Registration Dossier

Administrative data

Description of key information

The substance  was found to be non irritating in the in-vivo study for skin and eye irritation (OECD 404 and 405) and in the in-vitro EPISKIN test for skin irritation (EU B.46) (BSL 2009b and c, Bioassay 2013).

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:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and OECD guideline compliant study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5g
Duration of treatment / exposure:
single treatment
Observation period:
14 days
Details on study design:
The cutaneous reactions were assessed immediately after removal of the patch,
approximately 1, 24, 48 and 72 hours after removal of the patch and in weekly intervals
until day 14.

The following test item-related clinical observations were recorded during the course of

the study:

· Very slight to well-defined erythema (grade 1-2)

The cutaneous reactions were reversible in one animal within 72 hours and in another animal within 7 days after removal of the patch. In the third animal very slight erythema was still observed on day 14 (study termination).

Mean scores over 24, 48 and 72 hours for each animal were 0.0, 2.0 and 1.0 for erythema and 0.0, 0.0 and 0.0 for edema.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
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:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, guideline compliant
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Species: Healthy New Zealand White Rabbits
Strain: Crl:KBL (NZW)
Source: Charles River Deutschland, D-88353 Kisslegg
Sex: female
Body weight at the beginning of the study: 4.5, 4.5, 3.9 kg
Age at the beginning of the study: approximately 13 weeks old
Number of animals: 3
The animals were derived from a controlled full barrier maintained breeding system (SPF). According to Art. 9.2, No.7 of the German Act on Animal Welfare the animals were bred for experimental purposes.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
A dose of 0.1 g of the test item was applied to the test site.
Duration of treatment / exposure:
The test item was applied at a single dose in the conjunctival sac of one eye of each test animal after pulling the lower lid away from the eyeball. The lids were then gently held together for about 1 second in order to prevent loss of the material. The untreated contralateral eye served as control.
Observation period (in vivo):
The animals were observed for 72 hours after dosing.
Number of animals or in vitro replicates:
3
Details on study design:
The test item was ground to a fine powder in a mortar with the help of a pestle.

Approximately 24 hours before the test and immediately prior to the application both eyes of the test animals were examined. A health inspection was performed to ensure the good state of health of the animals. None of the animals showed eye irritation, ocular defects, or pre-existing corneal injury.

The test item was applied at a single dose in the conjunctival sac of one eye of each test animal after pulling the lower lid away from the eyeball. The lids were then gently held together for about 1 second in order to prevent loss of the material. The untreated contralateral eye served as control.

The results of the initial test did not indicate the test item to be corrosive or a severe irritant to the eye using the procedure described. In order to confirm the response, two additional animals were treated in the same manner.

The animals were observed for 72 hours after dosing.

The eyes were examined for signs of irritation throughout the observation period. The eye irritation was scored and recorded according to the grades in the table below. For calculation only the 24 h, 48 h and 72 hour readings were used. At the end of the observation period the treated eyes were examined with the aid of a fluorescein solution (Fluoreszein SE Thilo, Lot H 801, expiry date: 01/2010).

Individual reactions of each animal were recorded at each observation time. Nature, severity and duration of all lesions observed were described. For calculation only the 24 h, 48 h, 72 hour readings were used.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: Not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24, 48, 72 Hour Reading
Score:
0.66
Max. score:
1
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48, 72 Hour Reading
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 48h
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24, 48, 72 Hour Reading
Score:
0.66
Max. score:
1
Reversibility:
fully reversible within: 72h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24, 48, 72 Hour Reading
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 48h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24, 48, 72 Hour Reading
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
Under the conditions of the present study, single ocular instillation of the test item to rabbits at a dose of 0.1 g produced slightly irritant effects, which were fully reversible within 72 hours in animals no. 1 and 2 and within 48 hours in animal no. 3.
Other effects:
Neither mortalities nor significant clinical signs of toxicity were observed. There were no significant body weight changes during observation period.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The potential for skin irritation was assessed in vitro, using the EPISKIN test and following the procedure published in Commission Regulation (EC) No 761/2009 (Annex III - B.46). No indication irritancy as indicated by damage of the cultured human skin samples was observed (BSL 2009b). The EPISKIN model has been validated for classification and labelling purposes and therefore, the substance is considered to be non irritating without further testing in animals.

To fulfill requirements for new substance notifications outside the EU, a study for skin irritation in vivo had to be commissioned in 2013. This study confirmed that the substance does not require a hazard label for skin irritation (Bioassay 2013). It is included in this dossier for completeness of data only.

The potential for eye irritation was assessed in vivo (BSL 2009c), as there was at that time no in-vitro method that was adequate for classification and labelling purposes and because the substance was found to be non irritating in the skin model. The study followed the principles of GLP and the most recent version of OECD testing guideline 405. The substance caused mild findings in single animals that healed within 72 hours and therefore, it is considered to be non-irritating to eyes.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available in-vitro study is considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for skin irritation under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified as a skin irritant under Regulation (EC) No. 1272/2008.

Dangerous Substance Directive (67/548/EEC)

The available study is considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for eye irritation under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental study is reliable and suitable for classification purposes under Regulation 1272/2008 as amended for the seventh time in Regulation (EC) No 2015/1221. As a result the substance is not considered to be classified as an eye irritant under Regulation (EC) No. 1272/2008.