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EC number: 474-870-9 | 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
- 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
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Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 10 April 2002 to 30 April 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 003
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- -
- EC Number:
- 454-280-8
- EC Name:
- -
- Cas Number:
- 184889-95-0
- Molecular formula:
- Hill formula: C28H19ClN9Na3O12S4 CAS formula: C28H22ClN9O12S4.3Na
- IUPAC Name:
- Trisodium 7-((2-((aminocarbonylamino)-4-(4-chloro-6-((3-ethe nylsulfonyl)phenyl)amino)-1,3,5-triazine-2-yl)amino)phenyl)a zo-1,3,6-naphthalenetrisulfonate
- Test material form:
- solid: particulate/powder
- Details on test material:
- Test item: Structural Analogue 01
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species of animals: rat
Strain of animals: Hsd:Sprague Dawley
Origin (supplier) of animals: Harlan Winkelmann GmbH Gartenstrasse 27, 33178 Borchen
Animal identification: fur marking with KMn04 and cage numbering
Body weight at start of study: male animals
mean = 189.8 g (= 100 %)
min = 178 g (-6.2%)
max = 202 g (+6.4%)
n = 15
female animals
mean = 152.7 g (= 100 %)
min = 148 g (-3.1%)
max = 162 g (+6.1%)
n = 15
Age at start of study: male animals approximately 6 weeks, female animals approximately 6 weeks
Randomisation procedure: Randomisation schemes 2003.0198 and 2003.0199
Animal maintenance: five animals per cage in transparent macrolon cages (type IV) on soft wood granulate in an air-conditioned room (room number 011)
Room temperature: 22 °C ± 3 °C (except short lasting deviations due to disturbances of air condition)
Relative humidity: 50 % ± 20 % (except short lasting deviations due to disturbances of air condition)
Lighting times: 12 hours light / dark cycle
Acclimatisation: 5 days under study conditions
Food: rat/mice diet ssniff® R/M-H (V 1534), ad libitum ssniff® GmbH, Postbox 2039, 59480 Soest
Water:tap water in plastic bottles, ad libitum
Administration / exposure
- Route of administration:
- oral: unspecified
- Vehicle:
- - Vehicle(s)/solvent(s) used:Deionised water
- Justification for choice of solvent/vehicle: Historical use within the laboratory.
- Concentration of test material in vehicle: 200 mg/ml - Details on exposure:
- Frequency of administrations: two doses separated by an interval of 24 hours (except positive control with only one dose).
- Duration of treatment / exposure:
- 24 hours
- Frequency of treatment:
- Two doses
- Post exposure period:
- No post exposure period
Doses / concentrations
- Dose / conc.:
- 2 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Group Dose Concentration Volume No. of animals Animal No. Killing time
(mg/kg bwt.) (mg/ml) (ml/kg bwt.) and sex (hours p.a.)
1 0 0 10 5 males 1 – 5 24
5 females 6 -10
2 2000 200 10 5 males 11 – 15 24
5 females 16 – 20
3* 40 4.0 10 5 males 21 – 25 24
5 females 26 – 30
* = positive control: Endoxan® (batch no. 9M642A) containing cyclophosphamide, dissolved in distilled water
Hours p.a. = hours after administration - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Name: cyclophosphamide
Synonyms: Endoxan®
CAS-Register number: 6055-19-2
Batch number: 2K645B
Certificate of analysis: certified by the supplier, Quality Control, Dr. Hofmann dated 10-Dec-2002
Examinations
- Tissues and cell types examined:
- chromosomal damage (clastogenicity) in a rat bone marrow
- Details of tissue and slide preparation:
- PREPARATION AND STAINING
Extraction of the bone marrow
Animals were killed by carbon dioxide asphyxiation 24 hours after second dosing. One femoral bone was removed and the bone freed of muscle tissue. The proximal end of the femoral bone was opened, the bone marrow flushed into a centrifuge tube containing about 3 ml of fetal bovine serum and a suspension was prepared. The mixture was then centrifuged for 5 minutes at approx. 1200 rpm, after which almost all the supernatant was discarded. One drop of the thoroughly mixed sediment was smeared onto a cleaned slide, identified by project code and animal number and air-dried for about 12 hours.
Subsequently the slides were stained as follows:
Staining procedure
5 minutes in methanol
5 minutes in May-Grunwald's solution
brief rinsing twice in distilled water
10 minutes staining in 1 part Giemsa solution to 6 parts buffer solution, pH 7.2 (Weise)
rinsing in distilled water drying
coating with Entellan® - Evaluation criteria:
- SCORING AND EVALUATION OF DATA
Scoring
2000 polychromatic erythrocytes were counted for each animal. The number of cells with micro-nuclei was recorded, not the number of individual micronuclei. In addition, the ratio of polychro-matic erythrocytes to 200 normochromatic erythrocytes was determined. Main parameter for the statistical analysis, i.e. validity assessment of the study and mutagenicity of the test substance, was the proportion of polychromatic erythrocytes with micronuclei out of the 2000 counted erythrocytes. All bone marrow smears for evaluation were coded to ensure that the group from which they were taken remained unknown to the investigator.
