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EC number: 950-484-0 | 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
Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12-11-2018 to 13-11-2018
- 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)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- isopropyl (1s,3s)-3-(methylamino)cyclobutane-1-carboxylate succinate
- EC Number:
- 950-484-0
- Molecular formula:
- C9H17NO2*C4H6O4
- IUPAC Name:
- isopropyl (1s,3s)-3-(methylamino)cyclobutane-1-carboxylate succinate
- Test material form:
- solid
- Details on test material:
- Batch (Lot) Number: GR13335
Expiry date: 31 January 2020 (expiry date)
Physical Description: White solid
Purity/Composition: 97.1%
Storage Conditions: At room temperature
Constituent 1
Test animals / tissue source
- Species:
- cattle
- Strain:
- not specified
Test system
- Vehicle:
- physiological saline
- Controls:
- yes, concurrent positive control
- yes, concurrent negative control
- Amount / concentration applied:
- A 20% (w/v) solution of PF-07097547-24 was prepared in physiological saline.
- Duration of treatment / exposure:
- 240 minutes +/- 10 minutes
- Observation period (in vivo):
- N/A
- Duration of post- treatment incubation (in vitro):
- 90 minutes with Na-fluorescein
- Number of animals or in vitro replicates:
- 3 (three)
- Details on study design:
- SELECTION AND PREPARATION OF CORNEAS
Source: 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.
Transport: Eyes were collected and transported in physiological saline in a
suitable container under cooled conditions.
Preparation of Corneas
The eyes were checked for unacceptable defects, such as opacity, scratches, pigmentation and
neovascularization by removing them from the physiological saline and holding them in the
light. Those exhibiting defects were discarded.
The isolated corneas were stored in a petri dish with cMEM (Earle’s Minimum Essential
Medium (Life Technologies, Bleiswijk, The Netherlands) containing 1% (v/v) L-glutamine
(Life Technologies) and 1% (v/v) Fetal Bovine Serum (Life Technologies)). The isolated
corneas were mounted in a corneal holder (one cornea per holder) of BASF (Ludwigshafen,
Germany) with the endothelial side against the O-ring of the posterior half of the holder. The
anterior half of the holder was positioned on top of the cornea and tightened with screws. The compartments of the corneal holder were filled with cMEM of 32 ± 1°C. The corneas wereincubated for the minimum of 1 hour at 32 ± 1°C.
QUALITY CHECK OF THE ISOLATED CORNEAS
After the incubation period, the medium was removed from both compartments and replaced with fresh cMEM. Opacity determinations were performed on each of the corneas using an opacitometer (BASF-OP3.0, BASF, Ludwigshafen, Germany). The opacity of each cornea was read against a cMEM filled chamber, and the initial opacity reading thus determined wasrecorded. Corneas that had an initial opacity reading higher than 7 were not used.
NUMBER OF REPLICATES
Three corneas were selected at random for each treatment group.
NEGATIVE CONTROL USED
Physiological saline
SOLVENT CONTROL USED (if applicable)
POSITIVE CONTROL USED
20% imidazole in physiological saline
APPLICATION DOSE AND EXPOSURE TIME
The medium from the anterior compartment was removed and 750 µl of either the negative
control, positive control (20% (w/v) Imidazole solution) or 20% (w/v) solution of the test
item was introduced onto the epithelium of the cornea. The medium from the anterior
compartment was removed and 750 µl of the negative control and 20% (w/v) Imidazole
solution (positive control) were introduced onto the epithelium of the cornea. 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 ± 1°C.
TREATMENT METHOD:closed chamber
POST-INCUBATION PERIOD: no
REMOVAL OF TEST SUBSTANCE
After the incubation the solutions were removed and the epithelium was washed at least three times with MEM with phenol red (Earle’s Minimum Essential Medium Life Technologies). The medium in the posterior compartment was removed and both compartments were refilled with fresh cMEM and the opacity determinations were performed.
