Registration Dossier

Administrative data

Description of key information

Skin irritation
The substance was tested in a skin irritation test in rabbits equivalent or similar to OECD 404 guideline. It showed very slight to well-defined erythema 72 hours after patch removal in 7 animals. In one animal the erythema effects were fully reversible within 72 hours. In addition, the substance showed very slight oedema 72 hours after patch removal in 3 animals. In 4 animals the oedema was fully reversible within 48 hours and in 1 animal the erythema was fully reversible within 72 hours, though observations were not continued until day 14 to determine the reversibility of the effects. The scores averaged over 3 days do not indicate skin irritation and in several animals the effects were reversible within 72 hours. Therefore, the substance is not considered to be irritating to skin. Due to relatively low scores the reversibility can be anticipated within 14-day. In addition, the substance has no reactive functional groups. It also has a high log Kow limiting dermal absorption and this absorption is needed for skin irritation further limiting the skin irritation.
Eye irritation
The substance was tested (0.1 mL), in an eye irritation test in rabbits according to OECD 405 guideline. All 4 animals showed very slight redness of the conjunctivae 15 minutes after the substance was installed in the eye. Three rabbits were treated. The treated eyes of all 3 rabbits showed only a slight transient conjunctivitis. The corneas were unaffected by treatment at the 24 hours observation time. The observation period was not continued because of the low eye irritation potential. Although the observations were not performed at the 48 and 72 hours observation times, all animals showed a slight transient effect, disappearing within 24 hours (undiluted). As the substance is a liquid it is not expected to affect the eye later on in time.
Therefore, the substance is considered to be not 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:
May 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed equivalent or similar to OECD 404 guideline, but predating GLP.
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Observations were not continued until day 14 to detemine the reversibility of the effects.
GLP compliance:
no
Remarks:
Study performed around/just before the time GLP was introduced in Europe, but internal QA statement.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: commercial supplier
- Age at study initiation: no data available
- Weight at study initiation: no data available
- Housing: individually
- Diet: free access to pelleted food
- Water: free access to water
- Acclimation period: no data available

ENVIRONMENTAL CONDITIONS
- No data available.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: The untreated skin of each animal serves as its own control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
8
Details on study design:
STUDY DESIGN
The test is designed to investigate the irritant effects of a single application of a substance under semi-occlusive conditions. A standard substance (Geraniol) was applied for comparative purposes; no untreated control animals are used. The untreated skin of each animal serves as its own control.

TEST SITE
Three to four days prior to testing, the dorsal areas of the trunks of the animals were clipped to identify those which are in telogen (non-growth phase of the hair cycle) and which have no skin blemishes. Of these suitable rabbits, at least three and normally eight are selected for the test. A final clipping of the test animals is made approximately 24 hours before testing.

The test substance was applied to the skin of one flank, using a gauze patch of 25x25 mm.

REMOVAL OF TEST SUBSTANCE
Four hours after the application, the patches were removed and excess substance wiped from the skin with a damp tissue.

OBSERVATIONS
- Irritation: The animals were observed for signs of erythema and oedema and the response graded at 30 to 60 minutes, and then at 24, 48 and 72 hours after patch removal.


SCORING SYSTEM:
Dermal irritation is graded and recorded according to the system described in OECD 404. Further observations may be needed, as necessary, to establish reversibility. In addition to the observation of irritation, any serious lesions such as corrosion (irreversible destruction of skin tissue) and other
toxic effects are fully described.
Irritation parameter:
erythema score
Basis:
animal: #1 and #7
Time point:
other: mean of 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
no data
Irritation parameter:
erythema score
Basis:
animal: #2 and #8
Time point:
other: mean of 24, 48 and 72 hours
Score:
1.33
Max. score:
4
Reversibility:
no data
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean of 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
erythema score
Basis:
animal: #4, #5 and #6
Time point:
other: mean of 24, 48 and 72 hours
Score:
1.67
Max. score:
4
Reversibility:
no data
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean of 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean of 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
edema score
Basis:
animal: #3, #5 and #8
Time point:
other: mean of 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal: #4 and #7
Time point:
other: mean of 24, 48 and 72 hours
Score:
1.33
Max. score:
4
Reversibility:
no data
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: mean of 24, 48 and 72 hours
Score:
1.67
Max. score:
4
Reversibility:
no data
Irritant / corrosive response data:
The substance showed very slight to well-defined erythema 72 hours after patch removal in 7 animals. In one animal erythema was fully reversible within 72 hours.
The substance showed very slight oedema 72 hours after patch removal in 3 animals. In 4 animals oedema was fully reversible within 48 hours and in 1 animal the irritation effects were fully reversible within 72 hours.
No data is available after 72 hours. 7 animals still had very slight erythema, in addition 3 of these still had very slight oedema.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The substance was tested in a skin irritation test in rabbits equivalent or similar to OECD 404 guideline and GLP principles. The substance is considered to be not irritating.
Executive summary:

The substance was tested in a skin irritation test in rabbits equivalent or similar to OECD 404 guideline and GLP principles.

