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Description of key information

Skin corrosion, in vitro: skin corrosive (3-minutes viability 8.6% ; 1-hour viability 12%), EPIDERM, OECD TG 431, 2018

Eye irritation, in vitro: severely eye damaging/irritating (IVIS = 150), BCOP, OECD TG 437, 2018

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion
Remarks:
in vitro
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04-12-2017 to 12-03-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 431 (In Vitro Skin Corrosion: Reconstructed Human Epidermis (RHE) Test Method)
Deviations:
yes
Remarks:
Minor deviation in environmental conditions (humidity minimum 47%) which does not affect the reliability of the study
Qualifier:
according to guideline
Guideline:
other: EU Method B.40 BIS : In Vitro Skin Corrosion: Human Skin Model Test
Deviations:
yes
Remarks:
Minor deviation in environmental conditions (humidity minimum 47%) which does not affect the reliability of the study
GLP compliance:
yes
Test system:
human skin model
Source species:
human
Cell type:
non-transformed keratinocytes
Cell source:
foreskin from a single donor
Vehicle:
unchanged (no vehicle)
Details on test system:
EpiDerm Skin Model (EPI-200, Lot no.: 27636 kit L and M and 27667 Kit H and G). The test consists of topical application of the test item on the skin tissue for 3-minute and 1-hour. After exposure the skin tissue is thoroughly rinsed to remove the test item followed by immediate determination of the cytotoxic (corrosive) effect.
Cytotoxicity is expressed as the reduction of mitochondrial dehydrogenase activity measured by formazan production from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) at the end of the treatment. The EpiDerm Skin Model consists of normal, human-derived epidermal keratinocytes which have been cultured to form a multilayered, highly differentiated model of the human epidermis. It consists of organized basal, spinous and granular layers, and a multi-layered stratum corneum containing intercellular lamellar lipid layers arranged in patterns analogous to those found in vivo. The EpiDerm tissues (surface 0.6 cm²) were cultured on polycarbonate membranes of 10 mm cell culture inserts.

Preincubation:
On the day of receipt the tissues were kept on agarose and stored in the refrigerator. On the next day, at least one hour before starting the assay the tissues were transferred to 6-well plates with 0.9 ml DMEM.

Application of test item and rinsing:
The plates were incubated for approximately 1 to 1.5 hours at 37 ± 1.0°C. The medium was replaced with fresh DMEM just before the test item was applied. Two tissues were used for a 3-minute exposure and two for a 1-hour exposure. Test item: 50 µl of the undiluted test item was added into the 6-well plates on top of the skin tissues. Negative Control: similarly treated with 50 µl Milli-Q water only. Positive control: 50 µl 8N KOH (potassium hydroxide 8 normal solution). After the exposure periods (3 minutes and 1 hour, respectively), the tissues were washed with phosphate buffered saline to remove residual test item. The skin inserts were carefully dried. Rinsed tissues were kept in 24 well plates on 300 µl DMEM until 6 tissues (= one application time) were dosed and rinsed.

The repeat experiment 2 (3-minutes repeated exposure only), was similarly conducted.

All incubations, with the exception of the test item incubation of 3 minutes at room temperature, were carried out in a controlled environment, in which optimal conditions were a humid atmosphere of 80 - 100% (actual range 47- 84%), containing 5.0 ± 0.5% CO2 in air in the dark at 37.0 ± 1.0°C (actual range 36.0 - 37.3°C). Temperature and humidity were continuously monitored throughout the experiment. The CO2 percentage was monitored once on each working day. Temporary deviations from the temperature, humidity and CO2 percentage may occur due to opening and closing of the incubator door. Based on testing laboratory historical data these deviations are not considered significant.
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 μl
- Concentration (if solution): undiluted

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 50 μl
- Concentration (if solution): Not applicable

