[No public or meaningful name is available]

Endpoint summary

Description of key information

The test substance was found not to be irritating or corrosive to the skin, but causes irreversible damage to the 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:

key study

Study period:

Experiment start date - 11 January 2005; Experiment end date - 31 January 2005; Study completion date - 23 February 2005.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

Identity: FAT 40819/A
Description: Red brown powder
Batch number: Red ROE 420 BOP 01/04
Purity: approx. 77 %
Stability of test item: Stable under storage condition
Expiry date: 02 November 2009
Stability of test item dilution: Stable in PEG 300 for at least 7 days at room temperature
Storage conditions: At room temperature.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories France, BP 0109, F-69592 L'Arbresle
- Age at treatment: 12 weeks
- Body weight at treatment: 2113 - 2310 g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Füllinsdorf) and haysticks 4642 (batch no. 38/04, Provimi Kliba AG) were provided for gnawing.
- Diet: Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 68/04) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.
- Water: Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: Under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Controls:

no

Amount / concentration applied:

0.5 g test substance moistened with approximately 0.1 mL purified water.

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

1 male, 2 females

Details on study design:

TREATMENT
Four days before treatment, the left flank was clipped with an electric clipper, exposing an area of approximately 100 cm² (10 cm x 10 cm). The skin of the animals was examined one day before treatment, and regrown fur of all animals was clipped again. Animals with overt signs of skin injury or marked irritation which may have interfered with the interpretation of the results were not used in the test. On the day of treatment, 0.5 g of FAT 40819/A was placed on a surgical gauze patch (ca. 4 cm x 4 cm). This gauze patch was applied to the intact skin of the clipped area. The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape. The duration of treatment was 4 hours. Then the dressing was removed and the skin was flushed with lukewarm tap water to clean the application site.

OBSERVATIONS
Viability/Mortality: Daily from acclimatization of the animals to the termination of test.
Clinical signs: Daily from acclimatization of the animals to the termination of test.
Body weights: At start of acclimatization, on the day of application and at termination of observation.

SCORING SYSTEM:
The skin reaction was assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004 approximately 1, 24, 48 and 72 hours, as well as 7, 10 and 14 days after the removal of the dressing, gauze patch and test item. To allow further examination of the test sites two animals were re-clipped on completion of the 24 hour examination. If evident, corrosive or staining properties of the test item were described and recorded.

Grading of Skin Reactions
ERYTHEMA AND ESCHAR FORMATION
No erythema..................................................................................................................................... 0
Very slight erythema.......................................................................................................................... 1
Well-defined erythema....................................................................................................................... 2
Moderate to severe erythema.............................................................................................................. 3
Severe erythema (beet redness) or eschar formation (injuries in depth preventing erythema) reading.......... 4

OEDEMA FORMATION
No oedema........................................................................................................................... 0
Very slight oedema (barely perceptible)................................................................................... 1
Slight oedema (edges of area well-defined by definite raising)..................................................... 2
Moderate oedema (edges raised approximately 1 mm).............................................................. 3
Severe oedema (raised more than 1 mm and extending beyond the area of exposure) ..................4

Irritation parameter:

erythema score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0.11

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

- Very slight erythema was noted in the male animal one hour after application and in one female at the 24-hour reading. With the exception of staining, no abnormal findings were observed on the treated skin of any animal 48 hours after treatment.
- Neither alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

- Slight to moderate red staining of the treated skin produced by the test item was observed from the 1-hour to the 72-hour reading in all animals and persisted up to the 10-day examination in one female.
- No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.
- The body weights of all rabbits were considered to be within the normal range of variability.

Interpretation of results:

GHS criteria not met

Conclusions:

Test substance is considered to be not irritating or corrosive to the rabbit skin.

Executive summary:

In a GLP-compliant skin irritation study, performed according to OECD guideline 404, the test substance (moistened, 0.5 g) was applied, semi-occlusive, to the skin of three New Zealand White rabbits for 4 hours. After 4 hours, the dressing was removed and the skin was flushed with lukewarm tap water and observations were made for an additional 14 days. The test substance showed an 24/48/72h edema score of 0 and erythema score of 0.11 which was reversible within 48h. Slight red staining was observed on all animals up to 10 days after treatment. No corrosive effects were noted. Also no other clinical signs of test item related effects were observed. Under the conditions of this experiment, the test substance was found to be not irritating or corrosive.

