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Administrative data

Description of key information

Based on an in vitro skin irritation test, conducted according to OECD 439 and GLP principles, and based on an in vivo skin irritation test, conducted according to OECD 404 and GLP principles, it was concluded that the substance is not irritating to the skin. In an eye irritation study in the rabbit, conducted in accordance with OECD 405 and according to GLP principles, ocular effects were observed which were not all fully reversible.

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:
November 22, 2010 - November 26, 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
(2002)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
(1998)
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
- Source: Charles River Deutschland, 97633 Sulzfeld, Germany
- Age at study initiation: approx. 24 - 25 weeks
- Weight at study initiation: 4.8 - 5.2 kg
- Housing: individually in ABS - plastic rabbit cages
- Diet: ad libitum (autoclaved hay and Altromin 2123 maintenance diet)
- Water: ad libitum (tap water)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
other: the substance was moistened with aqua ad injectionem
Controls:
other: the untreated right side of the dorsal area served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g

VEHICLE
- Vehicle: aqua ad injectionem (Delta Select, lot no. 05007A, expiry date: June 2013)
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3 females (1 female subsequently followed by 2 females)
Details on study design:
TEST SITE
Approximately 25 hours before treatment, the dorsal fur was clipped with electric clippers.
The test item was applied to a gauze patch and was moistened with aqua ad injectionem.
The patch was then applied to the skin on a small area (approx. 6 cm^2) on the left side of the dorsal area.
The gauze was held in place with non-irritating tape. The patch was fixed with a semi-occlusive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing: yes, using tap water
- Time after start of exposure: 4 hours

OBSERVATIONS
- Clinical signs: approximately 1, 24, 48 and 72 hours after patch removal
- Body Weight: at the start of the study and 72 hours after patch removal
- Irritation: the skin reactions were assessed at approximately 1, 24, 48 and 72 hours after patch removal. The irritation scores and a description of all other (local) effects were recorded.

SCORING SYSTEM
The irritation was assessed according to the numerical scoring system according to OECD 404.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
No irritant or corrosive effects were observed
Other effects:
- No significant clinical signs of toxicity were observed
- No mortalities were observed
- No significant body weight changes were observed
Interpretation of results:
other: the substance does not need to be classified for skin irritation according to GHS and CLP
Conclusions:
In a skin irritation study with rabbits, performed in accordance with OECD 404 (2002), EU Method B.4 (2008), EPA OPPTS 870.2500 (1998) and according to GLP principles, no irritation was observed.
Executive summary:

In an in vivo skin irritation study in rabbits, conducted in accordance with OECD 404 (2002), EU Method B.4 (2008), EPA OPPTS 870.2500 (1998) and according to GLP principles, 3 female rabbits were semi-occlusively exposed for 4 hours to 0.5 g of the (moistened) substance. No irritant or corrosive effects were observed. No significant clinical signs of toxicity nor mortalities were observed. Based on the result of this study, the substance does not need to be classified for skin irritation/corrosion in accordance with the CLP Regulation.

Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17Oct 2011 - 26Oct 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EU Method B.46 (In Vitro Skin Irritation: Reconstructed Human Epidermis Model Test)
Version / remarks:
24 August 2009
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Version / remarks:
22 July 2010
Deviations:
no
GLP compliance:
yes
Test system:
human skin model
Source species:
human
Cell type:
other: epidermal keratinocytes
Cell source:
other: SkinEthic Laboratories, Nice, France
Source strain:
other: not applicable
Vehicle:
unchanged (no vehicle)
Details on test system:
RECONSTRUCTED HUMAN EPIDERMIS (RHE) TISSUE
- Model used: EPISKIN Standard ModelTM (EPISKIN-SMTM, 0.38 cm2)
- Lot no.: 11-EKIN-041
- This model is a three-dimensional human epidermis model, which consists of adult human-derived epidermal keratinocytes which have been seeded in 12-well plates on a dermal substitute consisting of a collagen type I matrix coated with type IV collagen. The keratinocytes were cultured for 13 days, which results in a highly differentiated and stratified epidermis model comprising the main basal, supra basal, spinous and granular layers and a functional stratum corneum.
- On the day of receipt the tissues were transferred to 12-well plates and preincubated with prewarmed Maintenance Medium for 24 hours at 37°C. The level of Maintenance Medium was just beneath the tissue. Maintenance medium and Assay medium were supplied by Skinethic Laboratories, Nice, France.