POSITIVE CONTROL
- Amount(s) applied (volume or weight): 50 μl
- Concentration (if solution): 8N KOH(aq) (pre-diluted)
Duration of treatment / exposure:
Observations are made 3-minutes and 1-hour post-test item application
Duration of post-treatment incubation (if applicable):
The DMEM was replaced by 300 µl MTT-medium and tissues were incubated for 3 hours at 37°C in air containing 5% CO2. After incubation the tissues were washed with PBS and formazan was extracted with 2 ml isopropanol (MatTek corporation) over night at room temperature.
Number of replicates:
1. Experiment 1: Duplicate; two tissues used for a 3-minute exposure to the test item and two tissues for a 1-hour exposure, and equivalent NC and PC tissue exposures.
2. Experiment 2 (3-minute exposure only): Duplicate; two tissues used for a 3-minute exposure to the test item, and equivalent NC and PC tissue exposures.
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
mean (n = 2)
Value:
35
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Basis: EXPERIMENT 1: mean. Time point: 3 minute exposure. Remarks: n = 2 ; CV = 41 % within range of 20 - 100% viability; Score in terms of percentage of negative control. Discarded and test repeated in EXPERIMENT 2.
Irritation / corrosion parameter:
% tissue viability
Remarks:
3 minute exposure
Run / experiment:
mean (n = 2)
Value:
8.6
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Basis: EXPERIMENT 2: mean. Time point: 3 minute exposure. Remarks: n = 2 ; CV = 45 % ; Score in terms of percentage of negative control.
Irritation / corrosion parameter:
% tissue viability
Remarks:
1 hour exposure
Run / experiment:
mean (n = 2)
Value:
12
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Basis: EXPERIMENT 1: mean. Time point: 1 hour exposure. Remarks: n = 2 ; CV = 85 % ; Score in terms of percentage of negative control.
Other effects / acceptance of results:
- OTHER EFFECTS:
- Visible damage on test system: None reported.
- Direct-MTT reduction: Screened prior to test. Not applicable.
- Colour interference with MTT: Screened prior to test. Not applicable.

DEMONSTRATION OF TECHNICAL PROFICIENCY: The test laboratory has validated the specified assay.

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Yes.
- Acceptance criteria met for positive control: Yes.
- Acceptance criteria met for variability between replicate measurements: Yes. Experiment 2 was conducted due to excessive variability in Experiment 1 in the 3-minute exposure, and a Coefficient of Variation between 20 and 100% viability of > 30% (35% and 12% in each replicate). In the repeated 3-minute exposure: the Coefficient of Variation between 20 and 100% viability was inapplicable as the viability was < 20%. The validity criterion was met.
- Range of historical values if different from the ones specified in the test guideline: Historic Control Data: Negative Control OD570: 3-minutes (n=111): 1.258 – 2.615 ; 1-hour (n=110): 1.371 – 2.371. Positive Control HCD data are presented within the full study report and the concurrent PC was within the specified ranges.
Interpretation of results:
Category 1A (corrosive) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this in vitro study, the test item is considered to be corrosive to the skin. The test item caused a mean tissue viability of < 50% after 3 minute exposure and < 15% after 1 hour exposure and would be classified under Regulation (EC) 1272/2008: skin corrosive - category 1A.
Executive summary:

The study was performed to OECD TG 431 and EU Method B.40 BIS to assess the skin corrosion potential of the test item in accordance with GLP using a human three-dimensional epidermal model (EpiDerm (EPI-200)). The test was performed on a total of 4 tissues per test item per experiment, together with a negative control and positive control. Four tissues were used for a 3-minute exposure to the test item (two in experiment 1 and two in experiment 2) and two for a 1-hour exposure (in experiment 1). 50 μl of the undiluted test item was added (with a pipette) into the 6-well plates on top of the skin tissues. The remaining tissues were treated with 50 μl Milli-Q water (negative control) and with 50 μl 8N KOH (positive control), respectively. The positive control had a mean relative tissue viability of 13% after 1 hour exposure. The absolute mean OD570 (optical density at 570 nm) of the negative control tissues was within the laboratory historical control data range. In the range of viability 20 - 100% the Coefficient of Variation between tissue replicates was < 8% for the negative control and 41% for the test item.The relative mean tissue viability obtained after 3-minute and 1-hour treatments with the test item compared to the negative control tissues was 35% and 12%, respectively. However, since the acceptability criteria were not met for the 3-minute exposure, this part of the test was repeated. In the repeat experiment 2, the positive control had a mean relative tissue viability of 15% after the 3-minute exposure. The absolute mean OD570 (optical density at 570 nm) of the negative control tissues was within the laboratory historical control data range. The relative mean tissue viability obtained after 3-minute treatment with the test item compared to the negative control tissues was 8.6%. Skin corrosion is expressed as the remaining cell viability after exposure to the test item. The relative mean tissue viability obtained after 3-minute and 1-hour treatments with the test item compared to the negative control tissues was 8.6% and 12%, respectively. Because the mean relative tissue viability for the test item was below 50% after the 3-minute treatment and below 15% after the 1-hour treatment the test item is considered to be corrosive. Under the conditions of this study, the test item is skin corrosive in the in vitro skin corrosion test and classified under Regulation (EC) 1272/2008: skin corrosive - category 1A.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05-12-2017 to 06-02-2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Guideline study performed under GLP. All relevant validity criteria were met.
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
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:
no
GLP compliance:
yes
Species:
other: bovine
Strain:
not specified
Details on test animals or tissues and environmental conditions:
SOURCE OF COLLECTED EYES
- Source: Bovine eyes from young cattle were obtained from the slaughterhouse (Recognised supplier)
- Number of animals: Not reported.
- Characteristics of donor animals (e.g. age, sex, weight): Young cattle.
- Storage, temperature and transport conditions of ocular tissue (e.g. transport time, transport media and temperature, and other conditions): Eyes were collected and transported in physiological saline in a suitable container under cooled conditions.
- Time interval prior to initiating testing: Not reported.
- indication of any existing defects or lesions in ocular tissue samples: 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.
- Indication of any antibiotics used: None.
- Housing: The isolated corneas were mounted in a corneal holder (one cornea per holder) of MC2 (recognised supplier) 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.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 32 ± 1
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent positive control
yes, concurrent negative control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 750 microlitres
- Concentration (if solution): undiluted

Duration of treatment / exposure:
10 ±1 minutes at 32 ± 1ºC.
Duration of post- treatment incubation (in vitro):
After treatment the corneas were incubated for 120 ± 10 minutes at 32 ± 1°C. After the completion of the incubation period opacity determination was performed.
Number of animals or in vitro replicates:
Three (3) per test item, or negative or positive controls, respectively.
Details on study design:
SELECTION AND 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. Following mounting: the anterior and posterior chambers of each BCOP holder were filled with complete Earle’s Minimum Essential Medium (cMEM) and the holders were incubated at 32 ± 1 ºC for a minimum of 1 hour. After the incubation period, the medium was removed from both compartments and replaced with fresh cMEM.

QUALITY CHECK OF THE ISOLATED CORNEAS: The corneas were examined for defects macroscopically. Only corneas with opacity ≥ 7.0 are discarded, in accordance with the guideline.

NUMBER OF REPLICATES: 3 (Triplicate)

NEGATIVE CONTROL USED: physiological saline

SOLVENT CONTROL USED (if applicable): Not applicable.

POSITIVE CONTROL USED: Ethanol ; > 99.9% purity

APPLICATION DOSE AND EXPOSURE TIME: 0.75 mL and 10 minutes

TREATMENT METHOD: Closed chamber

POST-INCUBATION PERIOD: Yes. Following exposure the holders were incubated, for 120 ± 10 minutes at 32 ± 1°C. A post-treatment opacity reading was taken and each cornea was visually observed.

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: At the end of the exposure period the test item and control items were removed from the
anterior chamber and the cornea was rinsed with fresh MEM containing phenol red before a final rinse with complete MEM without phenol red. The anterior chamber was refilled with fresh complete MEM without phenol red. A post treatment opacity reading was taken and each cornea was visually observed.
- POST-EXPOSURE INCUBATION: Following the final opacity measurement the posterior compartment was refilled with fresh cMEM. The anterior compartment was filled with 1 ml of 4 mg Na-fluorescein/ml cMEM solution Corneas were incubated in a horizontal position for 90 ± 5 minutes at 32 ± 1°C.

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: Measured through light transmission through the cornea quantitatively using an opacitometer
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of microtiter plate reader (OD490)
- Others (e.g, pertinent visual observations, histopathology): Any other pertinent visual observations would be recorded.