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:

Experiment start date - 01 February 2005; Experiment end date - 01 March 2005; Study completion date - 23 March 2005.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

RCC Ltd., Toxicology, Wölferstrasse 4, CH-4414 Füllinsdorf / Switzerland

Specific details on test material used for the study:

Identity: FAT 40819/A
Description: Red brown powder
Batch number: Red ROE 420 BOP 01/04
Purity: approx. 77 %
Stability of test item: Stable under storage condition
Expiry date: 02 November 2009
Stability of test item dilution: Stable in PEG 300 for at least 7 days at room temperature
Storage conditions: At room temperature.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories France, BP 0109, F-69592 L'Arbresle
- Age at treatment: 13 weeks
- Bodyweight at treatment: 2280-2435 g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd, Füllinsdorf) and haysticks 4642 (batch no. 38/04, Provimi Kliba AG) were provided for gnawing.
- Diet: Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 68/04 and 93/04) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.
- Water: Community tap water from Füllinsdorf, ad libitum.
- Acclimation period: Under laboratory conditions after health examination. Only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.1 g

Duration of treatment / exposure:

21 days

Observation period (in vivo):

up to 21 days

Number of animals or in vitro replicates:

1 male, 2 females

Details on study design:

TREATMENT:
The eyes of the animals were examined one day prior to test item administration. Animals with overt signs of ocular injury or irritation which may have interfered with the interpretation of the results were not used in the test. On the day of treatment, 0.1 g of FAT 40819/A was placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of test item. The right eye remained untreated and served as the reference control. The treated eyes were not rinsed after instillation.

OBSERVATIONS:
Viability/Mortality: Daily from acclimatization of the animals to the termination of test.
Clinical signs: Daily from acclimatization of the animals to the termination of test.
Body weights: At start of acclimatization, on the day of application and at termination of observation.

SCORING SYSTEM:
The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 2004/73/EC, April 29, 2004 at approximately 1, 24, 48 and 72 hours, as well as 7, 10, 14, 17, and 21 days after instillation. When present, corrosion and/or staining of conjunctivae, sclerae and cornea by the test item were recorded and reported.

CORNEA
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity.................................................................................................................................... 0
Scattered or diffuse areas of opacity (other than slight dulling of normal luster), 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

IRIS
Normal,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)............................................................................................. 1
No reaction to light, hemorrhage, gross destruction (any or all of these).................................................................... 2

CONJUNCTIVAE
Redness (refers to most severe reading of palpebral and bulbar conjunctivae when compared with control eye) Blood vessels normal.. 0
Some blood vessels definitely hyperemic (injected)...................................................................................................................... 1
Diffuse, crimson color, individual vessels not easily discernible...................................................................................................... 2
Diffuse beefy red........................................................................................................................................................................ 3

Chemosis: lids and/or nictitating membranes
No swelling.................................................................................................................................................. 0
Any swelling above normal (including 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................................................................................................................................................. 0
Any amount different to normal (does not include small amount observed in inner canthus of normal animal).......... 1
Discharge with moistening of the lids and hairs just adjacent to the lids.............................................................. 2
Discharge with moistening of the lids and hairs, and a considerable area around the eye (running)......................... 3

Note: Reddening of the sclerae will be assessed using the same scoring grades as conjunctivae.

TOOL USED TO ASSESS SCORE:
Eye examinations were made with a Varta Cliptrix diagnostic-lamp (Roth AG, CH-4153 Reinach/Switzerland).

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

1

Max. score:

3

Remarks on result:

other: Only two animals could be evaluated due to swelling of the conjunctivae in the other animal.

