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Diss Factsheets

Administrative data

Description of key information

Skin irritation

OECD 439: negative

OECD 404: negative

Eye irritation

OECD 492: negative

OECD 405 negative

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dec 16, 2019 - Apr 20, 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study was performed for registration outside EU. Official chemical regulation requires to perform this in vivo assay.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Species: Rabbit
Strain: New Zealand White
Condition: SPF-Quality
Source: Charles River France, L’Arbresle, France
Number of Animals: 3 Males
Age at the Initiation of Dosing: A young adult animal (approximately 15-17 weeks old) was selected.
Weight at the Initiation of Dosing: 2938 to 3303 g
Acclimatisation: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19- 20 °C
- Humidity (%): 46 to 56%.
- Air changes (per hr): 10 or greater
- Photoperiod (hrs dark / hrs light): 12/12 hours

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 g
Duration of treatment / exposure:
4 h
Observation period:
14 days
Number of animals:
1 female
Details on study design:
TEST SITE
Approximately 24 hours before dosing, the dorsal fur was clipped with an electric clipper, exposing an area of approximately 150 square centimeters (10x15 cm). To facilitate scoring,
the treated skin area was re-clipped at least 3 hours before the observations.
The animal was treated by dermal application of 0.5 grams of the test item. The test item was applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage. Four hours after the application, the dressing was removed and the skin cleaned of residual test item using tap water.

SCORING SYSTEM:
- Method of calculation:

The skin reactions were assessed at approximately 1, 24, 48 and 72 hours and 7 and 14 days after the removal of the dressings and test item. The irritation scores and a description of all other (local) effects were recorded. Adjacent areas of the untreated skin of the animal served as control.
The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

Erythema and eschar formation:
No erythema .............................................................................................................................................................. 0
Very slight erythema (barely perceptible) ................................................................................................................. 1
Well-defined erythema ............................................................................................................................................... 2
Moderate to severe erythema..................................................................................................................................... 3
Severe erythema (beef redness) * ............................................................................................................................ 4
*. Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the maximum grade for erythema (= 4) is given.

Oedema formation:
No oedema.................................................................................................................................................................. 0
Very slight oedema (barely perceptible)..................................................................................................................... 1
Slight oedema (edges of area well-defined by definite raising)................................................................................. 2
Moderate oedema (raised approximately 1 millimeter)................................................................................................ 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) ................................. 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
No skin irritation was caused by 4 hours exposure to the test material.
Other effects:
No signs of systemic toxicity were observed in the animal during the test period and no mortality occurred.
Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results the test material does not have to be classified and has no obligatory labelling requirement for skin irritation according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 04, 2018 - February 08, 2019
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:
July 26, 2013
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Council Regulation (EC) No. 440/2008 laying down test methods pursuant to Regulation (EC) No. 1907/2006. B.40.bis. In vitro skin corrosion: human skin model test
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test system:
human skin model
Source species:
human
Cell type:
non-transformed keratinocytes
Cell source:
foreskin from a single donor
Justification for test system used:
standard model
Vehicle:
unchanged (no vehicle)
Remarks:
No vehicle used in this study; The test item was applied neat to the tissues.
Details on test system:
CELL CULTURE
- Supplier: EpiSkin/SkinEthic Laboratories, Lyon, France)
- Source: human keratinocytes cultured on a polycarbonate filter in conditions which permit their terminal differentiation
- Format: 24 well plate
- Batch: 19-RHE-008
- Expires: Jan 28, 2019

TEMPERATURE USED FOR TEST SYSTEM
- Temperature used during treatment: room temperature
- Temperature of post-treatment incubation: 37°C

REMOVAL OF THE TEST MATERIAL AND CONTROL
At the end of the exposure periods, the test item, positive and negative control was removed immediately by gently rinsing with a minimum volume of 20 mL DPBS using a pipette. Excess DPBS was removed by gently shaking the tissue inserts and blotting the bottom of the tissue inserts with blotting paper.

Control samples:
yes, concurrent negative control
Amount/concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 20 mg ± 3 mg of solid test material
- Concentration (if solution): n/a

VEHICLE
- Amount(s) applied (volume or weight with unit): n/a
- Concentration (if solution): n/a
- Lot/batch no. (if required): n/a
- Purity: n/a

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): 40 µL ± 3 µl (deionised water )
- Concentration (if solution): n/a

POSITIVE CONTROL
- Amount(s) applied (volume or weight): 40 µL ± 3 µl
- Concentration (if solution): A dodecyl sulfate sodium salt solution dissolved deionised water pure was used as positive control.
Duration of treatment / exposure:
42 min
Number of replicates:
3
Controls:
yes, concurrent negative control
Amount / concentration applied:
16 mg
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
Mean relative viability in %
Value:
94.2
Vehicle controls validity:
not applicable
Remarks:
The test item was applied neat to the tissues
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Other effects / acceptance of results:
OTHER EFFECTS:
- Visible damage on test system: none
- Direct-MTT reduction: none
- Colour interference with MTT: none

ACCEPTANCE OF RESULTS:


-Acceptability of the Quality Control Data of the Skin Model with Reference to Historical Batch Data:
The negative control OD values were 1.734, 1.871 and 1.698 and, thus, in the range of ≥0.8 and ≤3.0.

