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EC number: 611-575-8 | CAS number: 577953-88-9
- 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
Eye irritation
Administrative data
- Endpoint:
- eye irritation: in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22 December to 23 December 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
Materials and methods
Test guidelineopen allclose all
- 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:
- equivalent or similar to guideline
- Guideline:
- EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)
- GLP compliance:
- yes
Test material
- Reference substance name:
- N-cyclohexylcyclohexanamine 2-[1-[[[(1R)-1-[3-[(1E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetate
- EC Number:
- 611-575-8
- Cas Number:
- 577953-88-9
- Molecular formula:
- C47H59ClN2O3S
- IUPAC Name:
- N-cyclohexylcyclohexanamine 2-[1-[[[(1R)-1-[3-[(1E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetate
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- White powder with lumps
Stored at room temperature
Constituent 1
Test animals / tissue source
- Species:
- cattle
- Strain:
- not specified
- Details on test animals or tissues and environmental conditions:
- Test System: Bovine eyes were used as soon as possible after slaughter on the same day.
Rationale: In the interest of sound science and animal welfare, a sequential testing strategy is recommended to minimise the need of in vivo testing (1-6). As a consequence a validated and accepted in vitro test for eye irritation should be performed before in vivo tests are conducted. One of the proposed validated in vitro eye irritation tests is the Bovine Corneal Opacity and Permeability (BCOP) test.
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.
Test system
- Vehicle:
- unchanged (no vehicle)
- Controls:
- yes, concurrent positive control
- yes, concurrent negative control
- Amount / concentration applied:
- 371.4 to 392.0 mg per cornea
- Duration of treatment / exposure:
- 4 hours
- 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.
- Number of animals or in vitro replicates:
- Corneas were treated in triplicate with either the test substance, positive control compound or negative control (0.9% sodium chloride solution).
- Details on study design:
- 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 (Eagle’s Minimum Essential Medium
(Invitrogen Corporation, Breda, The Netherlands) containing 1% (v/v) L-glutamine (Invitrogen
Corporation) and 1% (v/v) Foetal Bovine Serum (Invitrogen Corporation)). The isolated corneas were
mounted in a corneal holder (one cornea per holder) of MC2 (Clermont-Ferrand, France) 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 were incubated for the minimum of 1 hour at
32 ± 1°C.
Cornea selection and Opacity reading
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
(OP-KIT, MC2, Clermont-Ferrand, France). The opacity of each cornea was read against an air filled
chamber, and the initial opacity reading thus determined was recorded. Corneas that had an initial
opacity reading higher than 7 were not used. Three corneas were selected at random for each
treatment group.
Treatment of corneas and opacity measurements
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.
Montelukast dicyclohexylamine salt was weighed in a bottle and applied directly on the corneas in
such a way that the cornea was completely covered (371.4 to 392.0 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 ± 1°C. 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 (Eagle’s Minimum Essential
Medium, Invitrogen Corporation). Possible pH effects of the test substance 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.
Opacity measurement
The opacitometer determined the difference in the light transmission between each control or treated
cornea and an air filled chamber. The numerical opacity value (arbitrary unit) was displayed and
recorded. The change in opacity for each individual cornea (including the negative control) was
calculated by subtracting the initial opacity reading from the final post-treatment reading. The
corrected opacity for each positive control or test substance treated cornea was calculated by
subtracting the average change in opacity of the negative control corneas from the change in opacity
of each positive control or test substance treated cornea.
The mean opacity value of each treatment group was calculated by averaging the corrected opacity
values of the treated corneas for each treatment group.
Application of sodium fluorescein
Following the final opacity measurement, permeability of the cornea to Na-fluorescein (Merck) 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. 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 ± 1°C.
Permeability determinations
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 verified before the start of the experiment). OD490 values of less
than 1.500 were used in the permeability calculation.
The mean OD490 for each treatment was calculated using cMEM corrected OD490 values. If a dilution
was performed, the OD490 of each reading was corrected for the mean negative control OD
490 beforethe dilution factor was applied to the readings.
Electronic data capture
Observations/measurements in the study were recorded electronically using the following programme:
Magellan Tracker 7.0 (TECAN, Austria) for optical density measurement.
Results and discussion
In vitro
Resultsopen allclose all
- Irritation parameter:
- in vitro irritation score
- Value:
- ca. -0.5
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Irritation parameter:
- cornea opacity score
- Value:
- ca. -1
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Irritation parameter:
- fluorescein leakage
- Value:
- ca. 0.012
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Other effects / acceptance of results:
- Positive control results: opacity value 78; Permeability 1.786; and in vitro irritancy 104.8
Interpretation
In vitro irritancy score
The mean opacity and mean permeability values (OD490) were used for each treatment group to
calculate an in vitro score:
In vitro irritancy score (IVIS) = mean opacity value + (15 x mean OD490 value)
Additionally the opacity and permeability values were evaluated independently to determine whether
the test substance induced irritation through only one of the two endpoints.
The IVIS cut-off values for identifying the test substances as inducing eye damage (UN GHS
Category 1) and test substances not requiring classification for eye irritation or serious eye damage
(UN GHS No Category) are given hereafter:
≤ 3 No Category
> 3; ≤ 55 No prediction can be made
>55 Category 1
Acceptability of the assay
The assay is considered acceptable if:
- The positive control gives an in vitro irritancy score that falls within the laboratory historical mean
value.
- The negative control responses should result in opacity and permeability values that are less than
the upper limits of the laboratory historical range.
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- TThe 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 105 and within the
historical positive control data range (APPENDIX 3, Table 6). It was therefore concluded that the test
conditions were adequate and that the test system functioned properly.
Montelukast dicyclohexylamine salt did not induce ocular irritation through both endpoints, resulting in
a mean in vitro irritancy score of -0.5 after 240 minutes of treatment.
Finally, it is concluded that this test is valid and that Montelukast dicyclohexylamine salt is not irritant in
the Bovine Corneal Opacity and Permeability test under the experimental conditions described in this
report.
Since Montelukast dicyclohexylamine salt induced an IVIS ≤ 3, no classification is required for eye
irritation or serious eye damage.
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