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

3 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

- The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity and iris were 0.00 for all three animals. The individual mean scores for the conjunctivae were 1.00 for reddening and 0.00 for chemosis for all animals, respectively. No abnormal findings were observed in the iris of any animal at any of the measurement intervals. Very slight corneal opacity affecting the whole area which was attributed to staining produced by the test item was observed in one animal one hour after treatment. In one animal, reddening of the conjunctivae was not assessable one hour after treatment and at the observation performed 17 days after treatment due to marked swelling and due to staining produced by the test item, respectively. Slight reddening of the conjunctivae was noted in the remaining two animals at the 1-hour observation and in all animals from the 24-hour to the 72-hour examination. Additionally, slight reddening was noted in one animal at the readings 7, 10 and 17 days after treatment and in one further animal 10 days after treatment. Slight swelling to marked swelling with half-closed lids (chemosis) of the conjunctivae was observed one hour after treatment in all animals. Reddening of the sclerae was not assessable due to staining produced by the test item in all animals one hour after treatment, in two of these animals from the 24-hour reading to the 10-day examination and at the 17-day examination as well as in one animal at the observations performed 14 and 21 days after treatment. When assessable, no reddening of the sclerae was present. Slight to moderate ocular discharge with moistening of the lids and hair just adjacent to the lids was noted one hour after treatment in all animals. With the exception of staining produced by the test item no abnormal findings were observed in the treated eye of any animal 21 days after treatment, the end of the observation period for all animals.
- No corrosion of the cornea was observed at any of the reading times.

Other effects:

- Marked red staining of the treated eyes produced by the test item was observed in all animals one hour after treatment and persisted up to test day 10 or 21 in two animals. Slight red staining persisted up to the 72-hour reading in the third animal and was observed from the 14- to 21-day examination in one animal. Red remnants of the test item were observed in the eye or conjunctival sac of one animal 1 hour after treatment.
- No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred. One animal screamed after the application.
- The body weights of all rabbits were considered to be within the normal range of variability.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

The test substance causes irreversible effects on the eye.

Executive summary:

In a GLP-compliant eye irritation study, performed according to OECD guideline 405, test substance (0.1 g) was placed in the conjunctional sac of the left eye of 3 New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7, 10, 14, 17, and 21 days after test item instillation. The instillation of the test substance into the eye resulted in mild to moderate and early-onset ocular changes, such as corneal opacity, reddening of the conjunctivae, discharge and chemosis. Slight to marked staining of the treated eyes produced by the test item was observed in all animals from the 1- to 72-hour examination and persisted up to the observation 21 days after treatment in two animals. The mean 24/48/72 h for corneal opacity, iris, conjunctivae, chemosis scores were 0, 0, 1, 0, respectively. With the exception of the staining, these effects were reversible and were no longer evident 21 days after treatment, the end of the observation period for all animals. No abnormal findings were observed in the iris of any animal at any of the examinations, no corrosion was observed at any of the measuring intervals and no clinical signs were observed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In a GLP-compliant skin irritation study, performed according to OECD guideline 404, the test substance (moistened, 0.5 g) was applied, semi-occlusive, to the skin of three New Zealand White rabbits for 4 hours. After 4 hours, the dressing was removed and the skin was flushed with lukewarm tap water and observations were made for an additional 14 days. The test substance showed an 24/48/72 h edema score of 0 and erythema score of 0.11 which was reversible within 48 h. Slight red staining was observed on all animals up to 10 days after treatment. No corrosive effects were noted. Also no other clinical signs of test item related effects were observed. Under the conditions of this experiment, the test substance was found to be not irritating or corrosive.

 

Eye irritation:

In a GLP-compliant eye irritation study, performed according to OECD guideline 405, test substance (0.1 g) was placed in the conjunctional sac of the left eye of 3 New Zealand White rabbits. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7, 10, 14, 17, and 21 days after test item instillation. The instillation of the test substance into the eye resulted in mild to moderate and early-onset ocular changes, such as corneal opacity, reddening of the conjunctivae, discharge and chemosis. Slight to marked staining of the treated eyes produced by the test item was observed in all animals from the 1- to 72-hour examination and persisted up to the observation 21 days after treatment in two animals. The mean 24/48/72 h for corneal opacity, iris, conjunctivae, chemosis scores were 0, 0, 1, 0, respectively. With the exception of the staining, these effects were reversible and were no longer evident 21 days after treatment, the end of the observation period for all animals. No abnormal findings were observed in the iris of any animal at any of the examinations, no corrosion was observed at any of the measuring intervals and no clinical signs were observed.

Justification for selection of skin irritation / corrosion endpoint:
Only study available.

Justification for selection of eye irritation endpoint:
Only study available.

Effects on eye irritation: corrosive

Justification for classification or non-classification

Based on the findings in the skin irritation study the test substance does not need to be classified according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Based on the findings (staining of the eye at the end of the observation period) in the eye irritation study, the substance needs to be classified with Eye Dam. 1, H318 according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.