-Acceptability of the Positive and Negative Control:
After treatment with the positive control (5% aqueous solution of sodium dodecyl sulfate) the mean viability value was 1.6% (standard deviation: 6.3%) and, thus, lower than the acceptance criteria (< 40%).
After treatment with the negative control (DPBS-buffer) the mean OD was 1.768 (standard deviation: 5.2%) and, thus, higher than the historically established threshold of 1.20.


-Test Substance Data Acceptance Criteria:
The standard deviation between the three tissues replicates treated with the test item was 9.3% and, thus, ≤18%.
The standard deviations between the three tissue replicates of the negative control and the positive control were 5.2% and 6.3%, respectively, and, thus, ≤18%.

The study met all acceptance criteria.





 Group Time / [min]  Mean OD  Mean Relative viability / [%]
 Negative Control 42 1.768 100.00 

 Positive Control

42

0.029

1.60
 Test Material 42 1.666 94.2
Interpretation of results:
GHS criteria not met
Remarks:
Non-corrosive
Conclusions:
This study was performed according to GLP and the methods applied are fully compliant with OECD TG 439. Under the conditions of the present study, the test item is not considered to be irritant to skin.
Executive summary:

This study was performed according to GLP and the methods applied are fully compliant with OECD TG 439.Under the conditions of the present study, the test item is not considered to be irritant to skin.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dec 17, 2019 - Apr 02, 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study was performed for registration outside EU. Official chemical regulation requires to perform this in vivo assay.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L’Arbresle, France
- Age at study initiation: approximately 12-14 weeks old
- Weight at study initiation: 2560 to 3058 g.
- Housing: ndividually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18- 19
- Humidity (%): 53 - 55
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0,0489 mg (range 0,0487 – 0,491 mg) of the test item (a volume of approximately 0.1 mL)
Duration of treatment / exposure:
72 h
Observation period (in vivo):
1, 24, 48, 72 h
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
- Time after start of exposure:

SCORING SYSTEM:

The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:

CORNEAL IRRITATION
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal luster) .0
Scattered or diffuse areas of opacity, details of iris clearly visible .1
Easily discernible translucent area, details of iris slightly obscured .2
Nacreous area, no details of iris visible, size of pupil barely discernible .3
Opaque cornea, iris not discernible through the opacity .4
Area of cornea involved:
No ulceration or opacity .0
One quarter or less but not zero .1
Greater than one quarter, but less than half .2
Greater than half, but less than three quarters .3
Greater than three quarters, up to whole area .4
 
IRIS
Normal .0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of
these or combination thereof, iris still reacting to light (sluggish reaction is positive) .1
No reaction to light, hemorrhage, gross destruction (any or all of these) .2
CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal .0
Some blood vessels definitely hyperaemic (injected) .1
Diffuse, crimson color, individual vessels not easily discernible .2
Diffuse beefy red .3
Chemosis (refers to lids and/or nictitating membranes):
No swelling ………………………………………… .0
Any swelling above normal (includes nictitating membranes) .1
Obvious swelling with partial eversion of lids .2
Swelling with lids about half closed .3
Swelling with lids more than half closed .4
Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) 0
Any amount different from normal and/or lacrimation 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs (considerable area around the eye) 3

Where standard lighting was considered inadequate for observing minor effects, eye examinations were performed using an ophthalmic examination lamp.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.66
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal: 2,3
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.66
Max. score:
1
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Chemosis
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Discharge
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Instillation of the test item resulted in irritation of the conjunctivae, which consisted of redness, chemosis and discharge. The irritation had completely resolved within 24 hours in
one animal and within 72 hours in the other two animals. Iridial irritation was observed in two animals, which resolved within 24 hours in one animal and within 72 hours in the other
animal.
Other effects:
Remnants of the test item were present in the eye at 1 hour after instillation in all three animals. Remnants on the outside of the eyelids were present at 24 hours after instillation of
the test item in one animal only. No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual Eye Irritation Scores

