Registration Dossier

Administrative data

Description of key information

The substance is non irritant to the skin and eye of rabbits.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1980
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hacking & Churchill ltd., Huntingdon, UK.
- Weight at study initiation: 2.9 kg.
- Accommodation: individual cages.
- Diet: ad libitum.
- Water: ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25 °C.
- Humidity: 40 - 60 %.
- Photoperiod: 12 hours light and 12 hours dark.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
no
Amount / concentration applied:
0.5 g test substance.
Duration of treatment / exposure:
4 hours.
Observation period:
14 days.
Number of animals:
3 females.
Details on study design:
TEST SITE
- Area of exposure: ca. 2.5 × 2.5 cm.
- Type of wrap if used: gauze, secured with an elastic, air-permeable adhesive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing: yes.
- Time after start of exposure: 4 hours.

SCORING SYSTEM

Erythema and eschar formation:
0 no erythema
1 very slight erythema (barely perceptible)
2 well-defined erythema
3 moderate to severe erythema
4 severe eythema (beet redness) to slight eschar formation (injuries in depth)

Oedema formation:
0 no oedema
1 very slight oedema (barely perceptible)
2 slight oedema (edges of area well-defined by definite raising)
3 moderate oedema (raised approximately 1 mm)
4 severe oedema (raised more than 1 mm and extending beyond the area of exposure)
Irritation parameter:
erythema score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2.3
Remarks on result:
other: 14-d observation
Irritation parameter:
edema score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2.3
Remarks on result:
other: 14-d observation

animal no. 1h 24h 48h 72h 7d 14d
o. e. o. e. o. e. o. e. o. e. o. e.
1 0 0 0 0 0 0 0 0 0 0 0 0
2 0 0 0 0 0 0 0 0 0 0 0 0
3 - 0 0 0 0 0 0 0 0 0 0 0

o. = oedema

e. = erythema

Interpretation of results:
other: not classified according to the CLP Regulation (EC 1272/2008)
Conclusions:
Under test conditions, the substance is not irritant to the rabbit skin.
Executive summary:

Method

Study in 3 female rabbits by semiocclusive application of test material under a composite patch on clipped skin. Upon a 4 -hour exposure to the test material, patches were removed and the skin was rinsed with water. Observation and scoring at 1h, 24 h, 48 h, 72 h, 7 d and 14 d after application were done based on the Draize scale (1940).

Result

Animals were observed for erythema and oedema. A score was associated to each animal, averaging over results at 24, 48 and 72 hours. None of the animals showed any observable response to treatment throughout the observation period.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
1981
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hacking & Churchill ltd., Huntingdon, UK
- Weight at study initiation: 3.5 kg
- Accommodation: individual cages
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 25 °C
- Humidity: 40 - 60 %
- Photoperiod: 12 hours light and 12 hours dark
Controls:
other: untreated eye used as control
Amount / concentration applied:
0.1 g test substance.
Duration of treatment / exposure:
24 hours.
Number of animals or in vitro replicates:
3 males.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: yes, with physiological solution of NaCl.
- Time after start of exposure: 24 hours.

SCORING SYSTEM: Draize scale for ocular lesions (1944)
Cornea
Degree of opacity (most dense area used)
0 no opacity
1 scattered or diffuse areas, details of iris clearly visible
2 easily discernible translucent area, details of iris slightly obscured
3 opalescent areas, no details of iris visible, size of pupil barely discernible
4 opaque cornea, iris invisible

Area of cornea involved:
1 one quarter or less but not zero
2 greater than one quarter, but less than half
3 greater than half, but less than three quarters
4 greater than three quarters, up to whole area


Iris
0 normal
1 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)
2 no reaction to light, hemorrhage, gross detsruction (any or all of these)


Conjuctivae
Redness (refers to palpebral and bulbar conjuctivae, excluding cornea and iris)
0 vessels normal
1 vessels definitely injected above normal
2 more diffuse, deeper crimson red, individual vessels not easily discernible
3 diffuse beefy red

Chemosis:
0 no swelling
1 any swelling above normal (includes nictitating membranes)
2 obvious swelling with partial eversion of lids
3 swelling with lids about half closed
4 swelling with lids more than half closed

Discharge:
0 no discharge
1 any amount different from normal (does not include small amounts observed in inner canthus of normal animals)
2 discharge with moistening of the lids and hairs just adjacent to lids
3 discharge with moistening of the lids and hairs, and considerable area around the eye

