Registration Dossier

Administrative data

Description of key information

Not skin irritating.

Not eye 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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Internationally accepted guideline, well documented and scientifically acceptable.
Principles of method if other than guideline:
The procedure used is described in the Proposed Guidelines of the United States Environmental Agency (EPA) § 163.81-5 "Primary dermal irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978.
GLP compliance:
no
Remarks:
Pre GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IVANOVAS, 7964 Kisslegg/Allgäu, Germany and MADOERIN AG, 4414 Füllinsdorf, Switzerland.
- Age at study initiation: adult, age not specified.
- Weight at study initiation: 2 to 3 kg.
- Housing: housed individually in metal cages.
- Diet: ad libitum, standard rabbit food - NAFAG, No. 814, Gossau SG.
- Water: ad libitum.
- Acclimation period: prior to treatment they were adapted to our laboratories for a minimum of 4 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Relative humidity: 55 ± 10 %
- Photoperiod: 10 hours light cycle day.
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded.
Amount / concentration applied:
TEST MATERIAL
- Application: gauze patches of 2.5 x 2.5 cm laden with test substance.
- Amount of test substance: 0.5 ml.
Duration of treatment / exposure:
The dressing were removed after a 24 hours exposure.
Observation period:
7 days
Number of animals:
3 male and 3 female.
Details on study design:
TEST SITE
- Area of exposure: 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.
- Type of wrap if used: the patches were covered with an impermeable material and were fastened to the body of the rabbit with adhesive tape.

SCORING SYSTEM
The skin reaction was appraised upon removal and during an observation period of 7 days on the basis of the following evaluation scheme.

Erythema and Eschar Formation
No erythema: 0
Very slight erythema (barely perceptible): 1
Well defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth): 4
Maximum possible erythema score: 4

Edema Formation
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well defined by definite raising): 2
Moderate edema (raised approximately 1 mm): 3
Severe edema (raised more than 1 mm and extending beyond area of exposure): 4
Maximum possible erythema score: 4
Irritation parameter:
erythema score
Basis:
animal: 6/6
Time point:
other: mean 24, 48 and 72 hours
Score:
< 2.3
Reversibility:
fully reversible
Remarks on result:
other: both intact and abraded skin
Irritation parameter:
edema score
Basis:
animal: 6/6
Time point:
other: mean 24, 48 and 72 hours
Score:
< 2.3
Reversibility:
fully reversible
Remarks on result:
other: both intact and abraded skin
Irritant / corrosive response data:
Test substance was found to cause a minimal irritation when applied to intact and abraded rabbit skin.

Evaluation of the skin reactions

Intact skin

Animal/sex Reaction 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48 and 72 hrs
274 M Erythema 0 0 0 0 0 0
275 M Erythema 0 0 0 0 0 0
276 M Erythema 0 0 0 0 0 0
277 F Erythema 0 0 0 0 0 0
278 F Erythema 0 0 0 0 0 0
279 F Erythema 0 0 0 0 0 0
274 M Oedema 0 0 0 0 0 0
275 M Oedema 0 0 0 0 0 0
276 M Oedema 0 0 0 0 0 0
277 F Oedema 0 0 0 0 0 0
278 F Oedema 0 0 0 0 0 0
279 F Oedema 0 0 0 0 0 0

Abraded skin

Animal/sex Reaction 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48 and 72 hrs
274 M Erythema 0 0 0 0 0 0.00
275 M Erythema 1 1 0 0 0 0.67
276 M Erythema 1 0 0 0 0 0.33
277 F Erythema 1 1 0 0 0 0.67
278 F Erythema 1 1 0 0 0 0.67
279 F Erythema 2 2 1 0 0 1.67
274 M Oedema 0 0 0 0 0 0.00
275 M Oedema 0 0 0 0 0 0.00
276 M Oedema 0 0 0 0 0 0.00
277 F Oedema 0 0 0 0 0 0.00
278 F Oedema 0 0 0 0 0 0.00
279 F Oedema 0 0 0 0 0 0.00
Interpretation of results:
not irritating
Remarks:
Migrated information according to the CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
Non irritating.
Executive summary:

Method

The test was conducted following the procedures described in the Proposed Guidelines of the United States Environmental Agency (EPA) § 163.81 -5 "Primary dermal irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978.

