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EC number: 807-621-3 | CAS number: 1428450-95-6
- 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:
- 2014-03-31
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
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)
- Deviations:
- yes
- Remarks:
- The measurement of the opacity was performed with a photometer (570 nm) instead of an opacitometer. However, this can be seen as uncritical, because the opacity can be calculated from the extinction.
- 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)
- Deviations:
- yes
- Remarks:
- with acceptable restrictions: The measurement of the opacity was performed with a photometer (570 nm) instead of an opacitometer. However, this can be seen as uncritical, because the opacity can be calculated from the extinction.
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht, Mainz, Germany
Test material
- Reference substance name:
- N-[4-(2,4-dihydroxyphenyl)-1,3-thiazol-2-yl]-2-methylpropanamide
- EC Number:
- 807-621-3
- Cas Number:
- 1428450-95-6
- Molecular formula:
- C13H14N2O3S
- IUPAC Name:
- N-[4-(2,4-dihydroxyphenyl)-1,3-thiazol-2-yl]-2-methylpropanamide
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals / tissue source
- Species:
- cattle
- Strain:
- not specified
- Details on test animals or tissues and environmental conditions:
- TEST METHOD
The bovine corneal opacity and permeability (BCOP) test is an in-vitro test method used for identifying i) chemicals inducing serious eye damage and ii) chemicals not requiring classification for eye irritation or serious eye damage. The potential of a test substance to cause ocular corrosivity or severe irritancy is measured by its ability to induce opacity and increased permeability in an isolated bovine cornea. The opacity and permeability assessments of the cornea are combined to derive an in-vitro irritancy score (IVIS), which is used for classification.
IDENTIFICATION OF THE SOURCE OF THE EYES, STORAGE AND TRANSPORT CONDITIONS
- Source: Slaughterhouse Müller Fleisch GmbH, Birkenfeld, Germany
- Donor animals: between 12 and 60 months old
- Date and time of eye collection: on the day of the test
- Transport medium and temperature conditions: Hanks´ Balanced Salt Solution supplemented with 0.01% penicillin and 0.01% streptomycin
INCUBATION MEDIUM
- MEM (Minimum Essential Medium) without phenol red supplemented with 1% FCS, L-Glutamine and NaHCO3 (= complete MEM (cMEM) without phenol red); pre-warmed to 32±1 °C
- MEM (Minimum Essential Medium) with phenol red supplemented with 1% FCS and L-Glutamine (= complete MEM (cMEM) with phenol red); pre-warmed to 32±1 °C
PREPARATION OF THE EYES (BEFORE EXPOSURE)
- Eyes free of defects (scratches, neovascularisation): yes
- Dissection of the eyes and treatment: Corneas were dissected with a 2 to 3 mm rim of sclera. Isolated corneas were mounted in cornea holders.
- Equilibration time of the corneas: 1 h at 32±1 °C in cMEM without phenol red
- Quality check of the equilibrated corneas: free of macroscopic defects
DETERMINATION OF THE INITIAL OPACITY
After the initial incubation, the medium was changed and the baseline opacity for each cornea was recorded.
- Method: Corneal opacity was determined by the amount of light transmission through the cornea via a photometer at 570 nm.
- Specification of the device: spectral photometer, Specord 205, Analytik Jena, Germany
Test system
- Vehicle:
- other: olive oil
- Controls:
- yes, concurrent vehicle
- yes, concurrent positive control
- yes, concurrent negative control
- Amount / concentration applied:
- TEST MATERIAL
- Amount(s) applied in the test: 750 µL
- Concentration (if solution): 20% solution in olive oil
VEHICLE
- Substance: olive oil
- Amount(s) applied in the test: Example: 750 µL
POSITIVE SUBSTANCE
- Substance: 20% Imidazole solution in 0.9% NaCl
- Amount(s) applied in the test: 750 µL - Duration of treatment / exposure:
- 4 h at 32 ± 1 °C
- Observation period (in vivo):
- not applicable
- Number of animals or in vitro replicates:
- number of eyes for the test item: 3
number of eyes for the positive control: 3
number of eyes for the negative control: 3
number of eyes for the solvent control: 3 - Details on study design:
- TEST CONDITIONS
- Short description of the method used: open-chamber method
The glass window from the anterior chamber was removed prior to treatment. The controls or test substance were applied directly to the epithelial surface of the cornea. After dosing, the glass window was replaced on the anterior chamber to recreate a closed system. Corneas were exposed for 4 h with the test substance or the controls.
