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Diss Factsheets

Administrative data

Description of key information

Skin irritation: Irritating to the skin.

Eye irritation: Irritating to the eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin corrosion: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 435 (In Vitro Membrane Barrier Test Method for Skin Corrosion)
Version / remarks:
adopted 28 July 2015
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed on 23 October 2015
Test system:
artificial membrane barrier model
Vehicle:
unchanged (no vehicle)
Details on test animals or test system and environmental conditions:
Not applicable - Since this is an in-vitro study there is no information on test animals.
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
500 mL of the test item were carefully layered , as supplied, onto the surface of the membrane barrier and evenly distributed.
Duration of treatment / exposure:
60 minutes
Observation period:
Not applicable
Number of animals:
Not applicable
Details on study design:
TEST SYSTEM:
- Test kit:
Commercially available kit CORROSITEX supplied by INT.E.G.R.A. Srl, batch n° CT060115

- Preparation of the bio-barrier:
The fully constructed membrane barriers were prepared the day before the beginning of the classification assay as follows:
- 0.40g of biobarrier matrix were weighed in a vial and 4.0 mL of an aqueous solution were added in order to prepare a 100mg/mL solution.
- The vial was palced inside a water bath container on a hot plate and heated to 68°c with mediu speed stirring using a micro stirbar to avoid foaming. The temperature of the water bath was measured by a thermometer and never exceeded 70°C.
- Approximately 8 minutes later, when the biobarrier matrix powder was completely dissolved, the heat was turned off and the vial let sit in the water bath for few minutes until beginning of next step.
- 200 µL were dispensed into each membrane disc using a micropipette.
- The gel was checked to be of equal thickness and density throughout, and with no air bubbles or defects that could affect its functional integrity.
- The plate containing the newly prepared biobarriers was wrapped with plactic wrap to avoid dehydration and immediately stored at + 4°C until used.

EXPERIMENTAL PERFORMANCE:
- Compatibility test:
Prior to performing the membrane barrier test, a compatibility test was performed to insure that the test item and the CDS reagent were compatible. The CDS is a measurement system that must respond to the presence of the test item.
In the system used in this study, the CDS was composed of a pH 7.0 aqueous solution of two pH indicator dyes. The acid indicator dye, methyl orange, changes colour when the pH of the solution drops below 4.5. The basic indicator dye, phenol red, changes colour when the pH rises above 8.5. Therefore acids and bases that enter the CDS are detected because they promote a visible change in the colour of these indicator dyes. Chemicals that do not cause the pH to change appreciably will not be qualified for the assay because they fail to provoke a colour change.
The compatibility test was achieved few days before beginning the classificaiton assay at ambient temperature by using a Qualify test tube containing an amber liquid corresponding to an aliquot of the CDS reagent.
150 µL of the test item were added, as supplied, to the Qualify test tube. The tube was shaken and observed for the presence of any detectable change (colour or consistency).
In this study, the colour of the test item was too intense, dark blue, and prevented for the observation of a change of colouring in the CDS: the resulting colour was the test item's colour itself. This is why an adapted procedure was used for the categorisation of the test item (procedure with pH measurements).

Timescale category test: pH procedure:
The intensively coloured test item should then be subjected to a timescale category test. This category allows to establish apprpriate timescale for the corrosivity classification assay of the test item. This step utilizes indicator solutions to permit categorization in Category 1, typically strong acids/bases, or Category 2, typically weak acids/bases.
The test tubes A and B contain solutions of different ph indicators causing the colour change depending on the pH and having their own transition areas.
Thi adapted procedure for intensively coloured itens consists in successive pH measurements.
First a 10%v/v aqueous solution of the test item was prepared adding 2 mL of the test item after being shaken to 18 mL of distilled water and mixing manually and by vortex. The solution is heated few minutes to be dissolved, it was a blue solution with blue micelles. The pH of this 10% solution was measured: 2.26. If the pH of the 10% test iten solution is < 7.0, the Tube A has to be used to perform the Categorisation test (Tube B is used if ph > 7.0).
150 µL of the test item after being shaken were added to the Tube A, containing a yellow liquid, at ambient temperature. The tube was shaken and the pH of the resulting solution was measured: 5.48. For measurements performed with Tube A, if the pH is ≤ 5 the sample is Category 1; if the pH is > 5 the sample is Category 2. The test item was consequently assigned to Category 2.