- POST-EXPOSURE INCUBATION:
METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: The opacity of a cornea was measured by the diminution of light passing through the cornea.
The light was measured as illuminance (I = luminous flux per area, unit: lux) by a light meter.
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of microtiter plate reader (OD490) : After the incubation period, the medium in the posterior compartment of each holder was
removed and placed into a sampling tube labelled according to holder number. 360 µl of the
medium from each sampling tube was transferred to a 96-well plate. The optical density at
490 nm (OD490) of each sampling tube was measured in triplicate using a microplate reader (TECAN Infinite® M200 Pro Plate Reader). Any OD490 that was 1.500 or higher was diluted to bring the OD490 into the acceptable range (linearity up to OD490
of 1.500 was verifiedbefore the start of the experiment). OD490
values of less than 1.500 were used in thepermeability calculation.
- Others (e.g, pertinent visual observations, histopathology): (please specify)
Possible pH effects of the test item on the corneas were recorded. Each cornea was inspected visually for dissimilar opacity patterns.
SCORING SYSTEM: In Vitro Irritancy Score (IVIS)
DECISION CRITERIA: the decision criteria as indicated in the TG was used.
Results and discussion
In vitro
Results
- Irritation parameter:
- in vitro irritation score
- Run / experiment:
- 1
- Value:
- 16
- Vehicle controls validity:
- not applicable
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Other effects / acceptance of results:
- The assay is considered acceptable if:
• The positive control gives an in vitro irritancy score that falls within two standard
deviations of the current historical mean.
• The negative control responses should result in opacity and permeability values that are
less than the upper limits of the laboratory historical range.
Any other information on results incl. tables
The individual in vitro irritancy scores for the negative controls ranged from 4.1 to 6.3. The
corneas treated with the negative control item were clear after the 240 minutes of treatment.
The individual positive control in vitro irritancy scores ranged from 116 to 168.
The corneas treated with the positive control were turbid after the 240 minutes of
treatment.
The corneas treated with PF-07097547-24 showed opacity values ranging from 4.6 to 26 and
permeability values ranging from -0.008 to 0.460. The corneas were turbid and translucent
after the 240 minutes of treatment with PF-07097547-24. A pH effect of the test item was
observed on the rinsing medium, the corneas were rinsed until no colour change of the
medium was observed. Hence, the in vitro irritancy scores ranged from 4.5 to 33 after
240 minutes of treatment with PF-07097547-24.
Applicant's summary and conclusion
- Interpretation of results:
- study cannot be used for classification
- Conclusions:
- In conclusion, since PF-07097547-24 induced an IVIS > 3 ≤ 55, no prediction on the classification can be made.
- Executive summary:
The objective of this study was to evaluate the eye hazard potential of PF-07097547-24 as
measured by its ability to induce opacity and increase permeability in an isolated bovine
cornea using the Bovine Corneal Opacity and Permeability test (BCOP test).
This report describes the potency of chemicals to induce serious eye damage using isolated
bovine corneas. The eye damage of PF-07097547-24 was tested through topical application
for approximately 240 minutes.
The study procedures described in this report were based on the most recent OECD guideline.
Batch GR13335 of PF-07097547-24 was a white solid with a purity of 97.1%. The test item
was applied as a 20% (w/v) solution (750 µL) directly on top of the corneas
The negative control responses for opacity and permeability were less than the upper limits of
the laboratory historical range indicating that the negative control did not induce irritancy on
the corneas. The mean in vitro irritancy score of the positive control (20% (w/v) Imidazole)
was 140 and within two standard deviations of the current historical positive control mean. It
was therefore concluded that the test conditions were adequate and that the test system
functioned properly.
PF-07097547-24 induced ocular irritation through both endpoints, resulting in a mean in vitro
irritancy score of 16 after 4 hours of treatment.
In conclusion, since PF-07097547-24 induced an IVIS > 3 ≤ 55, no prediction on the
classification can be made.
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