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EC number: 700-890-7 | CAS number: 503614-91-3
- 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
Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 September 2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2003
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)
- Qualifier:
- according to guideline
- Guideline:
- other: An in vitro Assay for Occular Irritancy, Fundamental and Applied Toxicology 18: 442-449, 1992
- Qualifier:
- according to guideline
- Guideline:
- other: The Utility of a two-test in vitro battery to access the Ocular Irritancy of drug intermediates. Development in Animal and Veterinary Sciences. 27. Proceedings of the 2nd World Congress on alternative and Animal use in the Life Sciences.
- Principles of method if other than guideline:
- The purpose of the study is to evaluate the potential ocular irritancy/toxicity of a test article as measured by the test article's ability to induce opacity and permeability to sodium fluorescein in an excised bovine cornea, in vitro.
- GLP compliance:
- yes
- Remarks:
- Ec Commission Directive 1999/11/EC and OECD ENV/MC/CHEM(98)17
Test material
- Reference substance name:
- ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-3-carboxylate
- EC Number:
- 700-890-7
- Cas Number:
- 503614-91-3
- Molecular formula:
- C27 H28 N4 O5
- IUPAC Name:
- ethyl 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-1H,4H,5H,6H,7H-pyrazolo[3,4-c]pyridine-3-carboxylate
- Details on test material:
- Crystalline Solid
Constituent 1
Test animals / tissue source
- Species:
- cattle
- Strain:
- not specified
- Details on test animals or tissues and environmental conditions:
- Bovine eyes were obtained as by-product of freshly slaughtered animals, transported in Hank's Balanced Salt Solution supplemented with 1% penicillin/streptomycin solution. The corneas are used within 4 hour of slaughter. The tissue surrounding the eyeball were carefully pulled away and the corneas were excised such that a 2 to 3 mm rim of sclera was present around the cornea. The corneas are mounted in corneal folders with the endothelial side against the O-ring of the posterior half of the holder. The chambers were filled with cMEM and incubated at 32 ± 2°C for 60± 5 min.
Test system
- Vehicle:
- physiological saline
- Remarks:
- 20% (w/w) in 0.9% sodium chloride solution
- Controls:
- yes, concurrent vehicle
- yes, concurrent positive control
- Amount / concentration applied:
- An aliquot of 750ug was administered as 20 % w/v ( 200 mg/ml) suspension in saline.
- Duration of treatment / exposure:
- Corneas were exposed to the test material suspension for approximately four hours and then the corneas are removed from the incubator. The epithelial side of each cornea was rinsed three times with cMEM.
- Observation period (in vivo):
- Opacity measurements performed immediately after exposure period ends.
- Number of animals or in vitro replicates:
- Three corneas are tested with the test substance. Three negative controls (0.9% sodium chloride solution) and three positive controls (imidazole) were also used
- Details on study design:
- The study design requires determination of an opacity value and a permeability measurement. Positive and negative controls are used in the study. The positive controls use a 20 % (w/v) suspension of imidazole in complete MEM. The negative control use a 0.9% Saline. The corneas were exposed for approximately four hours and then the corneas are removed from the incubator. Then the opacity measurements are taken. Permeability measurements: Once opacity measurements are complete the medium was replaced with 1 ml of a 5 mg/ml fluorescein solution and incubated for another 90 minutes with the anterior chamber up. . The opacity density at 490 nm (OD 490) was determined If an OD 490 value was greater than 1.8, a 1:5 dilution of the sample in complete MEM was made. The dilution samples were then retested and final permeability measurements were made.
Results and discussion
In vitro
Resultsopen allclose all
- Irritation parameter:
- cornea opacity score
- Run / experiment:
- mean
- Value:
- 3.7
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: standard deviation = 2.3
- Irritation parameter:
- fluorescein leakage
- Run / experiment:
- mean
- Value:
- 0.001
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: standard deviation = 0.003
- Other effects / acceptance of results:
- Positive control results: opacity value; 87.0 ±8.7, Permeability; 2.678 ± 0.578
Negative control results: opacity value; 2.0 ± 1.7, Permeability; 0.009 ± 0.001
Any other information on results incl. tables
The bovine corneal opacity and permeability assay uses an opacity measurement and a permeability measurement to determine a final in vitro score. The opacity measurement is determined by the change in opacity of each cornea by subtracting the calculated pre-treatment opacity reading from the final opacity reading. The corrected opacity value of each cornea was calculated by subtracting the average change in opacity of the negative control corneas from that of the treated corneas. The mean opacity value of each treatment group was calculated by averaging the corrected opacity value of the treated corneas from each treatment condition. The permeability measurements: the corrected OD 490 is determined by subtracting the negative controls mean OD 490 from each of the treated cornea OD 490 value. The mean OD 490 of each treatment group was calculated by averaging the corrected OD 490 values. The formula used is: in vitro score = mean opacity value + ( 15 x mean OD 490 Value). The in vitro score is then compared to a classification system established based on studies with a wide range of test materials. The classification provides a good initial guide to interpret these in vitro data: an in vitro score from 0 to 25 is negative irritation and > 25.1 positve for irritation.
Applicant's summary and conclusion
- Interpretation of results:
- not irritating
- Conclusions:
- Based on an in vitro score of 3.7 ± 2.3 and valid positive and negative controls, the test material was classified according to this assay's classification scheme as a negative potential eye irritant.
- Executive summary:
The in vitro bovine corneal opacity and permeability assay was completed in 2002 in accordance with GLP and before the official adoption of the EU method B.47 method (2010) and OECD 437 (2009). However, the method used in 2002 is equivalent or similar to the current EU B.47 and OECD 437 method and considered as a Klimish 1.
.The bovine corneal opacity and permeability assay uses an opacity measurement and a permeability measurement to determine a final in vitro score. The opacity measurement is determined by the change in opacity of each cornea by subtracting the calculated pre-treatment opacity reading from the final opacity reading. The corrected opacity value of each cornea was calculated by subtracting the average change in opacity of the negative control corneas from that of the treated corneas. The mean opacity value of each treatment group was calculated by averaging the corrected opacity value of the treated corneas from each treatment condition. The permeability measurements: the corrected OD 490 is determined by subtracting the negative controls mean OD 490 from each of the treated cornea OD 490 value. The mean OD 490 of each treatment group was calculated by averaging the corrected OD 490 values. The formula used is: in vitro score = mean corrected opacity value + ( 15 x mean corrected OD 490 Value). The in vitro score is then compared to a classification system. The classification provides a good initial guide to interpret these in vitro data: an in vitro score from 0 to 25 as negative, and < 25.1 as positive
Based on an in vitro score of 3.7 ± 2.3 and valid positive and negative controls, the test material was classified according to this assay's classification scheme as a negative potential eye irritant.
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