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)

DECISION CRITERIA: 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). A test item that induces an In Vitro Irritancy Score ≥ 55.1 is defined as an ocular corrosive or severe irritant. A test item with an ≤ IVIS 3.0 is predicted to be not irritating to the eye (UN GHS and/or CLP Regulation (EC) 1272/2008 as amended).
Irritation parameter:
in vitro irritation score
Run / experiment:
mean (n=3)
Value:
150
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
positive indication of irritation
Other effects / acceptance of results:
OTHER EFFECTS:
- Visible damage on test system: Yes. The corneas treated with the test item were turbid post treatment. A pH effect was observed on the rinsing medium, the corneas were rinsed until no colour change of the medium was observed. The corneas treated with the negative control item were clear post treatment and post incubation. The corneas treated with the positive control item were turbid post treatment.

DEMONSTRATION OF TECHNICAL PROFICIENCY: The test laboratory has validated the specified assay.

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Yes.
- Acceptance criteria met for positive control: Yes. The test was conducted twice (details of first test not reported). The first test was rejected due to an inappropriate positive control response not in accordance with the acceptability criteria. The second test is reported.
- Range of historical values if different from the ones specified in the test guideline:
1. Ethanol was used for positive control purposes. The test was acceptable if the positive control produced an In Vitro Irritancy Score which fell within two standard deviations of the current historical control data (HCD) mean. ACTUAL: PC IVIS range of 43 to 56. Mean = 51.0.
2. Physiological saline solution was used for negative control purposes. The test was acceptable if the negative control produced an In Vitro Irritancy Score which is less than or equal to the upper limit for background opacity and permeability values for bovine corneas treated with the respective negative control of the current historical control data (HCD). When testing liquids the negative control limit for opacity should be ≤ 3.0 and for permeability -0.034 to 0.100. ACTUAL: NC IVIS = 1.2, opacity ≤ 2.1 and permeability -0.018.

Table 1.0 - Summary of opacity, permeability and in vitro scores

Treatment

Mean

Opacity #1

Mean

Permeability #1

Mean In vitro Irritation Score #1, #2

Negative control

1.4

-0.018

1.2

Positive control

(Ethanol)

28

1.536

51

Test item

130

1.361

150

#1: Calculated using the negative control mean opacity and mean permeability values for the positive control and test item.

#2: In vitro irritancy score (IVIS) = mean opacity value + (15 x mean OD490 value).

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this in vitro study, the test item is considered to be severely damaging/irritating to the eye. The test item caused a mean IVIS score 150 after 10 minute exposure and would be classified under Regulation (EC) 1272/2008: eye damage/irritation - category 1.
Executive summary:

The study was performed to OECD TG 437 and EU Method B.47 to assess the irritancy potential of the test item to the eye following exposure to bovine corneas in accordance with GLP. A total of 3 corneas per treatment group were used. A volume of 750 microlitres of the test item was placed the cornea. The negative control group received physiological saline and the positive control group received neat ethanol. For each group the corneas were incubated for 10 ± 1 minutes at 32 ± 1°C. After the incubation the solutions were removed and the corneas were washed with MEM with phenol red (Earle’s Minimum Essential Medium) and thereafter with cMEM. Possible pH effects of the test item the corneas were recorded. The medium in the posterior compartment was removed and both compartments were refilled with fresh cMEM. Subsequently the corneas were incubated for 120 ± 10 minutes at 32 ± 1°C. After the completion of the incubation period opacity determination was performed. Each cornea was inspected visually for dissimilar opacity patterns. Following the final opacity measurement, permeability of the cornea to Na-fluorescein was evaluated. 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 (ethanol) was 51.0 and was within two deviations of the historical positive control data mean and within the historical positive control range. It was therefore concluded that the test conditions were adequate and that the test system functioned properly. The corneas treated with the test item showed opacity values ranging from 108 to 142 and permeability values ranging from 0.935 to 1.177 and in vitro irritancy scores ranged from 137 to 157. The test item induced severe ocular damage/irritation through both endpoints, resulting in a mean in vitro irritancy score of 150 after 10 minutes of treatment. Based on these results the test item is considered to be severely damaging/irritating to the eye in the Bovine Corneal Opacity and Permeability test.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Corrosion:

