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EC number: 841-500-6 | CAS number: 1903008-80-9
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Remarks:
- Short term (7 days) repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2016-06-16 to 2016-06-29
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Justification for type of information:
- Considered bridging study - reference section 13
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
- Objective of study:
- absorption
- other: accumulation
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- The objective of study was to investigate the pharmacokinetics of YH25448 following repeated oral administrations of free form and mesylate salt of YH25448 to rats.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide
- EC Number:
- 841-500-6
- Cas Number:
- 1903008-80-9
- Molecular formula:
- C30H34N8O3
- IUPAC Name:
- N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide
- Test material form:
- solid: particulate/powder
Constituent 1
- Reference substance name:
- N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide
- EC Number:
- 841-500-6
- Cas Number:
- 1903008-80-9
- Molecular formula:
- C30H34N8O3
- IUPAC Name:
- N-{5-[(4-{4-[(dimethylamino)methyl]-3-phenyl-1H-pyrazol-1-yl}pyrimidin-2-yl)amino]-4-methoxy-2-(morpholin-4-yl)phenyl}prop-2-enamide
- Test material form:
- solid: particulate/powder
- Test material form:
- solid: particulate/powder
- Specific details on test material used for the study:
- *Test article 1
SOURCE OF TEST MATERIAL
- YH25448 (T003925, Lazertinib free base)
- lot/batch number of test material: 5138-117
- Appearance: Light yellow solid
- Purity: 98.7%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at 4°C
- Stability under storage conditions: not indicated
- Stability under test conditions: not indicated
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: not indicated
FORM AS APPLIED IN THE TEST: liquid
*Test article 2
SOURCE OF TEST MATERIAL
- YH25448A (YH25448, Lazertinib mesylate )
- lot/batch number of test material: 5138-156
- Appearance: Off -white solid
- Purity: 99.3%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at 4°C
- Stability under storage conditions: not indicated
- Stability under test conditions: not indicated
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: not indicated
FORM AS APPLIED IN THE TEST: liquid - Radiolabelling:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD (SD)
- Details on species / strain selection:
- Rationale for species selection: SD rats were commonly used species in pre-clinical studies with large historical scientific data and easy to handle.
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: 34 male Crl:CD (SD) rats from Orient Bio Inc.
- Age at study initiation: 7 weeks
- Weight at study initiation: 0.260 - 0.280 kg
- Fasting period before study: not indicated
- Housing: Three or four rats per cage were housed in polycarbonate cages (240 W x 400 L x 180 H mm) for acclimation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days
DETAILS OF FOOD AND WATER QUALITY: not indicated
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23±2°C
- Humidity (%): 40 - 60 %
- Air changes (per hr): 10 times/hr
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2016-06-17. To: 2016-06-28 - Route of administration:
- oral: gavage
- Vehicle:
- other: 50 mM citric acid/0.5% methyl cellulose and 0.5% methyl cellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- To prepare the oral dosing formulation, appropriate amounts of test item were weighed. The test items were dissolved in vehicle on the day of dosing to achieve the final concentrations.
Group 1: YH25448 (test item), 50 mg/kg (dose), 10 mL/kg (dose volume), 1.50 g (Weighed amount), 300 mL (Volume of vehicle added), 5 mg/mL (Final concentration)
Group 2: YH25448A (test item), 50 mg/kg (dose), 10 mL/kg (dose volume), 1.76 g (Weighed amount), 300 mL (Volume of vehicle added), 5 mg/mL* (Final concentration)
Group 3: YH25448A (test item), 50 mg/kg (dose), 10 mL/kg (dose volume), 1.76 g (Weighed amount), 300 mL (Volume of vehicle added), 5 mg/mL* (Final concentration)
*: corrected as free form with salt factor
VEHICLE
Citric acid/Methyl cellulose:
- Justification for use and choice of vehicle (if other than water): not indicated
- Concentration in vehicle: 50 mM (citric acid), 0.5% (methyl cellulose)
- Amount of vehicle (if gavage): 300 mL
- Lot/batch no. (if required): 104K0117
- Purity: not indicated
Methyl cellulose:
- Justification for use and choice of vehicle (if other than water): not indicated
- Concentration in vehicle: 0.5 %
- Amount of vehicle (if gavage): 300 mL
- Lot/batch no. (if required): SLBJ8516V
- Purity: not indicated
Vehicle preparation:
1) 50 mM citric acid/0.5 % methyl cellulose
The vehicle of 50 mM citric acid/0.5 % methyl cellulose was made by following procedure.
- 5 g of methyl cellulose and 10.51 g of citric acid were added to 1000 mL of bottle.