The substance showed very slight to well-defined erythema 72 hours after patch removal in 7 animals. In one animal the erythema effects were fully reversible within 72 hours. In addition, the substance showed very slight oedema 72 hours after patch removal in 3 animals. In 4 animals the oedema was fully reversible within 48 hours and in 1 animal the erythema was fully reversible within 72 hours though observations were not continued until day 14 to detemine the reversibility of the effects. The scores averaged over 3 days do not indicate skin irritation and in several animals the effects were reversible within 72 hours. Therefore, the substance is not considered to be irritating to skin. In addition, the substance has no reactive functional groups and it also has a high log Kow limiting dermal absorption and this absorption is needed for skin irritation.

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:
June 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was performed according to OECD 405 guideline, but predating GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
(1987)
Deviations:
yes
Remarks:
no observations at the 48 and 72 hours observation times.
GLP compliance:
no
Remarks:
Study performed around/just before the time GLP was introduced in Europe, but internal QA statement.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: commercial supplier
- Age at study initiation: at least 8 weeks
- Weight at study initiation: 2.29 - 2.76 kg
- Housing: individually housed in cages with wire mesh floors.
- Diet: free access to a certified pelleted commercial rabbit diet
- Water: free access to tap water
- Acclimation period: no data avaiable

ENVIRONMENTAL CONDITIONS
- No data available
Vehicle:
other: Tween 80
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.1 mL
- Concentration (if solution): undiluted and 50% test substance in Tween 80

Duration of treatment / exposure:
One single application.
Observation period (in vivo):
24 hours
Number of animals or in vitro replicates:
4 males
Details on study design:
STUDY DESIGN
Each test substance is applied to one eye of each of a group of rabbits and the subsequent responses assessed by macroscopic observation and by
measurement of corneal swelling. Observations are continued at intervals up to a maximum of 22 days after treatment or, if sooner, until the eyes are
considered to be of normal appearance.

TREATMENT
Only one eye of each animal is treated. Substances are applied to the conjunctival sac formed by gently pulling the lower eyelid away from the eyeball. After treatment the eye is closed and the eyelids released. Initially, each substance to be tested is applied to one rabbit per group.
If, 24 hours later, the responses in these rabbits are not unacceptably high then the remaining rabbits are treated.

REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM:
The eyes are examined with the aid of a hand-held torch. Conjunctival responses are assessed 15 minutes after treatment. Corneal thickness is measured with a slit lamp 24 hours after treatment and thereafter at daily intervals until the thickness has returned to its pretreatment value. Corneal, conjunctival and iridial responses are assessed 24 hours after treatment and thereafter at specified daily intervals up to 22 days after treatment. Assessments are stopped earlier if the eye has returned to normal.
The irritation was assessed according to OECD 405.

Irritation parameter:
cornea opacity score
Basis:
animal: #2, #3 and #4
Time point:
other: 24 hours
Score:
0
Max. score:
4
Remarks on result:
other: undiluted test substance.
Irritation parameter:
iris score
Basis:
animal: #2, #3 and #4
Time point:
other: 24 hours
Score:
0
Max. score:
2
Remarks on result:
other: undiluted test substance.
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
animal: #2, #3 and #4
Time point:
other: 24 hours
Score:
0
Max. score:
3
Remarks on result:
other: undiluted test substance.
Irritation parameter:
chemosis score
Basis:
animal: #2, #3 and #4
Time point:
other: 24 hours
Score:
0
Max. score:
4
Remarks on result:
other: undiluted test substance.
Irritant / corrosive response data:
All 4 animals showed very slight redness of the conjunctivae 15 minutes after the substance was installed in the eye.
50% Karanal in Tween 80: One rabbit was treated. The treated eye subsequently showed a moderate conjunctivitis characterised by marked oedema and slight
erythema. The cornea was unaffected by treatment at the 24 and 48 hours observation time. The conjunctival reaction rapidly lessened in intensity and the effects were fully reversible within 48 hours.
Undiluted Karanal: Three rabbits were treated. The treated eyes of all 3 rabbits showed only a slight transient conjunctivitis. The corneas were unaffected by treatment at the 24 hours observation time.
Remark: When at 24 hours no irritation was observed, no further observations were described.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance was tested in an eye irritation test in rabbits according to OECD 405 guideline. The substance is not considered to be irritating to eyes.
Executive summary:

The substance was tested (0.1 mL) in an eye irritation test in rabbits according to OECD 405 guideline. Three rabbits were treated. The treated eyes of all 3 rabbits showed only a slight transient conjunctivitis. The corneas were unaffected by treatment at the 24 hours observation time. Although the observations were not performed at the 48 and 72 hours observation times, all animals showed a slight transient effect, disappearing within 24 hours. As the substance is a liquid it is not expected to affect the eye later on in time.

Therefore, the substance is not considered to be irritating to eyes.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of skin irritation / corrosion endpoint:
The one study available is sufficiently adequate to cover this endpoint.

Justification for selection of eye irritation endpoint:
The one study available is sufficiently adequate to cover this endpoint.

Justification for classification or non-classification

The substance is not corrosive and based on the average scores after 72 hours of exposure classification is not warranted. The study receives a reliability 2 because reversibility of the effects up to day 14 was not studied, but in several animals full reversibility was already seen after 72 hours. Therefore, the substance is not considered to be irritating to skin and does not have to be classified for this effect in accordance with Regulation EC No. 1272/2008 and Directive 67/548/EEC.

In the key study for eye irritation the substance is considered to be not irritating to eyes and does not have to be classified for eye irritation in accordance with Regulation EC No. 1272/2008 and Directive 67/548/EEC.