Registration Dossier

Administrative data

Description of key information

Irritation:
- Skin: irritating (rabbit)
- eye: irritating (rabbit)

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication/ study report which meets basic scientific principles
Remarks:
The detailed protocole description for the Open Application Test was inserted into the study report by mistake. The correct protocole, based on a concurrent study report, is attachede to this endpoint study record for information.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Covered patch test in Rabbit (see attached protocole)
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 9 - 12 weeks
- Housing:individually

Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
0.5 ml of neat substance
Duration of treatment / exposure:
4 hours
Observation period:
4, 24, 48, and 72 hours
(grading for erythema, edema, cracking and scaling)
Number of animals:
8
Details on study design:
- standard controls: geraniol, cyclamen aldehyde, and diethyl phthalate
- statistics: Wilcoxon Matched-Pairs Signed Rank Test
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
177
Reversibility:
not fully reversible within: 72 h

Under the conditions of this study, the test substance caused moderate irritation to rabbit skin.

At 4 hours, produced marginal to distinct erythema and edema in most rabbits;

at 24 hours, the intensity of erythema and edema increased with 5/8 animals also showing marginal cracking;

at 48 hours, the intensity of erythema and edema stabilized and 6/8 animals had marginal to slight cracking with 1/8 animals having marginal scaling and

at 72 hours, 1/8 rabbits showed no erythema or edema; 7/8 had marginal to distinct erythema and edema; 7/8 had marginal to slight cracking and 5/8 had marginal scaling.

The overall irritation score was 177, mean score per site was 22.13, and mean score per site per day was 5.53.

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
Under the conditions of this study, the test substance caused only moderate irritation to rabbit skin.
However, due to the described irritation effects and choosing a conservative approach, methylionone is regarded as irritant to rabbit skin.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The test material is not the full substance (methyl ionone) but the pure main constituent (alpha-isomethyl ionone) from which a read-across is possible. The test material was tested only at 12.5%. Nevertheless, as the substance is classified as eye irritant based on this data, these restrictions are considered acceptable.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Test material (0.1 ml) was instilled into the right eye of 3 albino rabbits with no further treatment. The untreated left eye served as a control. Both eyes were examined every 24 hours for 4 days and on day 7. Scoring was according to the Draize scale for ocular lesions.
GLP compliance:
no
Species:
rabbit
Strain:
other: stated as "albino"
Vehicle:
not specified
Controls:
other: left eye
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): 12.5 %
Duration of treatment / exposure:
single application, substance remains in eye
Observation period (in vivo):
Both eyes were examined every 24 hours for 4 days and on day 7.
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM: acc. Draize scale for ocular lesions
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
>= 2
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
> 1
Max. score:
4
Reversibility:
fully reversible within: 7 d

12.5 %: irritant effects

- intense conjunctival irritation from days 1 to 4 involving chemosis and discharge that cleared by day 7

- no corneal opacity or iris congestion

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
In this eye irritation study, fully reversible irritant effects were observed when a 12.5% solution of alpha-isomethyl ionone (the pure main constituent and structural analogue of methyl ionone) was used.
Due to the clearly described irritation effects, the analogue alpha-isomethyl ionone is regarded as an eye irritant. Choosing a conservative approach, an eye irritating potential is also assumed for the target substance methylionone.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

Irritant effects to skin were evaluated in a study, where eight individually housed  New Zealand White rabbits were topically treated on the clipped dorsum (3-4 days prior to treatment) with 0.5 ml undiluted test substance or standard under a semi-occlusive patch (Quest, 1979). After removal of the patches, the sites were assessed at 4, 24, 48, and 72 hours and graded for erythema, edema, cracking and scaling on a scale ranging from “a” (marginal/very slight) to “h” (severe). The observed effect included marginal to distinct erythema and edema in most rabbits and marginal to slight cracking in seven of eight animals and marginal scaling in five of eight animals after 72 h. Although grades were converted to numerical scores and were used for calculating, only the overall irritation score of 177 was given. The mean score per site was 22.13 and the mean score per site per day was 5.53. However, due to described irritation effects, methylionone could be regarded as irritant to rabbit skin.

As part of a phototoxicity study a preliminary irritation test was performed (Quest, 1982). A total of six males and nine females in groups of five animals were treated with 0.1 ml of 10%, 30% or 100% of methylionone in ethanol, respectively. The solution was applied to clipped skin for 24 h. Skin reactions were assessed for erythema, edema, cracking, scaling, dryness, hemorrhage, ulceration, scabbing and exudation at 3, 6, 24, 48, and 72 hours using a standard 9-point scoring system ranging from “0” (absent) to “9” (missing value). The concentration causing minimal irritation was used for the photoirritation test. Rats were weighed at the beginning and end of the study. Application of 100% resulted in very slight to slight redness and swelling at 3 and 6 hours with intensity increasing to slight at 24 hours and slight to distinct by 72 hours. Although no cracking and scaling was observed until 24 hours, it was very slight and increased to slight to distinct at 48 hours, and was distinct to well developed by 72 hours. Concentration of 30% and 10% showed weaker effects, so that the author chose a concentration of 30% to be used for the main phototoxicity study. Due to the described effect, methylionone could be regarded as irritant to rat skin.

In another study, reading of irritant effects was only performed once after application, so that the found redness in 6/8 animals after the treatment under occlusion for 24 h was not further evaluated (Moreno, 1973).

Eye irritation

Due to the lack of reliable studies regarding irritation to eyes of methylionone, a study with iso-methyl-alpha-ionone (CAS 127 -51 -5), the main constituent of the methyl ionone and structural analogue to all methyl ionone isomers was taken into account. For more information on the basis of the read-across please refer to the read-across justification. In this study, 0.1 ml of a concentration of 12.5 % was instilled into the right eye of 3 albino rabbits with no further treatment while the untreated left eye served as a control. Both eyes were examined every 24 hours for 4 days and on day 7 and scoring was done according to the Draize scale for ocular lesions. No corneal opacity or iris congestion was observed, but intense conjunctival irritation from days 1 to 4 involving chemosis and discharge that cleared by day 7 was noted. Since "intense conjunctival irritation" was stated in reviews by Lapczynski et al. and Belsito et al. it could be assumed that the resulting Draize score was >=2, thus reflecting the irritant effects to eyes. Due to the structural similarity the same result could be expected for methylionone.


Effects on skin irritation/corrosion: irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Due to positive results regarding skin and eye irritancy provided by several studies using rabbits and rats, a classification is deemed necessary for both eye and skin irritancy.