- 750 mL of distilled water was added to the bottle and the mixture was stirred overnight to dissolve completely.
- Distilled water was added up to 1000 mL of final volume.
2) 0.5 % methyl cellulose
The vehicle of 0.5 % methyl cellulose was made by following procedure.
- 5 g of methyl cellulose was added to 1000 mL of bottle.
- 750 mL of distilled water was added to the bottle and the mixture was stirred overnight to dissolve
completely.
- Distilled water was added up to 1000 mL of final volume. - Duration and frequency of treatment / exposure:
- 7 days, daily
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Group 1, 2 and 3
- No. of animals per sex per dose / concentration:
- 6 males/group (3 groups), the animals in each group were divided into 2 subgroups again (n=3/time point). Dosing of 50 mg/kg in each group.
- Control animals:
- no
- Positive control reference chemical:
- yes, YH25448-d5 (Internal standard)
- Details on study design:
- - Dose selection rationale: The dose level was determined as 50 mg/kg for the study considering a dose level in 4-week repeated oral dose toxicity study in rats (COVANCE Study No.: 83337361)).
- Fasting period before blood sampling for clinical biochemistry: not indicated - Details on dosing and sampling:
- TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: Blood sampling were collected alternately from the 2 subgroups via jugular vein using 1 mL of disposable syringe at predose, 0.5, 1, 2, 4, 8, 12 and 24 hr post-dose on Day 1 and Day 7.
- Anaesthetic used for blood collection: no data
- Animals fasted: no data
- How many animals: 18
- Other: Plasma samples were obtained from blood samples after centrifugation at 13,000 rpm for 2 min and aliquoted 50 µL and residual plasma. All plasma samples were stored in deep freezer at approximately -70°C before analysis.
ANALYTICAL METHOD
- Plasma samples were quantitated following ‘Bioanalytical method validation for determination of YH25448 in mouse, rat, dog, monkey and human plasma by LC-MS/MS (RDTE152442))’. Using triple quadrupole mass spectrometer, YH25448 (reference standard, m/z 555.256 → 510.100) and YH25448-d5 (internal standard, m/z 560.377 → 515.200) were detected by MRM (multiple reaction monitoring) mode.
- Protein precipitation method was used for determination of YH25448 in plasma samples. 10 µL of internal standard solution (YH25448-d5, 1 µg/mL in 50% acetonitrile) and 500 µL of methanol for protein precipitation were added to 50 µL of plasma samples and vortexed for 1 min. The mixtures were centrifuged at 13,000 rpm for 10 min. 200 µL of deionized water was added to 200 µL of supernatants and vortexed for 10 sec. The mixtures were injected (2 µL) into LC-MS/MS system. - Statistics:
- no statistics available
- Key result
- Test no.:
- #2
- Toxicokinetic parameters:
- AUC: 30504.8 ng·hr/mL (group 1), 27408.6 ng·hr/mL (group 2) and 25391.4 ng·hr/mL (group 3)
- Key result
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 1873.2 ng/mL (group 1), 1741.7 ng/mL (group 2) and 1583.2 ng/mL (group 3)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 21180.2 ng·hr/mL (group 1), 13267.3 ng·hr/mL (group 2) and 19059.4 ng·hr/mL (group 3)
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 2.0 to 8.0 hr
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 1169.1 ng/mL (group 1), 1061.5 ng/mL (group 2) and 1170.9 ng/mL (group 3)
- Conclusions:
In conclusion, pharmacokinetics of YH25448 was generally similar after single and repeated dose of YH25448 (free base) or YH25448A (mesylate salt) to rats and moderate accumulation was observed after repeated administration.
Referenceopen allclose all
Constituent 1
Constituent 1
Test animals
Administration / exposure
Doses / concentrations
Results and discussion
Toxicokinetic / pharmacokinetic studies
Toxicokinetic parametersopen allclose all
Any other information on results incl. tables
After single oral administrations of YH25448 or YH25448A to rats at 50 mg/kg, Cmax for YH25448 was generally similar among groups. Although AUClast for YH25448 in Group 2 (YH25448A in 50 mM citric acid/0.5 % methyl cellulose) was slightly low compared with other groups, the difference was not significant (less than 2 fold).
After repeated oral administrations of YH25448 or YH25448A to rats for 7 days at 50 mg/kg, mean plasma concentration-time profiles and the values of Cmax and AUClast for YH25448 were generally similar among groups.
Accumulation was observed after repeated administration for 7 days with accumulation ratio of 1.3 to 2.1.
Applicant's summary and conclusion
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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