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

REMOVAL OF TEST MATERIAL AND CONTROLS
- Washing: phosphate buffered saline
- Time after start of exposure: 15 minutes

MTT DYE USED TO MEASURE TISSUE VIABILITY AFTER TREATMENT / EXPOSURE
- MTT concentration: 0.3 mg/mL
- Incubation time: 3 hours
- Spectrophotometer: TECAN Infinite® M200 Pro Plate Reader
- Wavelength: 570 nm

NUMBER OF REPLICATE TISSUES: 3
Control samples:
yes, concurrent negative control
yes, concurrent positive control
Amount/concentration applied:
TEST MATERIAL
- Amounts applied: 11.7 to 14.9 mg; 5 μL Milli-Q water to moisten skin.

NEGATIVE CONTOL
- Amount applied: 25 µL Phosphate buffered saline (PBS)

POSITIVE CONTROL
- Amount applied: 25 µL
- Concentration: 5% (aq) Sodium dodecyl sulphate in PBS
Duration of treatment / exposure:
15 minutes
Duration of post-treatment incubation (if applicable):
42 hours
Number of replicates:
3
Irritation / corrosion parameter:
% tissue viability
Run / experiment:
Mean of 3 replicates
Value:
102
Vehicle controls validity:
not applicable
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other: Positive control: 17%
Other effects / acceptance of results:
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

CAT was checked for possible direct MTT reduction by adding the test substance to MTT medium. Because no colour change was observed it was concluded that CAT did not interact with MTT.

Mean tissue viability for CAT was > 50%, therefore CAT is considered not to be irritant to the skin.

Interpretation of results:
other: the substance does not need to be classified for skin irritation according to GHS and CLP
Conclusions:
The in vitro skin irritation test was conducted according to OECD 439 guideline and GLP principles.
It is concluded that this test is valid and that CAT is not irritating in the in vitro skin irritation test.
Executive summary:

In an in vitro skin irritation test using a human skin model ( EPISKIN Standard Model), the influence of CAT on the viability of human skin was tested. The test substance was applied directly to 0.38 cm2 cultured skin (11.7 to 14.9 mg, in presence of 5 μl Milli-Q water).

After 15 minutes, the substance was removed and cells were cultured for 42 hours. The viability of the cells was tested by reduction of MTT. Survival of unexposed skin was set at 100%, the positive control had a mean cell viability of 17% whereas CAT showed cell viability of 102%. Since the mean relative tissue viability after exposure to CAT was above 50%, it can be concluded that CAT is not irritating in the in vitro skin irritation test.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 17, 2010 - January 19, 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Although since 1 June 2008 it has been mandatory to first consider and use whenever possible in vitro testing when generating new data for the eye irritation endpoint, an in vitro test was not performed before generating in vivo data because the registrant was incorrectly informed by the testing facility that "No validated in vitro method is available for assessing acute eye irritation/corrosion". As reported in their study report on page 14 as justification for the selection of the test method.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
(2002)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
(2008)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
(1998)
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 Deutschland, 97633 Sulzfeld, Germany
- Age at study initiation: approximately 23 weeks old
- Weight at study initiation: >2 kg
- Housing: individually housed in ABS - plastic rabbit cages, floor 4200 cm^2
- Diet: autoclaved hay and Altromin 2123 maintenance diet (lot no. 0955), ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): at least 10 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: November 28, 2010 To: December 20, 2010
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 g
Duration of treatment / exposure:
Not applicable (the treated eyes were not rinsed)
Observation period (in vivo):
The animals were observed for 72 hours after dosing. To determine the reversibility of the observed effects in animal no. 1, the observation period was extended to the maximum of 21 days after dosing.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE: Not applicable
SCORING SYSTEM: in accordance with OECD 405
TOOL USED TO ASSESS SCORE: fluorescein (only 72 hours after installation)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
- In animal #1, effects on the cornea (score: 1) were observed starting from 24 hours after installation up to the end of the observation period (21 days)
- In none of the animals, any effects on the iris were observed
- In animal #1, conjunctival redness (score: 1) was observed starting from 1 hour after installation up to day 6. In the other 2 animals, conjunctival redness (score: 1) was observed starting from 1 hour after installation up to 48 hours after installation.
- In animal #1, chemosis (score: 1) was observed starting from 1 hour after installation up to 72 hours after installation. In the other 2 animals, chemosis (score: 2) was observed 1 hour after installation and chemosis (score: 1) was observed at 24 and 48 hours after installation.
Other effects:
- All 3 animals had a slight discharge after 1 hour

