Registration Dossier

Administrative data

Description of key information

The test item did not cause any skin effects in an acute dermal irritating study according OECD test guideline 404.

Several in vivo eye irritation studies with the target substance are available. One conducted according OECD 405 was considered key study. Two studies were disregarded, as the obervation time lasted only 7 days despite the fact that not all effects were reversed. Concsequently, it is not possible to use them for classification according to CLP. Based on the available data and the assessment of the results of the key study, the test substace is classifies "Category 2" irritating to eyes.

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:
1989-08-29 to 1989-09-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS:
- Source: Dr. K. Thomae GmbH Chemisch-pharmazeutscieh Fabrik D-7950 Biberach/Riss
- Acclimatisation period: at least 5 days
- Housing: one animal per cage at 20 ± 3°C, 30-70% relative humidity and 12 hours light cycle day
- Diet: ad libitum Standard rabbit pellet - Nafag No. 814, Gossau, Switzerland
- Water: ad libitum
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5 g of test substance applied
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48, and 72 hours
Number of animals:
3 female rabbits
Details on study design:
TEST SITE
- Area of exposure: 12-16 cm²
- % coverage: full
- Type of wrap if used: covered with aluminum foil (approx. 36 cm2) and held in place with adhesive tape (Isoplast, Isoplast AG, CH-5200 Brugg)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not specified
- Time after start of exposure: 4 hours

SCORING SYSTEM:
- Method of calculation: Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Max. score:
0
Remarks on result:
not determinable
Remarks:
due to colouration of the skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Irritant / corrosive response data:
The indiviual scores are presented in Table 1 (see box "Any other information on results incl. tables"). No erythema scores according to Draize were awarded due to colouration of the skin by the test substance for the first 24 hours. From 48 hours to 72 hours no reactions were observed.

Table 1: Individual skin reaction score

 

Erythema

Edema

Animal number

660/F

CF/TF

954/F

CF/TF

976/F

CF/TF

660/F

CF/TF

954/F

CF/TF

976/F

CF/TF

After 1 h

0/*

0/*

0/*

0/0

0/0

0/0

After 24 h

0/*

0/*

0/*

0/0

0/0

0/0

After 48 h

0/0

0/0

0/0

0/0

0/0

0/0

After 72 h

0/0

0/0

0/0

0/0

0/0

0/0

Mean 24-72 h

0/0#

0/0#

0/0#

0/0

0/0

0/0

 

CF= control flank             TF = test flank

M = male                            F = female

* = dark blue staining   # = mean 48 - 72 hours 

Interpretation of results:
GHS criteria not met
Conclusions:
In the acute dermal irritation/corrosion study according to OECD 404 the test item is considered to be non-irritating to the skin.
Executive summary:

In a primary dermal irritation study, three female New Zealand White rabbits (approx. 12 -14 weeks old, 2160 - 2990 g) were dermally exposed to 0.5 g of the test item on a moistened gauze patch to the shaved flank. Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for 72 hours. Irritation was scored by the method of Draize. In this study, the test item is not a dermal irritant.

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:
1995-07-25 to 1995-09-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Test animals
- Source: Charles River, Stolzenseeweg 32-36 D-88353 Kisslegg
- Number of Animals/test: 1 mal; 2 females
- Age at treatment: 15 weeks
- Bodyweight at start of treatment: 2.7 kg (male); 2.4-2.8 kg (females)
- Acclimatization: 5 days
- Housing: one animal per cage under standardized conditions
- Diet (e.g. ad libitum): ad libitum Kilba 341, Batch no 90/95 rabbit maintenance diet (“Kilba”,Klingentalmühle A, CH-4303 Kaiseraugst)
- Water (e.g. ad libitum): ad libitum, tap-water from Ittingen