Results

Test substance was found to cause a minimal irritation when applied to intact and abraded rabbit skin.

Conclusion

According to the CLP Regulation (EC 1272/2008), test substance can be classified as non irritating. The mean value scored is less than 2.3 for erythema/eschar and for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal, in both the cases of intact and abraded skin.

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Internationally accepted guideline, well documented and scientifically acceptable.
Principles of method if other than guideline:
Test was conducted according to the Proposed Guidelines of the United States Environmental Protection Agency (EPA) § 163.81-4 "Primary eye irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978.
GLP compliance:
no
Remarks:
Pre GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: IVANOVAS, 7964 Kisslegg/Allgäu, Germany and MADOERIN AG, 4414 Füllinsdorf, Switzerland.
- Age at study initiation: adult, age not specified.
- Weight at study initiation: 2 to 3 kg.
- Housing: housed individually in metal cages.
- Diet: ad libitum, standard rabbit food - NAFAG, No. 814, Gossau SG.
- Water: ad libitum.
- Acclimation period: prior to treatment they were adapted to our laboratories for a minimum of 4 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Relative humidity: 55 ± 10 %
- Photoperiod: 10 hours light cycle day.
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 ml.
- Application: test substance was inserted into the conjunctival sac of the left eye of the rabbits and the lids were gently closed for a few seconds.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
Three males and three females.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: in 3 of the 6 rabbits approximately 30 seconds after treatment the treated eye was flushed with 10 ml of physiological saline.

TOOL USED TO ASSESS SCORE
The eye irritation was appraised with a slit-lamp on day 1, 2, 3, 4 and 7.

SCORING SYSTEM

Cornea
A Opacity-degree of density (area most dense taken for reading)
No opacity: 0
Scattered or diffuse area, details of iris clearly visible: 1
Easily discernible translucent areas, details of iris slightly obscured: 2
Opalescent areas, no details of iris visible, size of pupil barely discernible: 3
Opaque, iris invisible: 4
B Area of cornea involved
One quarter (or less) but not zero: 1
Greater than one quarter, but less than half: 2
Greater than half, but less than three quarters: 3
Greater than three quarters, up to whole area: 4
A x B x 5 Total maximum = 80

Iris
A Values
Normal: 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all 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
A x 5 Total maximum = 10

Conjunctivae
A Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Vessels normal: 0
Vessels definitely injected above normal: 1
More diffuse, deeper crimson red, individual vessels not easily discernible: 2
Diffuse beefy red: 3
B Chemosis
No swelling: 0
Any swelling above normal (includes nictitating membrane): 1
Obvious swelling with partial eversion of lids: 2
Swelling with lids about half closed: 3
Swelling with lids about half closed to completely closed: 4
C Discharge
No discharge: 0
Any amount different from normal (does not include small amounts observed in inner canthus of normal animals): 1
Discharge with moistening of the lids and hairs just adjacent to lids: 2
Discharge with moistening of the lids and hairs, and considerable area around the eye: 3
(A + B + C) x 2 Total maximum = 20
Irritation parameter:
cornea opacity score
Basis:
animal: 6/6
Time point:
other: mean 24, 48, 72 hours
Score:
< 1
Reversibility:
fully reversible
Remarks on result:
other: rinsed and unrinsed eyes
Irritation parameter:
iris score
Basis:
animal: 6/6
Time point:
other: mean 24, 48 and 72 hours
Score:
< 1
Reversibility:
fully reversible
Remarks on result:
other: rinsed and unrinsed eyes
Irritation parameter:
conjunctivae score
Basis:
animal: 6/6
Time point:
other: mean 24, 48 and 72 hours
Score:
< 2
Reversibility:
fully reversible
Remarks on result:
other: rinsed and unrinsed eyes
Irritation parameter:
chemosis score
Basis:
animal: 6/6
Time point:
other: mean 24, 48 and 72 hours
Score:
< 2
Reversibility:
fully reversible
Remarks on result:
other: rinsed and unrinsed eyes
Irritant / corrosive response data:
The substance was found to cause no irritation when applied to the rabbit eye mucosa.