- No mortalities nor significant clinical signs of toxicity were observed

Interpretation of results:
other: Category 1 (irreversible effects on the eye) based on GHS and CLP criteria
Conclusions:
In an acute eye irritation study in 3 rabbits, conducted in accordance with OECD 405 (2002), EU Method B.5 (2008), EPA OPPTS 870.2400 (1998) and according to GLP principles, irritant effects were observed which were not all fully reversible. Based on the results of this study, the substance needs to be classified as causing irreversible effects on the eye (Category 1).
Executive summary:

An acute eye irritation study was conducted in 3 rabbits in accordance with OECD 405 (2002), EU Method B.5 (2008), EPA OPPTS 870.2400 (1998) and according to GLP principles. In none of the animals, any effects on the iris were observed. In one animal, effects on the cornea (score: 1) were observed starting from 24 hours after installation up to the end of the observation period (21 days). In the same animal also conjunctival redness (score: 1) was observed starting from 1 hour after installation up to day 6 and chemosis (score: 1) starting from 1 hour after installation up to 72 hours after installation. In the other 2 animals, conjunctival redness (score: 1) was observed starting from 1 hour after installation up to 48 hours after installation and chemosis (score: 2) was observed 1 hour after installation and chemosis (score: 1) was observed at 24 and 48 hours after installation. Based on the results of this study, the substance needs to be classified as causing irreversible effects on the eye (Category 1).

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In an in vitro skin irritation test using a human skin model ( EPISKIN Standard Model), the influence of CAT on the viability of human skin was tested according to OECD guideline 439. The test substance was applied directly to 0.38 cm2cultured skin (11.7 to 14.9 mg, in presence of 5 μl Milli-Q water). After 15 minutes, the substance was removed and cells were cultured for 42 hours. Survival of unexposed skin was set at 100%, the positive control had a mean cell viability of 17% whereas CAT showed cell viability of 102%. Since the mean relative tissue viability after exposure to CAT was above 50%, it can be concluded that CAT is not irritating in the in vitro skin irritation test.

In an in vivo skin irritation study in rabbits, conducted in accordance with OECD 404 (2002), EU Method B.4 (2008), EPA OPPTS 870.2500 (1998) and according to GLP principles, 3 female rabbits were semi-occlusively exposed for 4 hours to 0.5 g of the substance. No irritant or corrosive effects were observed. No significant clinical signs of toxicity were observed.

Eye irritation

An acute eye irritation study was conducted in 3 rabbits in accordance with OECD 405 (2002), EU Method B.5 (2008), EPA OPPTS 870.2400 (1998) and according to GLP principles. In none of the animals, any effects on the iris were observed. In one animal, effects on the cornea (score: 1) were observed starting from 24 hours after installation up to the end of the observation period (21 days). In the same animal also conjunctival redness (score: 1) was observed starting from 1 hour after installation up to day 6 and chemosis (score: 1) starting from 1 hour after installation up to 72 hours after installation. In the other 2 animals, conjunctival redness (score: 1) was observed starting from 1 hour after installation up to 48 hours after installation and chemosis (score: 2) was observed 1 hour after installation and chemosis (score: 1) was observed at 24 and 48 hours after installation.


Justification for classification or non-classification

Based on the results of an in vitro skin irritation study and an in vivo skin irritation study, the substance does not have to be classified for skin irritation according to the CLP Regulation. Based on the results of an in vivo eye irritation study, the substance needs to be classified as causing irreversible effects on the eye (Category 1, H318) according to the CLP regulation.