Classification assay:
- Assembly of the test method component:The membrane barriers were taken out of the refirgerator. Their integrity was carefully checked, and they were positioned in a previously labelled vial containing the CDS so that they were in full contact with the indicator solution with no air bubbles present. Membrane barrriers were not allowed to stan in the vial longer than 2 minutes before adding the test items. The study was performed at ambient temperature.
- Application of the test item: 500 µL of the test item were carefully layered , as supplied, onto the surface of the membrane barrier and evenly distributed. The time of applying the test item to the membrane was recorded. Four replicates were run staggered to ensure than short corrosion times were accurately recorded.
- Controls: Concurrent controls were included in single in this study:
* Negative control, non corrosive: 500 µL of a 6% propionic aicd solution
* Positive control, corrosive: sodium hydroxide.
A CDS colour control was also included in single.

Endpoints measured:
Each vial was appropriately monitored and the time of the first change in the indicator solution, i.e. barrier penetration, was recorded. The elaspsed time between application and penetration of the membrane biobarrier was determined.

Study acceptability criteria:
Zccording to the established time parameters for each of the GHS corrosivity subcategories, the time (in minutes) elapsed between applicatin of a test item to the membrane barrier and barrier penetration was used to predict the corrosivity of the test item. For a study to be considered acceptable, the concurrent positive control should give the expected penetration response time, the concurrent negative control should not be corrosive, and when included, the concurrent solvent control should neither be corrosive nor should it alter the corrosivity potential of the test item.
The CORROSITEX assay will be accepted if the positive control time falls within +/- two standard deviations of the positive control historical mean breakthrough time.

Interpretation of results:
The time in minutes elapsed between applicaiton of the test substance to the membrane barrier and barrier penetration was used to classify the test substance in terms of corrosivity, and, if applicable, UN Packing Group. Cut-off time values for each of the three corrosive subcategories were established for each proposed test method. Final decisions on cut-off times considered the need to minimize under-classification of corrosive hazard (i.e. false negative).

Irritation / corrosion parameter:
penetration time (in minutes)
Value:
> 60
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: The test item did not disrupt the membrane after 60 minutes in the four replicates.
Other effects / acceptance of results:
The test item did not disrupt the membrane after 60 minutes in the four replicates.

As expected, the negative control (propionic acid 6%v/v) did not disrupt the mambrance and was not corrosive.

As expected, the positive control (sodium hydroxide) was found to be corrosive (GHS subcategory 1B) and disrupt the membrane after 14 minutes and 25 seconds.
Interpretation of results:
other: not corrosive
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
In accordance with Regulation EC 1272/2008, the test item does not have to be classified in category 1 'Corrosive'.
Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-10-28 to 2017-02-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Version / remarks:
adopted 28 July 2015
Deviations:
yes
Remarks:
The standard deviation of the negative control group was 21.7% instead of ≤ 18% as initially scheduled. Considering the results obtained, this deviation is considered as without impact on the conclusion of the study.
Qualifier:
according to guideline
Guideline:
EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
Qualifier:
according to guideline
Guideline:
other: ECVAM international validation study on in vitro tests for acute skin irritation (Altern Lab Anim. 2007 Dec; 35 (6):559-601)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 23 October 2015
Details on test animals or test system and environmental conditions:
Not applicable - Since this is an in-vitro study there is no information on test animals.
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
The test item was applied as supplied, at the dose of 16 µL, to the epidermal surface of 5 living human skin models, including two for the non-specific colour (NSC) control. To ensure good contact with the epidermis, during all the treatment period, the test item was recovered with a nylon mesh provided by Episkin SA.
In the same experimental conditions, a positive control (5% SDS), and a negative control ( DPBS - PAN BIOTECH GmbH - batch n° 9510916) were carried out. The 5% SDS solution was prepared by weighing 0.5 g of SDS (SIGMA - batch n° STBF1623V) in a 10 mL volumetric flask qsp 10 mL of distilled water. Then, the preparation was magnetically stirred, just before the treatment. To ensure good contact with the epidermis, during all the treatment period, all liquid items were recovered with a nylon mesh provided by Episkin SA.
Duration of treatment / exposure:
42 minutes
Observation period:
not applicable
Number of animals:
not applicable
Details on study design:
HUMAN SKIN MODEL
The 0.50 cm2 reconstructed epidermis (Episkin SA, RHE/S/17 batch n°16-RHE-124) were received on 29 November 2016. The same day, the insert (filter + epidermis) was gently removed from the agarose while avoiding leaving agarose on the polycarbonate filter. The inserts were placed in 6 wells culture plate which had been previously filled with 1 mL of growth medium (Episkin SA, batch n° 16 MPE 128) during 2 hours and 15 minutes. Then just before treatment, the inserts were placed in 24 wells culture plate which had been previously filled with 300 µL of maintenance medium (Episkin SA, batch 16 MA 072).

