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EC number: 810-753-4 | CAS number: 1374639-78-7
- 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
Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Aug 2017 - April 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)
- GLP compliance:
- yes
Test material
- Reference substance name:
- tert-Butyl 4-({6-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate
- EC Number:
- 810-753-4
- Cas Number:
- 1374639-78-7
- Molecular formula:
- C28H38N8O3
- IUPAC Name:
- tert-Butyl 4-({6-[7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}pyridin-3-yl)piperazine-1-carboxylate
- Test material form:
- solid: bulk
Constituent 1
Test animals / tissue source
- Species:
- cattle
- Strain:
- other: Bovine eyes were used as soon as possible after slaughter.
- Details on test animals or tissues and environmental conditions:
- Bovine eyes from young cattle were obtained from the slaughterhouse (Vitelco, -'s Hertogenbosch, The Netherlands), where the eyes were excised by a slaughterhouse employee as soon as possible after slaughter.
Test system
- Vehicle:
- unchanged (no vehicle)
- Controls:
- yes, concurrent positive control
- yes, concurrent negative control
- Amount / concentration applied:
- No correction will be made for the purity/composition of the test compound.
Since no workable suspension of LEE011-A3 in physiological saline could be obtained, the test item was used as delivered by the sponsor and added pure on top of the corneas.
The medium from the anterior compartment was removed and 750 l of the negative control and 20% (w/v) Imidazole solution (positive control) were introduced onto the epithelium of the cornea. LEE011-A3 was weighed in a glass tube and applied directly on the corneas in such a way that the cornea was completely covered (324.0 to 331.7 mg). - Duration of treatment / exposure:
- 240 ± 10 minutes
- Duration of post- treatment incubation (in vitro):
- The opacity of the corneas was determined directly after treatment and the permeability of the corneas was determined after a 90 minutes incubation period with sodium fluorescein.
After the incubation the solutions and the test compound were removed and the epithelium was washed at least three times with MEM with phenol red (Earle’s Minimum Essential Medium Life Technologies). Possible pH effects of the test item on the corneas were recorded. Each cornea was inspected visually for dissimilar opacity patterns. The medium in the posterior compartment was removed and both compartments were refilled with fresh cMEM and the opacity determinations were performed. - Number of animals or in vitro replicates:
- 3 corneas for each treatment group
- Details on study design:
- The medium from the anterior compartment was removed and 750 micro l of the negative control and 20% (w/v) Imidazole solution (positive control) were introduced onto the epithelium of the cornea. LEE011-A3 was weighed in a glass tube and applied directly on the corneas in such a way that the cornea was completely covered (324.0 to 331.7 mg). The holder was slightly rotated, with the corneas maintained in a horizontal position, to ensure uniform
distribution of the solutions over the entire cornea. Corneas were incubated in a horizontal position for 240 ± 10 minutes at 32 ± 1C. After the incubation the solutions and the test compound were removed and the epithelium was washed at least three times with MEM with phenol red (Earle’s Minimum Essential Medium Life Technologies). Possible pH effects of the test item on the corneas were recorded. Each cornea was inspected visually for dissimilar
opacity patterns. The medium in the posterior compartment was removed and both compartments were refilled with fresh cMEM and the opacity determinations were performed.
Following the final opacity measurement, permeability of the cornea to Na-fluorescein (Sigma-Aldrich, Germany) was evaluated.
The medium of both compartments (anterior compartment first) was removed. The posterior compartment was refilled with fresh cMEM. The anterior compartment was filled with 1 ml of 5 mg Na-fluorescein/ml cMEM solution (Sigma-Aldrich Chemie GmbH, Germany).
The holders were slightly rotated, with the corneas maintained in a horizontal position, to ensure uniform distribution of the sodium-fluorescein solution over the entire cornea. Corneas were incubated in a horizontal position for 90 ± 5 minutes at 32 ± 1C.
Results and discussion
In vitro
Resultsopen allclose all
- Irritation parameter:
- cornea opacity score
- Value:
- >= -0.6 - <= 1.2
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Irritation parameter:
- in vitro irritation score
- Value:
- >= -0.6 - <= 1.2
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
Any other information on results incl. tables
The individual in vitro irritancy scores for the negative controls ranged from -1.2 to 0.8. The individual positive control in vitro irritancy scores ranged from 156 to 170. The corneas treated with the positive control were turbid after the 240 minutes of
treatment.
The corneas treated with LEE011-A3 showed opacity values ranging from -0.6 to 1.2 and permeability values ranging from 0.013 to 0.018. The corneas were clear after the 240 minutes of treatment with LEE011-A3. No pH effect of the test item was observed on the rinsing medium.
Hence, the in vitro irritancy scores ranged from -0.6 to 1.2 after 240 minutes of treatment with LEE011-A3.
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- LEE011-A3 did not induce ocular irritation through both endpoints, resulting in a mean in vitro irritancy score of 0.1 after 240 minutes of treatment.
In conclusion, since LEE011-A3 induced an IVIS ≤ 3, no classification is required for eye irritation or serious eye damage.
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