POST-EXPOSURE TREATMENT
- Removal of the test substance: The test substance was removed from the anterior chamber and the epithelium washed at least three times.
- Medium for washing the corneas: cMEM containing phenol red
- Medium for final rinsing: cMEM without phenol red;
Thereafter both chambers of the cornea holder were filled with fresh cMEM without phenol red and final opacity was recorded.
DETERMINATION OF THE FINAL OPACITY
- Method: corneal opacity was determined via a photometer at 570 nm
- Specification of the device: Spectral photometer, Specord 205, Analytik Jena, Germany
DETERMINATION OF THE CORNEAL PERMEABILITY:
- Method: The cMEM without phenol red was then removed from the anterior chamber, and 1 mL sodium fluorescein solution (concentration 5 mg/mL) was added. The chambers were then closed again and incubated for 90 ± 5 min at 32 ± 1 °C. After incubation, the content of the posterior chamber was thoroughly mixed. Then, the permeability of the cornea was measured as optical density at 490 nm.
- Specification of the device: Spectral photometer, Specord 205, Analytik Jena, Germany
- Correction of Measured Absorption at 490 nm: As cuvettes with a pathlength of 0.2 cm are used in the measurement of the sodium fluorescein solution in the spectral photometer, the pathlength must be corrected to 1 cm. Coefficient: 1/0.2 = 5: all absorptions were multiplied with this coefficient.
Results and discussion
In vitro
Resultsopen allclose all
- Irritation parameter:
- in vitro irritation score
- Value:
- ca. 0.908
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
- Irritation parameter:
- cornea opacity score
- Value:
- ca. 0.668
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- no indication of irritation
Any other information on results incl. tables
The absorption (570 nm) and opacity values which were measured before and after exposureare given in the following table:
Table 1 Absorption and Opacity Values Negative Control and Positive Control
Parameter |
Negative control |
Positive control |
||||
Absorption before |
0.1567 |
0.1616 |
0.1597 |
0.1877 |
0.1214 |
0.1272 |
Absorption after |
0.2596 |
0.1937 |
0.2709 |
1.9489 |
1.6818 |
2.0496 |
Opacity before |
1.4345 |
1.4508 |
1.4444 |
1.5406 |
1.3225 |
1.3403 |
Opacity after |
1.8180 |
1.5621 |
1.8659 |
88.8996 |
48.0618 |
112.0986 |
Opacity Difference |
0.3835 |
0.1113 |
0.4215 |
87.3590 |
46.7393 |
110.7583 |
Mean opacity difference of the negative control is 0.3054.
Table 2 Absorption and Opacity Values Test Item and Solvent Control
Parameter |
Solvent control |
Test ItemN-[4-(2,4-dihydroxyphenyl)thiazol-2-yl]isobutyramide |
||||
Absorption before |
0.1990 |
0.1294 |
0.2167 |
0.1510 |
0.1651 |
0.1535 |
Absorption after |
0.3601 |
0.2348 |
0.4103 |
0.2368 |
0.2617 |
0.2209 |
Opacity before |
1.5812 |
1.3471 |
1.6470 |
1.4158 |
1.4625 |
1.4240 |
Opacity |
2.2914 |
1.7171 |
2.5722 |
1.7250 |
1.8268 |
1.6630 |
Opacity |
0.7101 |
0.3700 |
0.9251 |
0.3092 |
0.3643 |
0.2391 |
Mean opacity difference of the solvent control is 0.6684.