EVALUATION OF DIRECT INTERACTION WITH MTT
The direct interaction of MTT with the test item was checked by adding 16 µL of the test item to 300 µL of solution of MTT at 1 mg/L. A yellow solution with test item in the bottom of the welll was observed after 3 hours of incubation between 36.4°C and 37.1°C, 5% CO2. > Therefore there is no direct inteaction between the test item and MTT.

SPECTRAL ANALYSIS OF THE TEST ITEM IN ISOPROPANOL
The spectral properties at 570 nm of test item in isopropanol ware checked by adding 16 µL of the test item to 1.5 mL of isopropanol (same conditions as in the main test). A blue solution was obtained after 2 hours of incubation at ambient temperature with gentle shaking. The mean of the corrected OD (blank subtracted) was 0.331 which is higher than 0.08 (value corresponding to approximately twice the OD of the extracting solvent. > Therefore, the test item was identified as causing colour interference with the viability assay and two viable control tissues were added to the study which underwent the entire testing procedure but were incubated with meadium instead of MTT solution during the MTT incubbation step to generate a non-specific colour (NSC) control.

GRADING OF REACTIONS
42 minutes after the test item application, the nylon mesh was removed and the human epidermis were washed with 25 x 1 mL of DPBS (PAN BIOTECH GmbH, batch n° 9510916). The rinsed tissues were checked for any coloration and noted to be slight blue (parameter identified and managed with the additon of the non-specific colour control to the study).
They were incubated for 41 hours and 12 minutes post-treatment incubation-period in fresh medium at 37°C, 5% CO2. Then, the epidermis were put in contact with the MTT solution.

The cell viability was quantified by measurement of the cell succinate dehydrogenase activity. This enzyme was responsibel for the MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Thiazol blue; CAS n° 298-93-1)] reduction into bleu formazan crystal. The skin samples were placed in 300 µL of a MTT solution at 1.0 mg/L, except for the two for non-specific colour control which were placed in the maintenance medium (Episkin SA, batch n° 16 MA 072) for 3 hours at 37°C, 5% CO2. The precipitated blue formazan product was then extracted using isopropanol during 2 hours under gentle agitation in the dark, and the concentration of formazan was measured by determining the OD at 570 nm, just after dilution of the extracts 1:2 in isopropanol.
The OD was measured in triplicate of MTT extract.
The measured OD are proportional to the number of living cells.

The measurement of OD was performed using the ELx800 absorbance microplte reader (controlled every year and calibrated if necessary) supplied by BioTek and the validated software Gen5 ELISA V1.05.11 supplied by BioTek.

TREATMENT OF THE RESULTS
The results were expressed as a viability percentage compared with the negative control:
% viability = ODtest item / OD negative control * 100

Because the test item was identified as potentially causing colour interferences, the true viability was calculated as follows:
% true viability = [(OD of living tissues exposed to the test item - OD of living tissues exposed to the test item incubated with medium without MTT)/OD living tissues exposed to negative control] * 100

For each tissue, OD values and calculated percentage cell viability data for the test item, positive and negative controls, should be reported in tabular form, including data from replicate repeat experiments as appropriate, mean and individual values.
Irritation / corrosion parameter:
other: other: mean viability (%)
Value:
1.6
Negative controls validity:
valid
Remarks:
mean viability (%) = 100
Positive controls validity:
valid
Remarks:
mean viability (%) = 1.0
Remarks on result:
other:
Remarks:
Time point: after 42 min of exposure and 42 hours post-treatment incubation.
Irritant / corrosive response data:
After treatment with the test item, the mean viability wascalculated to be 1.6%. This value is below the threshold for irritancy of ≤ 50%. Therefore, the test item is considered to possess an irritant potential.

