Registration Dossier

Administrative data

Description of key information

Eye irritation: Irreversible effect in the eye
Skin irritation: Not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
other: experimnental result on similar substance
Adequacy of study:
key study
Study period:
From December 11 to 19, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to
Guideline:
other: "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO)
GLP compliance:
no
Remarks:
Study conducted before 1981
Species:
rabbit
Strain:
Himalayan
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: WIGA Versuchstierzuchtanstalt, 8741 Sulzfeld, Germany
- Weight at study initiation: 1.5 to 2 kg
- Housing: housed individually in metal cages
- Diet: standard rabbit food - NAFAG, Gossau SG ad libitum
- Water: ad libitum
- Acclimation period: for a minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1 °C
- Humidity (%): 55 ± 5 %
- Photoperiod (hrs dark / hrs light): 10 hours light cycle day
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
other: propylene glycol + saline (70 : 30 parts)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g of test material
- Concentration: 50 %
Duration of treatment / exposure:
24 hours
Observation period:
7 days
Number of animals:
3 male and 3 female
Details on study design:
PREPARATION
Before treatment the entire back and the flank of the rabbits were shaved with an electric clipper and immediately before treatment the shaven skin on one side was slightly scarified with the help of a "SchröpfSchnäpper", Aesculap, Switzerland
TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- Type of wrap if used: gauze patches. The patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.
Irritation parameter:
edema score
Basis:
animal: 265, 267, 268, 269
Time point:
other: mean score following grading at 24, 48, 72 hours
Score:
ca. 0.33
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal:
Time point:
other: 266, 270
Score:
ca. 0
Max. score:
0
Reversibility:
other: No dermal effects observed
Remarks on result:
other: intact skin

Due to intensive staining by the test compound erythema was not assessable. For the purpose of calculating the primary irritation index erythema was assumed to be equal to edema based on the correlation existing (Marzulli and Maibach, Fol. Cosm. Tox. 13, 355, 1975).

Interpretation of results:
other: CLP criteria not met
Conclusions:
Non irritant
Executive summary:

Method:

The skin irritation was determined in an irritation test on rabbits according to the Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1959), the US Association of Food and Drug Officials (AFDO), similar to OECD guideline 404. During the test 3 male and 3 female of Hymalaian rabbit were exposed to the substance on intact and abradeed skin, nevertheless in order to evaluate the irritation potential of the substance only the scores registered on intact skin were considered.

Due to intensive staining by the test compound erythema was not assessable. For the purpose of calculating the primary irritation index erythema was assumed to be equal to edema based on the correlation existing (Marzulli and Maibach, Fol. Cosm. Tox. 13, 355, 1975).

Result:

Not irritating

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:
other: experimnental result on similar substance
Adequacy of study:
key study
Study period:
December 11 to 19, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to
Guideline:
other: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" (1959), the US Association of Food and Drug Officials (AFDO)
GLP compliance:
no
Remarks:
Study conducted before 1981
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: WIGA Versuchstierzuchtanstalt, 8741 Sulzfeld, Germany
- Weight at study initiation: 1.5 to 2 kg
- Housing: individually in metal cages
- Diet: standard rabbit food - NAFAG, Gossau SG ad libitum
- Water: ad libitum
- Acclimation period: for a minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1 °C
- Humidity (%): 55 ± 5 %
- Photoperiod (hrs dark / hrs light): 10 hour light cycle day
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 g of test substance applied as such
- Application: The test material in an amount of 0.1 g was inserted into the conjunctival sac of the left eye of the rabbits and the lids were gently closed for a few seconds.
Duration of treatment / exposure:
30 seconds
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 male and 3 female
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: flushed with 10 ml of physiological saline
- Time after start of exposure: approximately 30 seconds after treatment
Irritation parameter:
cornea opacity score
Remarks:
Opacity
Basis:
animal: 268
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
cornea opacity score
Remarks:
Opacity
Basis:
animal: 269
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 2
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
cornea opacity score
Remarks:
Opacity
Basis:
animal: 270
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 1
Max. score:
1
Reversibility:
fully reversible within: 4 days
Remarks on result:
other: washed eyes
Irritation parameter:
iris score
Basis:
animal: 268
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 1
Max. score:
1
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
iris score
Basis:
animal: 269, 270
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 0
Max. score:
0
Reversibility:
other: no signs of irritation
Remarks on result:
other: washed eyes
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: 268
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: 269
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 2
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: 270
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 1.66
Max. score:
2
Reversibility:
fully reversible within: 4 days
Remarks on result:
other: washed eyes
Irritation parameter:
chemosis score
Basis:
animal: 268, 269
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 2
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: washed eyes
Irritation parameter:
chemosis score
Basis:
animal: 290
Time point:
other: mean score following grading at 24, 48, 72 h
Score:
ca. 1.66
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: washed eyes
Interpretation of results:
other: Category 1 (irreversible effects on the eye) based on CLP criteria
Conclusions:
Irreversible effects on the eye
Executive summary:

Method

The eye irritation was determined in an irritation test according to the Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1959), the US Association of Food and Drug Officials (AFDO), similar to OECD guideline 405. During the test 3 male and 3 female of Hymalaian rabbit were exposed to the substance as such (3 animals rinsed; 3 animals not rinsed). Approximately 30 seconds after treatment the test item was flushed with 10 ml of physiological saline. The irritation scores were registered after 24, 48, 72 hours, 4 and 7 days and the evaluation of the eye irritatation potential of the test item was conducted considering the mean score following grading at 24, 48 and 72 h for each animal.

