |
23 ± 1 |
15 ± 2 |
38 ± 4 |
134 ± 5 |
60 ± 4 |
|||
333 µg |
22 ± 5 |
13 ± 2 |
47 ± 6 |
136 ± 13 |
73 ± 11 |
|||
1000 µg |
15 ± 4 |
16 ± 3 |
35 ± 3 |
116 ± 13 |
69 ± 3 |
|||
2500 µg |
9 ± 3 M R |
8 ± 1 M R |
28 ± 2 M R |
48 ± 7 M R |
66 ± 1 |
|||
5000 µg |
5 ± 1 M R |
1 ± 1 M R |
13 ± 2 M R |
34 ± 5 M R |
59 ± 4 |
|||
2-AA |
2.5 µg |
245 ± 16 |
191 ± 30 |
1267 ± 70 |
1506 ± 43 |
|||
2-AA |
10.0 µg |
232 ± 24 |
||||||
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 |
Summary of Results Experiment II
Study Name: 1211000 |
Study Code: Harlan CCR 1211000 |
Experiment: 1211000 HV2 Pre |
Date Plated: 01/10/2008 / 14/10/2008* |
Assay Conditions: |
Date Counted: 08/10/2008 / 17/10/2008* |
Metabolic Activation |
Test Group |
Dose Level (µg/plate) |
Revertant Colony Counts (Mean ±SD) |
|||||
TA 1535 |
TA 1537 |
TA 98* |
TA 100 |
WP2 uvrA |
||||
Without Activation |
Deionised water |
19 ± 6 |
12 ± 4 |
22 ± 2 |
131 ± 5 |
51 ± 8 |
||
Untreated |
16 ± 6 |
10 ± 2 |
24 ± 4 |
137 ± 12 |
46 ± 8 |
|||
Hostapon SG |
3 µg |
17 ± 4 |
14 ± 5 |
23 ± 2 |
131 ± 8 |
55 ± 1 |
||
10 µg |
18 ± 4 |
15 ± 2 |
24 ± 2 |
127 ± 9 |
52 ± 8 |
|||
33 µg |
18 ± 3 |
11 ± 6 |
24 ± 4 |
122 ± 1 |
55 ± 6 |
|||
100 µg |
22 ± 6 |
14 ± 3 |
23 ± 1 |
101 ± 15 R |
56 ± 2 |
|||
333 µg |
12 ± 5 |
10 ± 4 |
15 ± 2 |
75 ± 7 R |
47 ± 4 |
|||
1000 µg |
5 ± 2 R M |
2 ± 3 M R |
10 ± 1 M R |
39 ± 5 M R |
49 ± 5 |
|||
2500 µg |
2 ± 2 M R |
0 ± 0 M R |
3 ± 2 M R |
31 ± 10 M R |
46 ± 5 |
|||
5000 µg |
1 ± 1 M R |
0 ± 0 M R |
0 ± 0 M R |
5 ± 2 M R |
37 ± 7 |
|||
NaN3 |
10 µg |
1799 ± 67 |
1998 ± 31 |
|||||
4-NOPD |
10 µg |
1637 ± 116 |
||||||
4-NOPD |
50 µg |
105 ± 5 |
||||||
MMS |
3.0 µL |
418 ± 20 |
||||||
With Activation |
Deionised water |
17 ± 4 |
16 ± 5 |
26 ± 3 |
138 ± 9 |
58 ± 5 |
||
Untreated |
18 ± 4 |
19 ± 7 |
29 ± 3 |
142 ± 37 |
64 ± 7 |
|||
Hostapon SG |
3 µg |
19 ± 4 |
17 ± 4 |
27 ± 0 |
131 ± 11 |
59 ± 3 |
||
10 µg |
22 ± 4 |
17 ± 4 |
25 ± 2 |
132 ± 8 |
58 ± 3 |
|||
33 µg |
20 ± 2 |
19 ± 3 |
24 ± 2 |
141 ± 15 |
59 ± 6 |
|||
100 µg |
21 ± 1 |
15 ± 3 |
22 ± 5 |
140 ± 7 |
57 ± 5 |
|||
333 µg |
18 ± 4 |
14 ± 4 |
19 ± 3 |
110 ± 5 R |
53 ± 2 |
|||
1000 µg |
11 ± 3 M R |
12 ± 2 M R |
10 ± 2 M R |
74 ± 7 R |
54 ± 1 |
|||
2500 µg |
9 ± 3 M R |
8 ± 2 M R |
4 ± 3 M R |
31 ± 2 M R |
59 ± 4 |
|||
5000 µg |
0 ± 0 M R |
0 ± 0 M R |
0 ± 0 M R |
31 ± 4 M R |
61 ± 3 |
|||
2-AA |
2.5 µg |
256 ± 8 |
105 ± 10 |
1616 ± 151 |
1346 ± 157 |
|||
2-AA |
10.0 µg |
334 ± 24 |
||||||
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 |
* Repeated experiment
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Justification for classification or non-classification
Based on all available data (i.e mammalian chromosomal aberration test in human lymphocytes and an HPRT test using CHO AA8 cells) with the registered substance as well as available data (Ames test) with the analogue substance, registered substance is not considered to be mutagenic. Accordingly, classification & labelling does not apply.
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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.