For the permeability measurement, three replicates for each treatment group were measured. The optical density values at 490 nm are given in the following tables:
Table 3 Optical density at 490 nm Negative Control and Positive Control
Repl. |
Negative Control |
Positive Control |
||||
Meas. |
0.0090 |
0.0076 |
0.0075 |
0.2231 |
0.2604 |
0.2774 |
Corr. |
0.0450 |
0.0380 |
0.0375 |
1.1155 |
1.3020 |
1.3870 |
Mean |
0.0402 |
-- |
Table 4 Optical density at 490 nm Test Item and Solvent Control
Repl. |
Solvent control |
Test ItemN-[4-(2,4-dihydroxyphenyl)thiazol-2-yl]isobutyramide |
||||
Meas. |
0.0116 |
0.0078 |
0.0056 |
0.0095 |
0.0074 |
0.0065 |
Corr. |
0.0580 |
0.0390 |
0.0280 |
0.0475 |
0.0370 |
0.0325 |
Mean |
0.0417 |
|
Note: In order to correct the path length, a factor of 5 was taken into account when calculating the IVIS
The calculated IVIS for each replicate and the corresponding means are presented in the following table:
Table 5 IVIS
Test Group |
IVIS |
Mean IVIS |
Relative Standard Deviation IVIS |
Negative Control |
1.059 |
0.908 |
22.0 % |
0.681 |
|||
0.984 |
|||
Solvent control Olive oil |
1.580 |
1.293 |
24.4 % |
0.955 |
|||
1.345 |
|||
Test Item 20% suspension in olive oil |
-0.272 |
-0.405 |
37.0 % |
-0.375 |
|||
-0.567 |
|||
Positive Control |
103.183 |
99.733 |
32.9 % |
65.361 |
|||
130.655 |
Applicant's summary and conclusion
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- CLP: not classified
Note: Guidance on the Application of Regulation (EC) No. 1272/2008
3.3.2.1.2.4 Testing methods: in-vitro methods
“The OECD has at present adopted three in vitro tests for the identification of substances inducing serious eye damage, i.e. the Isolated Chicken Eye (ICE) test (OECD TG 438; TM B.48), the Bovine Corneal Opacity and Permeability (BCOP) test (OECD TG 437; TM B.47) and the Fluorescein Leakage (FL) test (OECD TG 460). These tests are recommended for use as part of a tiered-testing strategy for regulatory classification and labelling (e.g. Top-Down Approach). A substance can be considered as causing serious eye damage (Category 1) based on positive results in the ICE test, the BCOP test, the FL test, the Isolated Rabbit Eye (IRE) test or the Hen's Egg Test on Chorio-allantoic Membrane (HET-CAM) test78. Negative results from the ICE and BCOP test methods can be used for classification purposes i.e. ‘bottom-up approach’. For other test methods the negative in vitro corrosivity responses in these tests must be followed by further testing (Guidance on IR/CSA Section R.7.2.4.1).
In addition an in vitro test method has been validated by ECVAM and is under consideration for the development of an OECD TG: the Cytosensor Microphysiometer (CM) test. This can be used for the identification of category 1-substances within a Top-Down Approach.
There are no in vitro tests with regulatory acceptance for eye irritation at present. However, two human corneal epithelium models, EpiOcular and SkinEthic, have been submitted to ECVAM for validation.”
3.3.2.3.2. In-vitro data
“A substance can be considered as causing serious eye damage (Category 1) based on positive results in the ICE test, the BCOP test, the Isolated Rabbit Eye (IRE) test or the Hen's Egg Test on Chorio-allantoic Membrane (HET-CAM) test79. Negative results from the ICE and BCOP test methods can be used for classification purposes i.e. ‘bottom-up approach’, but for other test methods the negative in vitro corrosivity responses in these tests must be followed by further testing (Guidance on IR/CSA Section R.7.2.4.1).
There are currently no validated in vitro eye irritation test methods available.” - Executive summary:
One valid experiment was performed.
Bovine corneas were used. They were collected from slaughtered cattle which were between
12 and 60 months old.
The test item N-[4-(2,4-dihydroxyphenyl)thiazol-2-yl]isobutyramide was tested as 20%
suspension in olive oil.. 750 μL of the suspension were brought onto the cornea of a bovine
eye which had been incubated with cMEM without phenol red at 32 ± 1 °C for one
hour and whose opacity had been measured. The test item was incubated on the cornea
for 4 hours at 32 ± 1 °C. After removal of the test item, opacity and permeability values
were measured.
Physiological sodium chloride solution was used as negative control. The negative control
showed no irritating effect on the cornea.
Olive oil was used as solvent control. The solvent control showed no irritating effect on the
cornea.
20% Imidazole solution (dissolved in 0.9% NaCl) was used as positive control. The positive
control induced serious eye damage on the cornea.
The test item N-[4-(2,4-dihydroxyphenyl)thiazol-2-yl]isobutyramide (tested as 20% suspension
in olive oil) showed no effects on the cornea of the bovine eye. The calculated
IVIS (in vitro irritancy score) is -0.405.
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