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EC number: 465-100-2 | 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2005
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- solid: particulate/powder
- Details on test material:
- Batch number: 022401
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Details on species / strain selection:
- Rats are recommended by the test guideline.
The strain chosen (F344) is commonly used in our laboratory for subacute toxicity studies.
Background data are therefore available, if necessary. - Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species, strain: Rats, Fischer, F344/NHsd, SPF.
Supplier: Harlan Winkelman GmbH, D-33176 Borchen.
Number of animals and sex: 30 males and 30 females. Females were nulliparous and non-pregnant.
All animals were within ±20 % of the mean weight per sex at the time of the allocation to the groups.
Age at delivery: About 6 weeks.
Age at time of the first administration: About 7 weeks.
Health status: The animals were supplied in an SPF-status and subjected to a health check prior to first dosing.
All animals were in a good state of health at this term.
Hygiene: Optimal hygienic conditions.
Room temperature: Average of 22.3 °C (continuous control and recording).
Relative humidity: Average of 56.1% (continuous control and recording).
Air exchange: 12 per hour.
Light :Artificial light from 6 a.m. to 6 p.m.
Cages: Single caging
Makrolon cages: Type III, high version (39 cm x 23 cm ground area, 18 cm height).
Bedding material: Aspen wood chips (ABEDD Dominik Mayr KEG, A-8580 Köflach), autoclaved. Bedding material was changed weekly. Acceptable contaminants are identical with the limits for contaminants in the feed.
Feed: Altromin 1324 forte, gamma irradiated with 25 kGy60Co, ad libitum. Exception: Feed was withdrawn on the day before blood sampling at about 5 p.m. and was offered again immediately
thereafter. Random samples of the feed are analysed for contaminants by Altromin GmbH, D-32791 Lage. One sample was additionally analysed by Agrar- und Umweltanalytik GmbH, D-07749 Jena. Acceptable limits of contaminants were taken from the animal feed regulation of the
Federal Republic of Germany.
Water: Tap water, acidified with HCl to pH ≥3, from an automatic watering system, ad libitum. Random samples of the water are analysed by the "Bundesanstalt für Lebensmitteluntersuchung
und –forschung", A-1090 Vienna, to check, if the water fulfils the requirements for drinking water for humans (exception: the pH).
Environmental enrichment: Nesting material and nibbling wood bricks (sized 10 cm x 2 cm x
2 cm), same material and source as the bedding material, were offered freshly once week.
Identification: By tattooing the individual animal number into the right pinna and cage tag.
Acclimatisation: 5 days.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- An oral administration was performed by stomach intubation using a metal gavage once a
day in the morning on 7 days per week.
The individual dose volumes were calculated using the last determined body weights.
The oral administration is a common route in toxicity testing of chemicals. - Vehicle:
- other: Water. An aqueous solution of the test substance was used in the dosed groups.
- Details on oral exposure:
- Method of administration:
Stomach intubation. - Analytical verification of doses or concentrations:
- yes
- Remarks:
- Determinations of the test substance in some selected preparations for stability and concentration were performed by HPLC.
- Details on analytical verification of doses or concentrations:
- System: Thermo Separation Instruments Thermoquest 1.
Software: Chrom Quest Chromatography Data System; version 4.2.
Column: Aquasil C18 5 μM 100*2.1 mm; SN0451685X, Lot. P5A02 Fa.Thermo Electron Corporation.
Column temperature: 30 °C.
Autosampler temperature: 20 °C.
Flow: 0.4 mL/min.
Mobile phase: 40 % methanol, 60 % 50 mM KH2PO4 + 2.3 mM KHSO4 + 5 mM heptane 1 -
sulfonic acid Na-salt.
Injection volume: 10 μL.
Detection: UV-absorption at 268 nm.
The following analytical method was developed to determine the concentration of the test
substance (as it is, in aqueous solutions) using high performance liquid chromatography.
The method was validated according to:
• "Validation of analytical procedures": Methodology ICH Q2B, December 1996 (as far as
applicable)
Calculation of linearity and variance homogeneity was performed according to:
• "Calibration of analytical methods": DIN 38402 part 51, May 1986
Sample Pre-treatment
All samples were diluted with water/methanol 60/40 (v/v), to obtain concentrations within the
calibration range
Test substance
Name: STI571 F8
Batch No.: 022401
Reference substance
The test substance "as it is" was used as reference substance.
Solutions of the test substance: Water/acetonitrile 60/40 (v/v).