Key study : in vitro, OECD TG 431, 2018 : The study was performed to OECD TG 431 and EU Method B.40 BIS to assess the skin corrosion potential of the test item in accordance with GLP using a human three-dimensional epidermal model (EpiDerm (EPI-200)). The test was performed on a total of 4 tissues per test item per experiment, together with a negative control and positive control. Four tissues were used for a 3-minute exposure to the test item (two in experiment 1 and two in experiment 2) and two for a 1-hour exposure (in experiment 1). 50 μl of the undiluted test item was added (with a pipette) into the 6-well plates on top of the skin tissues. The remaining tissues were treated with 50 μl Milli-Q water (negative control) and with 50 μl 8N KOH (positive control), respectively. The positive control had a mean relative tissue viability of 13% after 1 hour exposure. The absolute mean OD570 (optical density at 570 nm) of the negative control tissues was within the laboratory historical control data range. In the range of viability 20 - 100% the Coefficient of Variation between tissue replicates was < 8% for the negative control and 41% for the test item.The relative mean tissue viability obtained after 3-minute and 1-hour treatments with the test item compared to the negative control tissues was 35% and 12%, respectively. However, since the acceptability criteria were not met for the 3-minute exposure, this part of the test was repeated. In the repeat experiment 2, the positive control had a mean relative tissue viability of 15% after the 3-minute exposure. The absolute mean OD570 (optical density at 570 nm) of the negative control tissues was within the laboratory historical control data range. The relative mean tissue viability obtained after 3-minute treatment with the test item compared to the negative control tissues was 8.6%. Skin corrosion is expressed as the remaining cell viability after exposure to the test item. The relative mean tissue viability obtained after 3-minute and 1-hour treatments with the test item compared to the negative control tissues was 8.6% and 12%, respectively. Because the mean relative tissue viability for the test item was below 50% after the 3-minute treatment and below 15% after the 1-hour treatment the test item is considered to be corrosive. Under the conditions of this study, the test item is skin corrosive in the in vitro skin corrosion test and classified under Regulation (EC) 1272/2008: skin corrosive - category 1A.

 

Eye Irritation:

Key study : in vitro, OECD TG 437, 2018 : The study was performed to OECD TG 437 and EU Method B.47 to assess the irritancy potential of the test item to the eye following exposure to bovine corneas in accordance with GLP. A total of 3 corneas per treatment group were used. A volume of 750 microlitres of the test item was placed the cornea. The negative control group received physiological saline and the positive control group received neat ethanol. For each group the corneas were incubated for 10 ± 1 minutes at 32 ± 1°C. After the incubation the solutions were removed and the corneas were washed with MEM with phenol red (Earle’s Minimum Essential Medium) and thereafter with cMEM. Possible pH effects of the test item the corneas were recorded. The medium in the posterior compartment was removed and both compartments were refilled with fresh cMEM. Subsequently the corneas were incubated for 120 ± 10 minutes at 32 ± 1°C. After the completion of the incubation period opacity determination was performed. Each cornea was inspected visually for dissimilar opacity patterns. Following the final opacity measurement, permeability of the cornea to Na-fluorescein was evaluated. 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 (ethanol) was 51.0 and was within two deviations of the historical positive control data mean and within the historical positive control range. It was therefore concluded that the test conditions were adequate and that the test system functioned properly. The corneas treated with the test item showed opacity values ranging from 108 to 142 and permeability values ranging from 0.935 to 1.177 and in vitro irritancy scores ranged from 137 to 157. The test item induced severe ocular damage/irritation through both endpoints, resulting in a mean in vitro irritancy score of 150 after 10 minutes of treatment. Based on these results the test item is considered to be severely damaging/irritating to the eye in the Bovine Corneal Opacity and Permeability test.

 

Respiratory Irritation:

No data available.

Justification for classification or non-classification

The substance meets classification criteria under Regulation (EC) 1272/2008 for skin corrosion: category 1A: H314: Causes severe skin burns and eye damage

 

The substance meets classification criteria under Regulation (EC) 1272/2008 for eye damage/eye irritation: category 1: H318: Causes serious eye damage

As the duplicate Regulation (EC) No 1272/2008 eye damage/eye irritation: category 1: H318: Causes serious eye damage - is considered redundant when skin corrosion: category 1A: H314 is already applied, this duplicate classification criterion is omitted during hazard communication in accordance with Regulation (EC) 1272/2008: Annex III - Part 1: paragraph (b).

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