Registration Dossier

Administrative data

Description of key information

Several studies in rabbits were performed to evaluate irritating or corrosive properties of the test material to skin or eyes (OECD guideline 403, 404 and AFDO regulation). Application of the test substance did not provoke skin irritation. Treatment of rabbits eyes caused slight conjuctival irritation. All reaction resolved within 2 days or were below the treshold of regualtion. Therefore, the substance is considered to be 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:
experimental study
Adequacy of study:
key study
Study period:
october 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
7 days post observation period only
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Chemisch pharmazeutische Fabrik Dr. K. Thomae, 88400 Biberach
- Age at study initiation: about 3 - 5 months
- Weight at study initiation: 2.3 - 2.7 kg
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: /

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 ·C
- Humidity (%): 55 ± 20 %
- Photoperiod (hrs dark / hrs light): 12 hours per day
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
other: PEG 400
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g
- Concentration (if solution): pasted with 0.9 ml polyethylene glycol 400

VEHICLE (PEG 400, Riedel-de Häen Ag, Seelze)
- Amount(s) applied (volume or weight with unit): about 1 ml
Duration of treatment / exposure:
4h
Observation period:
30 - 60 minutes, and 24, 48 and 72 hours after removal of the patches
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: dorsal region
- % coverage: 25 cm2
- Type of wrap if used: surgical plaster and semi-occlusive bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after 4h, with luke warm water

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Three days after the application 2 animals showed very slight up to well-defined erythema. The skin surfaces were slightly discolourered, and dry-rough and fine up to coarse scales were noted. Seven days after the application all signs of irritation were reversible.
Interpretation of results:
GHS criteria not met
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 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
7 days post observation period only
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Chemisch pharmazeutische Fabrik Dr. K. Thomae, 88400 Biberach
- Age at study initiation: about 3 - 5 months
- Weight at study initiation: 2.3 - 3 kg
- Housing: singly
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: /

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 °C
- Humidity (%): 55 ± 20 %
- Photoperiod (hrs dark / hrs light): 12 hours per day
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg
Observation period (in vivo):
1, 24, 48 and 72 hours after application
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): 24 hours after application and at all other designated examination times at which the tr ated eyes still showed discharge or at which a corneal examination with fluorescein-sodium solution took place, the treated eyes were washed out thoroughly with physiological saline at approx. 37 °C.

SCORING SYSTEM:

CORNEA

Degree of opacity (most dense area used)

No opacity................................................................ 0
SCattered or diffuse areas, details of iris clearly visible............... 1
Easily discernible translucent areas, details of iris slightly obscured... 2
Op&lescent areas, no details of iris visible, size of pupilbarely di scernib1e. . . . . . . .3
Opaque, iris invisible ...........4

IRIS

Normal ................0
Folds above normal, congestion, swelling, circumcorneal injection
(any of all of these or cOMbination of any thereof); iris still reacting to light (sluggish reaction is positive)......................... 1
No reaction to light, haemorrhage, gross destruction (any or all of these) ................ 2

CONJUNCTIVAE

Redness (refers to palpebral and bulbar coniunctivae)

Blood vessels nomal......... 0
Blood vessels definitely injected above normal............................ 1
More diffuse, deeper crimson red, individual blood vessels not easily discernible..........................2
Diffuse beefy red............................3

Chemosis (refers to palpebral and bylbar conjunctivae)

no swelling..............0
Any swelling bove normal (includes nictitating membran).................. 1
Obvious swelling with partial eversion of lids............................ 2
Swell ing with lids about half closed...................................... 3
Swelling with lids half closed to completely closed....................... 4

Discharge

No discharge............................................................... 0
Any a.ount different from normal (does not include small amounts normally observed in inner canthus) ..........1
Discharge with moistening of the lids and hairs just adjacent to the lids...................2
Discharge with moistening of the lids and hairs, and considerable area around the eye........................................... 3

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
3
Reversibility:
fully reversible within: 2d
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
One hour up to 24 hours after application of the test substance the conjunctiva of the animals showed definitely injected blood vessels and slight swellings. Additionally clear from substance coloured discharge was observed up to one hour after application. Two days after application all signs of irritationes were reversible.
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Procedure and observations

Two key tests each and several supporting studies were performed to evaluate the irritating potential of the test substance to skin and eyes.

In the first, pre-GLP study, six rabbits (3/sex/dose) were each administered a single dose of 0.5 g given as 50% suspension of the test substance onto shaved skin of back and flanks (Ciba 1974). Occlusive application of the test material to intact rabbit skin for 24 hours did not cause any reaction on animals skin.

The second, GLP and OECD guideline study was conducted in 1993 (Hoechst 1993). The test material (0.5g, 50% solution) was applied onto shaved, intact dorsal skin of 6 rabbits (3/sex/dose) for 4h under semi-occlusive conditions. After removal of the test substance effects and symptoms were scored at 0.5, 1, 24, 48 and 72h. Slight erythema formation was observed. All effects resolved fully within 7 days.

In addition, several supporting studies on skin irritation studies are available (Hoechst 1973, 1982 and 1988). In two of these tests the test item did not cause any skin reaction; in a third assay slight erythema were observed. All symptoms resolved within post observation period. All of the supporting studies are described very briefly, include no or only limited data on method and animals or were performed with a mixture of unknown composition. Therefore, these tests are considered as not reliable or not assignable.

To evaluate the eye irritation potential of the test material, six rabbits (3/sex/dose) were each administered a single ocular dose of 100 mg of the test substance and observed for seven days after instillation (Ciba 1974). In half of the animals the eye was rinsed 30 sec after installation, the eyes of the remaining animals were not rinsed. The substance did not cause any effect. Neither swelling, not redness or chemosis were observed.

In a second key study (Hoechst 1993) 0.1 g test material were administrated into the conjunctival sac of one each rabbits eye. The eyes were not rinsed and effects were scored 1, 24, 48 and 72h after application. The single instillation of the test material into the eye of the rabbits elicited slight swelling and injected blood vessels which was not fully reversible within 2 days.

In addition, several supporting studies on eye irritation tests are available (Hoechst 1973, 1982 and 1988). In all of these assays the test substance induced slight sweling and redness. All symptoms resolved latest within 48h.

There are no data available about irritation to the respiratory system.

Discussion

Application of the test substance onto skin did not cause corrosion or irritation. Appllication into the conjunctival sac of the eye caused slight conjuctival irritation which was latest reversible within 2 days and which was below the treshold of regulation.

Justification for classification or non-classification

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 for irritation under Regulation (EC) No. 1272/2008.