Results after treatment with test item and the controls

Dose group

Treatment

Mean OD
Skin 1*

 

Mean OD
Skin 2*

 

Mean OD Skin 3*

 

Mean OD Product

 

Mean Viability % 

Negative control

42 min

1.619

1.276

1.052

1.316

100.0

Positive control

42 min

0.014

0.013

0.011

0.013

1.0

Test item

42 min

0.030

0.017

0.019

0.022

1.7

 Test item NSC Control

   42 min

 0.002 0.001     0.002  0.1
  

Test item corrected

         

 1.6

OD = Optical Density

The standard deviations between the % variabilities of the test item, the positive and negative controls were respectively 21.7 - 0.1 - 0.5%. The threshold of the "OECD TG 439 Guideline for the Testing of Chemicals 439: In vitro Skin Irritation: Reconstructed Human Epidermis Test Method” is 18%. Considering the results obtained, this deviation is considered as without impact on the conclusion of the study.

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
In accordance with the Regulation EC n° 1272/2008 and considering the results of the study CTX-PH-16-0450 (OECD 435 / test item classified as not corrosive), the test item has to be classified in Category 2 'Irritating to skin'. The hazard statement 'H315: Causes skin irritation' with the signal word 'Warning' are required.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-10-28 to 2017-02-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 438 (Isolated Chicken Eye Test Method for Identifying Ocular Corrosives and Severe Irritants)
Version / remarks:
adopted 26 July 2013
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU method B.48 (Isolated chicken eye test method for identifying occular corrosives and severe irritants)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
dated 23 October 2015
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
30 µL of the test item was applied, as supplied, to the cornea such that the entire surface of the cornea was evently covered with the test item. The test item was applied for 10 seconds and then rinsed from the eye with 20 mL of physiological saline at ambient temperature.
Concurrent negative control (physiological saline - Dutscher batch n° 3012316) and positive control (5% Benzalkonium chloride) were included in this experiment. The 5% Benzalkonium chloride was prepared as follows: 0.25 g of Benzalkonium chloride (Sigma, batch n° BCBQ4374V) was weighed in a flask qsp. 5 mL with physiological saline. The preparation was magnetically stirred during 10 minutes to obtain a colourless solution just before the administration.
Observation period (in vivo):
All observations of the cornea and measurement of corneal thickness were performed using a Haag-Streit BP900 slit-lamp microscope with depth-measuring device n° I. For the measurement of corneal thickness, the slit-width was set at 9½ equalling 0.095 mm.
Treated corneas are evaluated pretreatment and starting at 30, 75, 120, 180 and 240 minutes (+/- 5 min.) after the post-treatment rinse.
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
0
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 0 min
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
0.3
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 30 min
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
0.8
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 75 min
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
1.5
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 120 min
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
2.2
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 180 min
Irritation parameter:
cornea opacity score
Remarks:
mean
Value:
2.3
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 240 min
Irritation parameter:
fluorescein retention score
Remarks:
mean
Value:
0.5
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 0 min
Irritation parameter:
fluorescein retention score
Remarks:
mean
Value:
3
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 30 min
Irritation parameter:
percent corneal swelling
Remarks:
mean
Value:
4
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 30 min
Irritation parameter:
percent corneal swelling
Remarks:
mean
Value:
6
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 75 min
Irritation parameter:
percent corneal swelling
Remarks:
mean
Value:
10
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 120 min
Irritation parameter:
percent corneal swelling
Remarks:
mean
Value:
12
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 180 min
Irritation parameter:
percent corneal swelling
Remarks:
mean
Value:
13
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: time = 240 min
Irritant / corrosive response data:
Corneal opacity: maximal mean score = 2.3 at 240 min corresponding to ICE class IIII
Fluorescein retention: maximal mean score = 3.0 at 30 min corresponding to ICE class IV
Corneal swelling: maximal mean = + 13% at 240 min corresponding to ICE class II
Combination of the 3 endpoints: 1 x IV, 1 x III, 1 x II
The results obtained under these experimental conditions lead to the category 'No prediction can be made'.

