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Diss Factsheets

Administrative data

Description of key information

Skin irritation

OECD 439: not irritating to skin

OECD 404: mild irritating to skin (GHS catogery 3; no catogery according to CLP)

Eye irritation

OECD 492: not irritating to eye

OECD 405 not irritating to eye

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
30 Sep 2019 - 14 Jan 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study was performed for a registration in a non-EU country.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2015
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
EC No 440/2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF Guidelines
Version / remarks:
2000
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: young adult animals (approximately 12-15 weeks old) were selected.
Weight at the Initiation of Dosing: 2571 to 3184 g
Acclimatisation: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 °C
- Humidity (%): 48 to 76%.
- 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:
The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner two weeks later, after considering the degree of skin irritation observed in the first animal.
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:
animal #1
Time point:
24/48/72 h
Score:
2.3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
probability of mild irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of mild irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.3
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of mild irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 h
Remarks on result:
probability of mild irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of mild irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of mild irritation
Irritant / corrosive response data:
Four hours exposure to 0.5 g of the test material resulted in very slight, well defined or moderate to severe (scattered) erythema and very slight to well-defined oedema in the treated skin areas of all three rabbits. Scaliness of the skin was noted in one animal after 7 days. The skin irritation resolved completely within 7 days in two animals and within 14 days after exposure in the remaining animal.
Other effects:
No staining of the treated skin by the test item was observed and no test item remnants were seen.
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.
Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments), the test material should be classified as: mild skin irritant (Category 3).
According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), the test material does not have to be classified and has no obligatory labelling requirement for skin irritation.
Executive summary:

The objective of this primary skin irritation study was to assess the possible irritation or corrosion potential of a single dose of the test material when administered to the intact skin of rabbits.

Three rabbits were exposed to 0.5 grams of the test material, moistened with 0.3 mL water by application onto clipped skin for 4 hours using a semi-occlusive

dressing. Skin reactions were assessed 1, 24, 48 and 72 hours and 7 and 14 days after exposure.

The exposure resulted in very slight, well defined or moderate to severe (scattered) erythema and very slight to well-defined oedema in the treated skin areas of all three rabbits. Scaliness of the skin was noted in one animal after 7 days. The skin irritation resolved completely within 7 days in two animals and within 14 days after exposure in the remaining animal.

Based on these results:

• According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments), the test material should be classified as: mild skin irritant (Category 3).

• According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), the test material does not have to be classified and has no obligatory labelling requirement for skin irritation.

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:
weight of evidence
Study period:
Sep 30, 2019 - May 14, 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The study was conducted for a registration in a non-EU country.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2017
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
EC No 440/2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF Guidelines
Version / remarks:
2000
Deviations:
no
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 15-24 weeks old
- Weight at study initiation: 3267 to 3874 g.
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 54 - 61
- Air changes (per hr): >10
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
Animals were treated by instillation of about 78 mg (range 0.0643 - 0.0783 mg) of the test item (a volume of approximately 0.1 mL),
Duration of treatment / exposure:
The lids were gently held together for about one second to prevent loss of the test item and the test item was washed out after completion of the 1 and 24 hour examination.
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): Yes
- Time after start of exposure: 24 hours

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.

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
3
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Instillation of the test item (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in very slight irritation of the conjunctivae, which consisted of redness and chemosis in all animals and discharge in two out of three animals. The irritation had completely resolved within 24 hours in one animal and within 48 hours in the other two animals.
No iridial irritation or corneal opacity was observed, and treatment of the eyes with 2% fluorescein 24 hours after test item instillation revealed no corneal epithelial damage.
Other effects:
No staining of (peri) ocular tissues by the test item was observed and no test item remnants were seen
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)
4501
1 hour
0
0
n.a.
0
1
1
1
-
24 hours
0
0
0
0
1
0
0
-
48 hours
0
0
n.a.
0
0
0
0
-
72 hours
0
0
n.a.
0
0
0
0
-
458
1 hour
0
0
n.a.
0
1
1
0
-
24 hours
0
0
0
0
0
0
0
-
48 hours
0
0
n.a.
0
0
0
0
-
72 hours
0
0
n.a.
0
0
0
0
-
459
1 hour
0
0
n.a.
0
1
1
1
-
24 hours
0
0
0
0
1
0
0
-
48 hours
0
0
n.a.
0
0
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
-  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).
Executive summary:

The objective of this acute eye irritation study was to assess the possible irritation or corrosion potential when a single dose of the test material was placed in the conjunctival sac of the rabbit eye.

Single samples of approximately 0.05 mg of the test material (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours after instillation. Instillation of the test item resulted in irritation of the conjunctivae, which consisted of redness and discharge in all animals and chemosis in one animal only. The irritation had completely resolved within 24 hours in one animal and within 48 hours in the other two animals. No iridial irritation or corneal opacity was observed and treatment of the eyes with 2% fluorescein 24 hours after test item instillation revealed no corneal epithelial damage.

Remnants of the test item were present in the eye at one hour after instillation in all animals. 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:
weight of evidence
Study period:
Apr 18 - Jun 12, 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)
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: Art. 8.09711
Synonym: Methyl acetate
Supplier: Merck KGaA
CAS No.: 79-20-9
Batch No.: S7451611
Appearance: Liquid
Content (GC): 99.6 % (a/a)
Expiry Date: June 30, 2022
Storage conditions: Tightly closed, dark, at room temperature (15 – 25°C)


Duration of treatment / exposure:
30 ± 2 minutes
Number of animals or in vitro replicates:
in vitro: duplicate design
Irritation parameter:
other: Viability %
Run / experiment:
Run 1 / Experiment 1
Value:
114.8
Vehicle controls validity:
valid
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:
The results are acceptable if:
1. The negative control OD is >0.8 and <2.5 (1.607 and 1.731).
2. The mean relative viability of the positive control is below 50% of the negative control viability (30.8%).
3. The difference of viability between the two relating tissues of a single chemical is <20% (values between 6.6% to 9.4%) 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 1.669 100.0% 
 Positive Control 0.514 30.8%
 Test Item 1.916 114.8%
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:

Objective

The objective of the present study was to investigate the potential of the test item to induce eye irritation in anin vitrohuman cornea model.

Study Design

The test item was applied topically to a reconstructed human cornea-like epithelium model (EpiOcular) followed by determination of the cell viability. Cell viability was determined by enzymatic conversion of vital dye MTT into a blue formazan salt and measurement of the formazan salt after extraction from tissues. The percent reduction of cell viability in comparison to untreated negative controls was used to predict the eye irritation potential.

Duplicates of the EpiOcular-model were treated with the test item, the negative or the positive control for 6 hours (± 15 minutes). 50 mg of the test item and 50 µL of either the negative control (sterile deionized water) or the positive control (methyl acetate) were applied to the tissues.

Results

After treatment with the negative control (sterile deionized water) the mean OD was 1.669 (study acceptance criterion: >0.8 and <2.5). Treatment with the positive control (methyl acetate) revealed a mean viability value of 30.8% (study acceptance criterion: <50%). Thus, the acceptance criteria were met.

Following treatment with the test item the test material, the tissue viability was 114.8% and, thus, higher than 60%, i.e. according to OECD 492 the test item is identified as not requiring classification and labeling according to UN GHS (No Category).

Conclusion

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 provided information the test item is not classified for skin and eye irritation according to the EU Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging of Substances and Mixtures.

According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments), the test material should be classified as: mild skin irritant (Category 3).