Rabbit eye irritation scores

Animal Eye 24 hrs 48 hrs 72 hrs 4 days 7 days Mean 24, 48, 72 hrs

Cornea

274 eye not rinsed 0 0 0 0 0 0.00
275 eye not rinsed 0 0 0 0 0 0.00
276 eye not rinsed 0 0 0 0 0 0.00
277 rinsed after 30 sec. 0 0 0 0 0 0.00
278 rinsed after 30 sec. 0 0 0 0 0 0.00
279 rinsed after 30 sec. 0 0 0 0 0 0.00

Iritis

274 eye not rinsed 0 0 0 0 0 0.00
275 eye not rinsed 0 0 0 0 0 0.00
276 eye not rinsed 0 0 0 0 0 0.00
277 rinsed after 30 sec. 0 0 0 0 0 0.00
278 rinsed after 30 sec. 0 0 0 0 0 0.00
279 rinsed after 30 sec. 0 0 0 0 0 0.00

Conjunctival redness

274 eye not rinsed 0 0 0 0 0 0.00
275 eye not rinsed 0 0 0 0 0 0.00
276 eye not rinsed 0 0 0 0 0 0.00
277 rinsed after 30 sec. 0 0 0 0 0 0.00
278 rinsed after 30 sec. 0 0 0 0 0 0.00
279 rinsed after 30 sec. 0 0 0 0 0 0.00

Conjunctival chemosis

274 eye not rinsed 0 0 0 0 0 0.00
275 eye not rinsed 0 0 0 0 0 0.00
276 eye not rinsed 0 0 0 0 0 0.00
277 rinsed after 30 sec. 0 0 0 0 0 0.00
278 rinsed after 30 sec. 0 0 0 0 0 0.00
279 rinsed after 30 sec. 0 0 0 0 0 0.00
Interpretation of results:
not irritating
Remarks:
Migrated information according to the CLP Regulation Criteria used for interpretation of results: EU
Conclusions:
Not irritating.
Executive summary:

Method

Test was conducted following the procedure used is described in the Proposed Guidelines of the United States Environmental Protection Agency (EPA) § 163.81-4 "Primary eye irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978.

Results

The substance was found to cause no irritation when applied to the rabbit eye mucosa.

Conclusion

According to the CLP Regulation (EC 1272/2008), the substance can be classified as not irritating, because when applied to the eye of an animal does not produce 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Several studies were performed and presented in this dossier, according to the procedure described in the Proposed Guidelines of the United States Environmental Agency (EPA) § 163.81-5 "Primary dermal irritation study", Federal Register, Vol. 43, No. 163, August 22, 1978 (Pre-GLP). The procedures are well described and the results can be re-evaluated according to the criteria actually used (CLP Regulation (EC 1272/2008)).

Within the whole category eleven over fourteen registered substances were tested and none of the existing tests arisen any concern for skin and eye irritation.

All substances of the category were modelled with OECD Toolbox and the provisional results about skin and eye irritation were calculated for all members. No alerts were reported (see category Justification Report attached to the section 13) for inclusion for any substance.

The substance under registration can be considered not irritant for skin and eye.

Justification for selection of skin irritation / corrosion endpoint:

Several studies with the same reliability agree on the result. The most recent has been taken as a reference.

Justification for selection of eye irritation endpoint:

Several studies with the same reliability agree on the result. The most recent has been taken as a reference.

Justification for classification or non-classification

According to CLP regulation (EC 1272/2008), 3.2 Skin corrosion/irritation section, skin Irritation means the production of reversible damage to the skin following the application of a test substance for up to 4 hours.

In all the studies available, the mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in at least 2 of 3 animals for both erythema/eschar and oedema reactions. Also in the cases in which the reaction scores at 48 hours was not reported, the mean values scored are in all cases reasonably expected to be less than 2.3 for erythema/eschar and for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal.

According to the Regulation EC 1272/2008 (CLP) substances that have the potential to induce reversible eye irritation are classified in Category 2 (irritating to eyes) if, 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 values from gradings at 24, 48 and 72 hours for both rinsed and unrinsed eyes, in all the studies available were 0 in all animals for all the reactions scored, therefore, the substance resulted not irritating.

The available experimental data are adequate for classification and labelling and the results show that the substance does not need to be labelled for eye and skin irritation, according to CLP Regulation (EC 1272/2008).