The combination of the 3 endpoints for the positive control, Benzalkonium chloride, was 3 x IV. Therefore the positive control is classified as 'Corrosive/severe irritant' as expected.

The combination of the 3 endpoints for the negative control, physiological saline, was 2 x I, 1 x II. Therefore the negative control as 'No category' as expected.

Interpretation of results:
other: No prediction can be made.
Conclusions:
In accordance with Regulation EC 1272/2008, the results obtained under these experimental conditions lead to the category 'No prediction can be made' as defined by the O.E.C.D. test guideline n° 438. Therefore, the test item is not predicted as causing sever eye damage (Caetegory) or as not classified for eye irritation/serious eye damage (No category) with the Isolated Chicken Eye test method. Additional testing are required to establish a definitive classification.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25-01-19 to 17-05-19
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
dated 27 April 2017
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 mL
Duration of treatment / exposure:
0.1 mL of the test item was instilled, as supplied, into the conjunctival sac of one eye after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second in order to prevent loss of the test item. The other eye remained untreated serving as control.
Initially, a single animal was treated. After consideration of the responses in the first animal, two additional animals were treated under the same experimental conditions.
Observation period (in vivo):
Ocular examinations were performed on both eyes 1 hour, 24, 48 and 72 hours following treatment.
Number of animals or in vitro replicates:
3 animals
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.7
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.7
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
The ocular reactions observed during the study have been slight to moderate and totally reversible:
- at the conjunctivae level: a slight to moderate redness noted 1 or 24 hours after the test item instillation in all animals and totally reversible between Days 2 and 21, associated with a slight to moderate chemosis noted 1 or 24 hours after the test item instillation in all animals and totally
reversible between Days 1 and 3.
- at the iris level: an injection noted 1 hour after the test item instillation in two animals and totally reversible on Day 1.
- at the corneal level: a slight to moderate opacity, noted 24 hours after the test item instillation in all animals and totally reversible between Days 7 and 21.
Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The results obtained, under these experimental conditions, enable to conclude that the test item has to be classified in category 2 “Irritating to eye” in accordance with the Regulation (EC) No. 1272/2008.
The signal word “Warning” and hazard statement H319 “Causes serious eye irritation” are required.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Skin corrosion:

The Corrositex test (Colas, 2016) conducted according to OECD guideline 435 is considered as the key study for skin corrosion and will be used for classification. The test item did not disrupt the membrane after 60 minutes in the four replicates.

Therefore, the classification criteria according to regulation EC 1272/2008 as corrosive to the skin are not met, hence no classification is required.

Skin irritation:

Reference Colas (2017) is considered as the key study for skin irritation and will be used for classification. According to the OECD 439 guideline, the mean corrected percent viability of the treated tissues was 1.6% after 42 minutes of exposure and 42 hours of post-treatment incubation.

Results meet the criteria for classification (tissue viability after 42 minutes of exposure and 42 hours post-treatment incubation ≤ 50%) according to regulation (EC) 1272/2008 as skin irritant, hence substance is to be classified in Category 2 'Irritating to the skin'. The hazard statement 'H315: Causes skin irritation' is required.

Eye irritation:

The reference Colas (2017) is considered as the key study for severe eye irritation.

According to the Isolated chicken eye test method, the ocular reactions observed were:

- maximal mean score of corneal opacity: 2.3 corresponding to ICE class III;

- maximal mean score of fluorescein retention: 3.0, corresponding to ICE class IV;

- maximal mean corneal swelling: - 13%, corresponding to ICE class II.

In accordance with regulation EC 1272/2008, the results obtained under these experimental conditions lead to the category 'no prediction can be made'. Additional testing was required to establish a definitive classification.

Reference Richeux (2019) is considered as the key study for in vivo eye irritation and will be used for classification. During the study the test item was applied to one eye of three animals each. The following mean scores (24, 48 and 72 hours) were obtained for the three animals:

cornea: 1.0 - 1.7 - 1.0

iris: 0.0 for the 3 animals

conjunctival redness: 1.0 - 07 - 0.7

chemosis: 1.0 - 0.0 - 0.3

The ocular reactions observed during the study have been slight to moderate and totally reversible within 21 days. Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will be classified as Category 2.

Respiratory irritation:

The available data do not allow any conclusion on respiratory irritation.