HPLC equipment and conditions:
System: Thermo Separation Instruments Thermoquest 1, SCM1000 Vacuum Membrane Degasser, SpectraSYSTEM® Gradient pump P2000, SpectraSYSTEM® autosampler AS3000, SpectraSYSTEM® UV6000LP Photodiode Array Detector with 50mm flowcell
Software: ChromQuest Chromatography Data System version 4.2
Column: Aquasil C18, 5 μm 100*2.1 mm, SN 0451685X, Lot No. P5A02 Fa.Thermo Electron Corporation.
Column temperature: 30 °C
Autosampler temperature: 20 °C
Flow: 0.4 mL/min.
Injection volume: 10 μL
Detection: UV-absorption at 268 nm
Mobile phase: 60 % 50 mmol/L KH2PO4 + 2.2 mmol/L KHSO4 + 5 mmol/L, Heptane 1-sulfonic acid sodium salt, 40 % methanol LiChrosolv - Duration of treatment / exposure:
- Test duration: 28 days
- Frequency of treatment:
- Dosing regime: 7 days/week
- No. of animals per sex per dose:
- Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 20 mg/kg bw/day
Male: 5 animals at 65 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 20 mg/kg bw/day
Female: 5 animals at 65 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Test substance administration:
The test substance was administered as a freshly prepared aqueous solution, orally by
gavage to 3 groups of 5 male and 5 female F344 rats each, once a day for 28°consecutive
days (Days 1 to 28).
Doses used:
• Group A (low dose): 20 mg "STI571 F8"
per kg body weight and day,
• Group B (mid dose): 65 mg "STI571 F8"
per kg body weight and day,
• Group C (high dose): 200 mg "STI571 F8"
per kg body weight and day.
An equally sized negative control group (group K) received the vehicle for the test substance.
The dose volume was uniformly 10 mL per kg body weight.
In addition, two groups of 5 males and 5 females each, i.e. one high dose satellite group
(group CS) and one control satellite group (group KS), were treated in the same way as their
corresponding groups, but were kept for further 14 days without test substance
administration in an attempt to observe the reversibility or persistence of test substance
induced lesions.
Examinations
- Observations and examinations performed and frequency:
- Investigations:
• Animal observations: all animals, once a day (plus a daily check for viability).
• Detailed clinical observations: all animals, once a week.
• Functional observations: all animals, once, in the last week of the dosing period.
• Body weights: all animals, once a week.
• Feed consumption: all animals, for each week.
• Haematology: all animals of groups K, A, B and C, on Day 29 and all animals of groups KS and CS on Day 43.
• Clinical biochemistry: all animals of groups K, A, B and C on Day 29 and all animals of groups KS and CS on Day 43.
• Necropsy with gross pathological examination: all animals of groups K, A, B and C on Day 29 and all animals of groups KS and CS on Day 43.
• Organ weight determination: all animals at necropsy.
• Histopathological examination: all animals of groups K and C. - Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes- Statistics:
- Analysis of variance followed by the Scheffé-test: all data with means and standard deviations determined, comparison of more than two groups
t-test: all data with means and standard deviations determined, for comparison of two groups only
H-test of Kruskal and Wallis followed by the test of Nemenyi: counted events with scoring or in cases where the requirements for the analysis of variance were not fulfilled
Chi2-test: counted events
Fisher's exact test counted: events, if the Chi2-Test was not applicable.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Haematological findings:
- effects observed, non-treatment-related
- Clinical biochemistry findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Details on results:
- Clinical observations:
Mortality: none in any group.
Observations in life, clinical and functional observations:
There were no test substance related effects.
Body weight gain: No relevant changes were observed,
compared to the control.
Feed consumption: No relevant changes were observed,
compared to the control.
Laboratory findings:
Haematology: No relevant changes were observed, compared to
the control.
Blood chemistry: No relevant changes were observed, compared
to the control.
Effects in organs:
Necropsy: no relevant findings.
Organ weights: no relevant findings.
Histopathology: no relevant findings.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- gross pathology
- histopathology: non-neoplastic
- Dose descriptor:
- NOEL
- Effect level:
- 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- gross pathology
- haematology
- histopathology: non-neoplastic
- other: original NCD unit is mg/kg/day.
Target system / organ toxicity
- Critical effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Classified as: Not classified
No target organ or specfic toxic effect could be elucidated.
According to EU-Directive 2001/59/EC, the application of "R48" is not considered as necessary for " STI571 F8", as no toxic effects were noted at doses of 200 mg/kg and below.
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.
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