Criteria for assay validity
An one-sided Wilcoxon-Test was performed to check the validity of the study. The study was considered as valid if the proportion of polychromatic erythrocytes with micronuclei in the positive control was significantly higher than in the negative control (p<0.05).
Data analysis
Assuming the study is valid based on a monotone-dose-relationship, one-sided Wilcoxon tests were performed initially comparing control values with those of the highest dose group. A significance level of 5% is adopted for all tests.
CRITERIA FOR A POSITIVE RESPONSE
Both biological and statistical significances were considered together for evaluation purposes.
A substance is considered as positive if there is a significant or dose-related increase in the number of micronucleated polychromatic erythrocytes compared with the concurrent negative control group. A test substance producing no significant or dose-related increase in the number of micronucleated polychromatic erythrocytes is considered as non-clastogenic in this system. - Statistics:
- As detailed above under "Evaluation Criteria".
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- Rats were treated twice at an interval of 24 hours with 2000 mg/kg body weight to study the induction of micronuclei in bone marrow cells.
All animals survived after treatment. No signs of toxicity were observed in the main study.
The dissection of the animals revealed no test substance related macroscopic findings.
The bone marrow smears were examined for the occurrence of micronuclei in red blood cells.
A very slight increase of micronucleated polychromatic erythrocytes (mean value) was observed in the animals treated with 2000 mg/kg of the test compound. However, the incidence of micronucleated polychromatic erythrocytes in this dose group was within the historical range of the negative control groups (mean of micronucleated polychromatic erythrocytes per 2000 cells: 1.7-4.9). Moreover, the increase was not statistically significant. It was therefore considered as incidental finding without biological relevance.
The ratio of polychromatic erythrocytes to total erythrocytes remained essentially unaffected by the test compound and differed less than 20% from the control values.
Cyclophosphamide (Endoxan®) induced a marked and statistically significant increase in the number of polychromatic erythrocytes with micronuclei, thus indicating the sensitivity of the test system.
Any other information on results incl. tables
SUMMARY TABLES AND STATISTICS
Sex |
Dose mg/kg b.w. |
Killing time |
Number of animals |
Poly / animal counted |
Poly/Ery
Mean |
Poly/Ery SD Mean |
Poly with MN
Mean |
Poly with MN [%] Mean |
Poly with MN SD Mean |
Male |
0 – Control |
24 h |
5 |
2000 |
0.48 |
0.08 |
2.4 |
0.12 |
0.08 |
Male |
2000 |
24 h |
5 |
2000 |
0.48 |
0.04 |
2.6 |
0.18 |
0.04 |
Male |
40 – Endoxan |
24 h |
5 |
2000 |
0.43 |
0.05 |
28.2* |
1.41 |
0.70 |
Female |
0 – Control |
24 h |
5 |
2000 |
0.50 |
0.04 |
2.4 |
0.12 |
0.08 |
Female |
2000 |
24 h |
5 |
2000 |
0.47 |
0.04 |
3.4 |
0.17 |
0.10 |
Female |
40 – Endoxan |
24 h |
5 |
2000 |
0.40 |
0.05 |
18.8* |
0.94 |
0.24 |
Sex |
Dose mg/kg b.w. |
Killing time |
Number of animals |
Poly / animal counted |
Poly/Ery
Mean |
Poly/Ery SD Mean |
Poly with MN
Mean |
Poly with MN [%] Mean |
Poly with MN SD Mean |
Mut. I. |
Pooled |
0 – Control |
24 h |
10 |
2000 |
0.49 |
0.06 |
2.40 |
0.1 |
0.07 |
1.0 |
Pooled |
2000 |
24 h |
10 |
2000 |
0.48 |
0.04 |
3.50 |
0.2 |
0.07 |
1.5 |
Pooled |
40 – Endoxan |
24 h |
10 |
2000 |
0.42 |
0.05 |
23.5* |
1.2 |
0.55 |
9.8 |
Mut. I. = Mutagenic Index
Control = Vehicle (deionised water)
* = Significantly different from control (p < 0.05)
A cross comparison of individual data and pooled data may show discrepancies since the values are rounded.
Applicant's summary and conclusion
- Conclusions:
- The results lead to the conclusion that the test item did not cause a substantial increase in micronucleated polychromatic erythrocytes and is not clastogenic in the micronucleus test in vivo under the conditions described in this report.
- Executive summary:
The test compound was suspended in deionised water and was given twice at an interval of 24 hours as oral doses of 2000 mg per kg body weight to male and female rats (Hsd:Sprague Dawley), based on the results of a previous dose range finding assay. Endoxan® was used as positive control substance and was administered once orally at a dose of 40 mg per kg body weight.
The number of polychromatic erythrocytes containing micronuclei in all dose groups was not significantly increased compared with the control. The ratio of polychromatic erythrocytes to total erythrocytes in both male and female animals remained unaffected by the treatment with the test item and differed less than 20% from the control value.
Endoxan® induced a marked statistically significant increase in the number of polychromatic cells with micronuclei, indicating the sensitivity of the test system. The ratio of polychromatic erythrocytes to total erythrocytes was not changed to a significant extent.
Under the conditions of the present study the results indicate that the test item is not clastogenic in the micronucleus test in vivo.
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