Observations

After 7 days the irritation effects were reversible only in one animal (rinsed).

Result

Irreversible effects on the eye.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

No studies on Irritation/Corrosion are available for the substance in itself.

Nevertheless studies have been conducted with an analogue molecule, with a different salification of the same core structure (Similar Substance 01). Further information are reported in the Read Across justification attached to section 13.

 

Skin Irritation

The test substance was evaluated in the key study (Huntsman, 1979) for its skin irritation potential according to the Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1959), the US Association of Food and Drug Officials (AFDO), similar to OECD guideline 404. During the test 3 male and 3 female of Hymalaian rabbit were exposed to the substance on intact and abradeed skin, nevertheless in order to evaluate the irritation potential of the substance only the scores registered on intact skin were considered.

The mean score of observed values of irritation/corrosion , calculated for each rabbit, after 24, 48, 72 hours, were always under the limit for irritation potential set out in the OECD guideline.

In the supporting study (Huntsman, 1979), during the test 3 male and 3 female of New Zeland White rabbit were exposed to the substance on intact and abradeed skin, nevertheless in order to evaluate the irritation potential of the substance only the scores registered on intact skin were considered. Even in the supporting study the mean score value calculated for the test substance was always under the limit of classification. These results are in line with that achieved by other tests available.

 

Eye Irritation 

The test substance was evaluated in the key study (Huntsman, 1979) for its eye irritation potential according to the Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1959), the US Association of Food and Drug Officials (AFDO), similar to OECD guideline 405.

During the test 3 male and 3 female of Hymalaian rabbit were exposed to the substance as such (3 animals rinsed; 3 animals not rinsed). Approximately 30 seconds after treatment the test item was flushed with 10 ml of physiological saline. The irritation scores were registered after 24, 48, 72 hours, 4 and 7 days and the evaluation of the eye irritatation potential of the test item was conducted considering the mean score following grading at 24, 48 and 72 h for each animal. After 7 days the irritation effects were reversible only in one animal (rinsed).

In the supporting study (Huntsman, 1980) during the test 3 male and 3 female of New Zealand White rabbit were exposed to the substance as such (3 animals rinsed; 3 animals not rinsed). Approximately 30 seconds after treatment the test item was flushed with 10 ml of physiological saline. The irritation scores were registered after 24, 48, 72 hours, 4 and 7 days and the evaluation of the eye irritation potential of the test item was conducted considering the mean score following grading at 24, 48 and 72 h for each animal. After 7 days the irritation effects were not reversible in all animals.

These results are in line with that achieved by other tests, listed in the table below.

Justification for classification or non-classification

SKIN IRRITATION/CORROSION

A corrosive substance is a substance that produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least 1 tested animal after exposure up to 4 hour duration.

Three subcategories are provided within the corrosive category 1:

Subcategory 1A where responses are noted following up to 3 minutes exposure and up to 1 hour observation;

Subcategory 1B where responses are described following exposure between 3 minutes and 1 hour and observations up to 14 days;

Subcategory 1C where responses occur after exposures between 1 hour and 4 hours and observations up to 14 days

To classify a substance as irritant, the major criterion is that at least 2 of 3 tested animals have a mean score of ≥ 2,3 - ≤ 4,0.

Category 2:

- Mean value of ≥ 2,3 - ≤ 4,0 for erythema/ eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

- Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or

- In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical eposure in a single animal but less than the criteria above.

The substance is not classified as skin irritant because in the performed tests it doesn't meet the classification criteria of the CLP regulation n. 1272/2008.

EYE IRRITATION

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance to the anterior surface of the eye, which is not fully reversible within 21 days of application.

Eye irritation means the production of changes in the eye following the application of test substance to the anterior surface of the eye, which are fully reversible within 21 days of application.

Irreversible effects on the eye (Category 1):

If, when applied to the eye of an animal, a substance produces:

- at least in one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/ or

- at least in 2 of 3 tested animals, a positive response of corneal opacity ≥ 3 and/or iritis > 1,5 calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material.

These observations include animals with grade 4 cornea lesions and other severe reactions (e.g., destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Substances are also classified in Category 1 if they fulfil the criteria of corneal opacity ≥ 3 or iritis > 1,5 detected in a Draize eye test with rabbits, recognising that such severe lesions usually do not reverse within a 21-day observation period.

The substance does not meet the requirements to be classified in Category 1.

Irritating to eyes (Category 2)

when applied to the eye of an animal, a substance produces:

- at least in 2 of 3 tested animals, a positive response of: corneal opacity ≥ 1 and/or iritis ≥ 1, and/or conjunctival redness ≥ 2 and/or conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the test material, and which fully reverses within an observation period of 21 days.

The mean score value calculated in both experiment meets the classification requirements for Category 2 (Irritant).

Nevertheless, as the symptoms never reverse in the observation period (7 days), and as trend doesn't decrease in this observation window, it is supposed that in an hypothetical 21 days observation period there is not reversibility of the events recorded. For this reason, using a conservative approach, the test substance is considered to cause irreversible eye effects and shall be classified as Category 1 ( H318 ‘Causes serious eye damage).