Environmental Conditions
- Temperature (°C): 20 ± 3
- Humidity (%): 40-70
- Photoperiod (hrs dark/hrs light): 12/12, music during light period
- Air changes per hour: 10-15
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
0.1 g test substance
Observation period (in vivo):
examination after 1 h, 24h, 48h, 72 h, 7 days and 14 days
Number of animals or in vitro replicates:
1 male, 2 females
Details on study design:
Treatment:
The eyes of the animals were examined for intactness once, one day prior to test article administration. Only those animals with no signs of ocular injury or irritation were used on the test.
On the test day, 0.1 g of the test article (undiluted) 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 gently held together for about one second to prevent loss of the test article. The right eye remained untreated and served as the reference control.
In case of equivocal results when comparing the treated and untreated eyes, the illustration guide from the Consumer Product Safety Commission Washington, D.C. 20207 was used for additional control purposes (Washington, 1977).
Irritation Scores:
The eyes of each animal were examined for ocular irritation approximately 1, 24, 48, and 72 hours, as well as 7 and 14 days after administration. Any findings ascertained during examination were recorded and the numerical irritation scores were assigned thereafter based upon the severity of the individual findings. Therefore the description of observed finding may differ slightly from the respective numerical irritation scores.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
mean
Time point:
72 h
Score:
ca. 0.33
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1.89
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
The test article showed a primary irritation score of 4.00, when applied to the conjunctival sac of the rabbit eye. Slight to moderate chemosis and/or reddening of the conjunctivae was noted in all animals, in most cases combined with hyperemia of the scleral blood vessels and discharge. These findings were reversible by day 14 after administration.
At 72 hours after administration a delay/reduction of the iridic light reflex was noted in one rabbit only- Re-examination on day7 revealed no abnormalities.
Blue and/or violet staining of the cornea, conjunctivae and/or sclera was noted up to and including the seventh day after administration. The duration of staining varied between animals and tissues, but was fully reversible in all cases. Staining was no longer evident in any animal (with insignificant exceptions of periocular fur) after 14 days of observation.
A corneal opacity was noted in one rabbit from 24 to 72 hours after administration. This finding was no longer present after seven days. No corrosion (i.e. visible roughening of the epithelium) of the cornea was observed at any of the reading times.

For detailed results see Table 1 (Box: any other information on results, incl. tables)

Table 1: According to EEC Commission Directive 93/21/EEC (April 27, 1993), the mean values of the scored for each type of lesion calculated for each animal separately:

Animal No.

Mean values 24-72- hours

Cornea Opacity

Iris

Conjunctivae Redness

Conjunctivae Chemosis

22, male

0.00

0.00

1.67

1.33

23, female

2.00

0.33

2.00

1.33

24, female

0.00

0.00

2.00

1.33

 

Table 2: Eye irritation scores

 

Animal

sex

 

Cornea opacity

Iris

Conjunctivae

Redness

Conjunctivae

Chemosis

Cumul. Score

Mean Cumul. Score

1 hour

22

M

Not rinsed

0

0

-

2*

2

2.00

23

F

Not rinsed

0

0

-

2*

2

24

F

Not rinsed

0

0

-

2*

2

24 hours

22

M

Not rinsed

0

0

2*

2*

4

4.67

23

F

Not rinsed

2*

0

2*

2*

6

24

F

Not rinsed

0

0

2*

2*

4

48 hours

22

M

Not rinsed

0

0

2*

1

3

3.67

23

F

Not rinsed

2*

0

2*

1

5

24

F

Not rinsed

0

0

2*

1

3

72 hours

22

M

Not rinsed

0

0

1

1

2

3.67

23

F

Not rinsed

2*

1*

2*

1

6

24

F

Not rinsed

0

0

2*

1

3

7 days

22

M

Not rinsed

0

0

1

1

2

2.00

23

F

Not rinsed

0

0

1

1

2

24

F

Not rinsed

0

0

1

1

2

14 days

22

M

Not rinsed

0

0

0

0

0

0.00

23

F

Not rinsed

0

0

0

0

0

24

F

Not rinsed

0

0

0

0

0

* Positive effect

- Could not be assessed. Strong reaction to treatment may preclude evaluation of some parameters. Therefore the primary irritation score may differ from the mean cumulative score at 24, 48, and 72 hours

M male

F female

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Based on the fully reversibility of the staining and other relvant findings and the conjunctival redness score of 2 in two of the three rabbits, the test material is classified as "Category 2" (irritating to eyes).
Executive summary:

In a primary eye irritation study according to OECD 405, 0.1 g of the test substance was instilled into the conjunctival sac of the left eye of 3 young adult New Zealand White rabbits (1 male/ 2 females). The treated eyes were not rinsed after application. Scoring of irritation effects was performed approximately 1, 24, 48 and 72 hours, as well as 7 and 14 days after test article application. Irritation was scored by the method of Draize. The scores of each animal at 24, 48 and 72 hours were used for calculating the respective mean values for each type of lesion. The primary irritation score was calculated by totalling the individual cumulative scores at 24, 48, and 72 hours and then dividing the resulting total by the number of figures. It was found to be 4.00 (max.13). Chemosis and/or reddening of the conjunctivae, hyperemia of the scleral blood vessels and discharge were reversible by day 14 after administration.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The test item did not cause any skin effects in acute dermal irritating studies according to OECD test guideline 404. Therefore, the target substance does not warrant classification for skin irritation. Based on the available data from a suitable in vivo eye irritation studies with the target substance classification for eye irritation Category 2 is warranted.