TOOL USED TO ASSESS SCORE: one drop of 1 % fluorescein applied in the eye, then rinse with physiological NaCl solution and examination under UV light.
Irritation parameter:
cornea opacity score
Basis:
animal: 2/3
Time point:
24/48/72 h
Score:
< 1
Reversibility:
fully reversible within: 21 d
Irritation parameter:
cornea opacity score
Basis:
animal: 1/3
Time point:
24/48/72 h
Score:
> 1
Reversibility:
fully reversible within: 21 d
Irritation parameter:
iris score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 1
Reversibility:
fully reversible within: 21 d
Irritation parameter:
conjunctivae score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2
Reversibility:
fully reversible within: 21 d
Irritation parameter:
chemosis score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2
Reversibility:
fully reversible within: 21 d

1h 24h 48h 72h 7d 21d
animal 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3
corneal opacicity 0 0 0 0 1 0 1 2 0 1 2 0 0 2 0 - 0 -
corneal surface 0 0 0 0 3 0 1 2 0 1 2 0 0 4 0 - 0 -
iris 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - 0 -
conjuctivae redness 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - 0 -
chemosis 0 0 0 1 1 1 1 1 0 1 1 1 0 1 0 - 0 -
Interpretation of results:
other: not classified according to the CLP Regulation (EC 1272/2008)
Conclusions:
Under test conditions, the substance is not irritant to the rabbit eye.
Executive summary:

Method

Eye irritation study was conducted in 3 male rabbits by instillation of 0.1 g of test material into one eye (the other eye serves as control). After 24 hours, rinse of eye was done with physiological NaCl solution. Observation and scoring were carried out at 1h, 24 h, 48 h, 72 h, 7 d and 21 d after application, based on the Draize scale (1944).

Result

Animals were observed for corneal opacity, iritis, conjuctival redness and chemosis. A score was associated to each animal at each time point. Evaluation was done averaging over results at 24, 48 and 72 hours and considering reversibility within 21 days. All responses were fully reversible within 21 days.

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

Additional information

Local changes induced by the substance at the site of contact, namely skin and eye, were evaluated irrespective of whether the substance may become systemically available. Skin and eye irritation of the substance were tested on rabbits by topical application and instillation, respectively.

As for the dermal application, no signs of irritation were noted over the observation period.

As for the eye instillation, the key study (1983) reported slight effects on cornea, iris and conjuctivae, which were fully reversible within the 21 -day observation period.

In additions, two more studies were available. The first one (1979) reported effects on eye, still present 7 days after exposure. However, this study does not fulfil current criteria, indeed the eye was not rinsed after instillation and the observation was not continued beyond the 7th day. In the second one (1993), only one rabbit was tested and sacrificed after 48 hours due to evidence of discomfort. No information on rinsing was available.

In the acute inhalation toxicity study in rats (1990), signs of irritation of the respiratory tract were noted upon exposure to high dust concentrations, but not upon exposure to aerosol. It should be outlined that:

- the respirable fraction of particles (size < 3 µm) was 4 % in dust and 61 % in aerosol;

- test substance concentration in dust was higher than in aersol: 5070 mg/m3 vs. 1075 mg/m3.

On these bases, no conclusion could be drawn on the irritation potential of the substance as different outcomes upon exposure to either dust or aerosol might be due to:

- the physical form of the substance, i.e. high respirable fraction in aerosol compared to larger dust particles that may settle on the upper respiratory tract and dry mucous membranes;

- higher concentration in dust.


Justification for classification or non-classification

The substance is not classified according to the CLP Regulation (EC 1272/2008).

As for skin irritation, since all animal tested showed no signs of erythema and oedema over 24, 48 and 72 hours, mean scores were below the threshold for classification, i.e. 2.3.

As for eye irritation, classification was not attributed based on results and reliability of available studies. In the key study, average scores over 24, 48 and 72 hours were below the thresholds for classification, i.e. 1 for cornea and iris, and 2 for conjuctivae redness and chemosis, in at least 2 over 3 tested animals. Moreover, all signs were reversible within 21 days from exposure.

Two further studies of eye irritation were disregarded. One study (1979) was disregarded due to significant differences with respect to current recommendations, in terms of duration of the observation period (7 days instead of 21 days) and of eye rinsing. Both these aspects were expected to influence the outcome. Similarly, a second study (1993) was not included in the assessment, due to the limited number of animals (1 instead of 3), the short duration (sacrifice 48 h after application of the test substance to the eye) and the lack of eye rinse.