Animal
 Timepoint after Dosing
 Cornea
 Iris
 Conjunctivae
 Comments
Opacity
(0-4)
 Area
(0-4)
 Fluor Area / [%]2
 (0-2)
 Redness
(0-4)
 Chemosis
(0-4)
 Discharge
(0-4)
4761
 1 hour
 0
 0
 n.a.
 1
 1
 1
 1
 b
24 hours
 0
 0
 0
 1
 0
 0
 0
 -
48 hours
 0
 0
 n.a.
 1
 0
 0
 0
 -
72 hours
 0
 0
 n.a.
 0
 0
 0
 0
 -
475
 1 hour
 0
 0
 n.a.
 0
 2
 1
 1
 b
24 hours
 0
 0
 0
 0
 1
 0
 0
 c
48 hours
 0
 0
 n.a.
 0
 1
 0
 0
 -
72 hours
 0
 0
 n.a.
 0
 0
 0
 0
 -
478
 1 hour
 0
 0
 n.a.
 1
 2
 1
 1
 b
24 hours
 0
 0
 0
 0
 1
 0
 0
 -
48 hours
 0
 0
 n.a.
 0
 1
 0
 0
 -
72 hours
 0
 0
 n.a.
 0
 0
 0
 0
 -

1 Sentinel
2Green staining after fluorescein treatment (% of total corneal area) indicating corneal epithelial damage
n.a. not applicable
b  Remnants of the test item in the eye

c  Remnants of the test item outside the eye

-  No comments

Interpretation of results:
GHS criteria not met
Conclusions:
Based on these results, the test material does not have to be classified and has no obligatory labelling requirement for eye irritation according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jul 30 - Sep 09, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 492 (Reconstructed Human Cornea-like Epithelium (RhCE) Test Method for Identifying Chemicals Not Requiring Classification and Labelling for Eye Irritation or Serious Eye Damage)
Version / remarks:
October 9, 2017
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: DB-ALM Protocol No. 164: Ocular Irritation Assay for Chemicals using EpiOcular™ EIT,
Version / remarks:
September 14, 2015
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EpiOcular Eye Irritation Test (OCL-200-EIT) for the prediction of acute ocular irritation of chemicals; For use with MatTek Corporation`s Reconstructed Human EpiOcular Model; MatTek Corporation
Version / remarks:
June 29, 2015
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Specific details on test material used for the study:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Before application, the test item was pre-warmed to 37°C to get a liquid, which was applied neat to the tissues..
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent positive control
yes, concurrent negative control
Amount / concentration applied:
TEST MATERIAL: 50 µL per tissue

NEGATIVE / VEHICLE CONTROL: 50 µL per tissue

Sterile deionized water was used as negative control.


POSITIVE CONTROL: 50 µL per tissue

Designation: Methyl acetate
Supplier: Merck KGaA
Lot-No.: S7451611
Catalog #: 8.09711
Purity (GC): 99.6%
Appearance: Liquid
Expiration date: June 30, 2022
Storage: 15 to 25°C

Duration of treatment / exposure:
30 ± 2 minutes
Number of animals or in vitro replicates:
in vitro: duplicate design
Details on study design:
Characterization of the Test System
Designation: EpiOcular™ Tissue (OCL-200, OCL-212)
Lot No.: 30621
Keratinocyte strain: 4F1188
Supplier: MatTek In Vitro Life Science Laboratories
Irritation parameter:
other: Viability %
Run / experiment:
Run 1 / Experiment 1
Value:
86.4
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
no indication of irritation
Other effects / acceptance of results:
OTHER EFFECTS:
- Visible damage on test system: No observations

ACCEPTANCE OF RESULTS:
1. The negative control OD is >0.8 and <2.5 (2.086 and 2.183).
2. The mean relative viability of the positive control is below 50% of the negative control viability (13.1%).
3. The difference of viability between the two relating tissues of a single chemical is <20% (values between 0.6% to 4.5%) in the same run (for positive and negative control tissues and tissues of single chemicals).


The study met all acceptance criteria

   Mean OD  Mean Viability
 Negative Control 2.135 100.0% 
 Positive Control 0.280 13.1%
 Test Item 1.845 86.4%
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the present study, the test item did not show an eye hazard potential. The test item is identified as not requiring classification and labeling according to UN GHS (No Category).
Executive summary:

This study was performed according to GLP and the methods applied are fully compliant with OECD TG 492. Under the conditions of the present study, the test item did not show an eye hazard potential. The test item is identified as not requiring classification and labeling according to UN GHS (No Category).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on the data provided, the test material does not have to be classified and has no obligatory labelling requirement for skin or eye irritation according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling

and packaging of items and mixtures (including all amendments).