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EC number: 692-722-3 | CAS number: 835621-07-3
- 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
Bioaccumulation: aquatic / sediment
Administrative data
- Endpoint:
- bioaccumulation in aquatic species: fish
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Oct 2011 - Jan 2012
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted with the base (BAY 73-4605) according to OECD guideline under GLP
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
- Report date:
- 2012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 305 (Bioconcentration: Flow-through Fish Test)
- Deviations:
- no
- Principles of method if other than guideline:
- not relevant
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-Nmethylpyridine- 2-[14C]carboxamide
- IUPAC Name:
- 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-Nmethylpyridine- 2-[14C]carboxamide
- Details on test material:
- - Name of test material (as cited in study report): Regorafenib (14-C)
- Analytical purity: 98%
- Lot/batch No.: GCM 1569-1-13 A
- Radiochemical purity (if radiolabelling): 98%
- Specific activity (if radiolabelling): 98% / 2.55 MBq/mg
Constituent 1
- Radiolabelling:
- yes
Test solutions
- Vehicle:
- no
Test organisms
- Test organisms (species):
- Lepomis macrochirus
Study design
- Route of exposure:
- aqueous
- Test type:
- flow-through
- Water / sediment media type:
- natural water: freshwater
- Total exposure / uptake duration:
- 28 d
- Total depuration duration:
- 14 d
Test conditions
- Nominal and measured concentrations:
- 0.16 and 1.6 ¿g/L (nominal)
0.05 and 0.45 ¿g/L (measured) - Details on estimation of bioconcentration:
- BASIS INFORMATION
- Measured/calculated logPow: 3.9
BASIS FOR CALCULATION OF BCF
- Estimation software: SAS 9.2
- Result based on measured log Pow of: 3.9
Results and discussion
Bioaccumulation factoropen allclose all
- Type:
- BCF
- Value:
- 2 874 dimensionless
- Basis:
- total lipid content
- Calculation basis:
- steady state
- Remarks on result:
- other: Conc.in environment / dose:0.16
- Type:
- BCF
- Value:
- 4 444 dimensionless
- Basis:
- total lipid content
- Calculation basis:
- steady state
- Remarks on result:
- other: Conc.in environment / dose:1.6
Depuration
- Elimination:
- yes
- Parameter:
- DT50
- Depuration time (DT):
- 6 d
Any other information on results incl. tables
TT 1: | Concentration of regorafenib in fish | |||||||||
Nominal concentration of regorafenib [ìg/L] | Accumulation phase | Depuration phase | ||||||||
Day 4 [µg/kg] (n=4) | Day 6 [µg/kg] (n=4) | Day 8 [µg/kg] (n=4) | Day 14 [µg/kg] (n=4) | Day 21 [µg/kg] (n=4) | Day 28 [µg/kg] (n=4) | Day 30 [µg/kg] (n=4) | Day 32 µg/kg] (n=4) | Day 38 [µg/kg] (n=4) | Day 42 [µg/kg] | |
0,16 | 59 | 78,6 | 93,9 | 149,2 | 143,8 | 138,2 | 102 | 51,9 | 9,8 | 8,8 (n=4) |
1,6 | 789,9 | 1155,6 | 1498,4 | 2301,8 | 1690 | 2007,7 | 2042,2 | 1082,7 | 292 | 64,3 (n=2) |
TT 2: | Concentration of regorafenib in water (exposure phase) | |||||||||
Nominal concentration of regorafenib [ìg/L] | Day 4 [ng/L] | Day 6 [ng/L] | Day 8 [ng/L] | Day 14 [ng/L] | Day 21 [ng/L] | Day 28 [ng/L] | Mean measured concentration (MV) [ng/L] | |||
Control | 0 | 0 | 0 | 0 | 0 | 0 | 0 | |||
0,16 | 71,5 | 54,4 | 15 | 39,3 | 28,6 | 69,6 | 46,4 | |||
1,6 | 722,6 | 426,6 | 314,7 | 348,7 | 207,1 | 702,8 | 453,8 | |||
TT 3: | Concentration of regorafenib in water (depuration phase) | |||||||||
Nominal concentration of regorafenib [ìg/L] | Day 30 [ng/L] | Day 32 [ng/L] | Day 38 [ng/L] | Day 42 [ng/L] | Mean measured concentration (MV) ng/L] | |||||
Control | 0 | 0 | 0 | 0 | 0 | |||||
0,16 | 15,8 | 7,4 | 11,9 | 25,5 | 15,2 | |||||
1,6 | 76,9 | 25,5 | 16,3 | 12,8 | 32,8 | |||||
Applicant's summary and conclusion
- Validity criteria fulfilled:
- yes
- Conclusions:
- No substance related mortality or abnormal behavior was observed neither in the test nor in the vehicle control solutions during the whole
experimental period. Thus, it was shown that the exposure had no toxic effect on the fish at the concentrations tested.
The low and high concentration differed in the BCF by an approximate factor of 1.5. The BCF was greater than 10, thus, the uptake of the
substance in fish is established to be significant according to the guideline. - Executive summary:
Regorafenib is a multi-kinase inhibitor for cancer therapy. The aim of this study was to identify the bioaccumulation potential of regorafenib in fish. The study was conducted in accordance with the test guideline OECD 305.
The test consisted of two phases: the exposure (uptake) and post-exposure (depuration) phase.
During the uptake phase, separate groups of fish of the species Lepomis macrochirus were
exposed to the test substance. During depuration, the substance delivery was discontinued and
only tap water was provided.
The fish were exposed to 14C labeled regorafenib at two concentrations (nominally 0.16 and
1.6 ¿g/L) and additionally to the control for a period of 28 days. Subsequently, the fish were
depurated over a period of 14 days. Two replicate tanks for the test concentrations and one tank for the control were used.
A stock solution with a nominal concentration of regorafenib (as ethanolic solution) of 0.8 mg/L for group 2 and 8 mg/L for group 3 were prepared. The stock solutions were delivered continuously to the tanks.
80 fish were used for the test solutions and 10 for the vehicle control group. Mortalities and visible abnormalities of the fish were recorded daily over the uptake and depuration phase.
The hydrographic parameters were recorded weekly. The oxygen concentration should be > 60 % of the air saturation value, the temperature should be maintained at 20 ¿ 25°C and the pH-value between 6.0 and 8.5. These parameters were met.
The concentration of the test substance in the fish and in water was determined through both phases of the test by measurement of the radioactivity. The 14-C concentration in the fish was analyzed by liquid scintillation after liquid degradation of the fish by oxidation (SOLUENE-350) in samples taken on day 4, 6, 10, 14, 21 and 28 (uptake) and on day 30, 32, 38 and 42
(depuration). The 14-C concentration in the water was analyzed by liquid scintillation in samples taken on the
same time points. The bioconcentration factor in fish (BCF) was calculated as the ratio of the mean values of the
14-C concentration in fish and in water, taken at steady state.
In group 2 (low concentration, 0.16 ¿g/L) the mean concentration of regorafenib in water was 0.05 ¿g/L. At steady state, i.e. at sampling days 14 - 28 in group 2, the concentration in fish was 143.72 ¿g/kg. In group 3 (high concentration, 1.6 ¿g/L) the mean value in water was 0.45 ¿g/L. At steady state, i.e. at sampling day 14 - 28 in group 3, the concentration in fish was 1999.84 ¿g/kg.
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