Registration Dossier

Administrative data

Description of key information

Limited study reports on irritant properties of the test substance are available. The protocol of the studies differs from the generally accepted OECD 404 and OECD 405 guidelines. Based on the information available it can however be concluded that the test substance is moderately irritant to the skin. The studies with Benzoic acid (EC No. 231-987-8) and Sodium benzoate (EC No. 232-379-5) are considered less suitable for read-across for local skin effects related to the test substance as the test substance is a precursor of both substances and not a metabolite that might be formed after application. The studies with benzoic acid and sodium benzoate cannot exclude irritant properties of the test substance, but provide information that the metabolites that may be formed in the skin are considered to be non-irritant.
For eye irritation existing study as performed by Thyssen has been supplemented by recent lab communications indicating a protocol design similar to OECD 405 was employed. This is suggestive that the substance is at most slightly irritant. Registrants have commissioned new in-vitro eye corrosion/irritation studies to enhance the robustness of data for this endpoint. For the time being the substance is classified as eye damage category 2 on a precautionary basis.

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:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: No guideline followed, very limited report.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The shaved skin of guinea pigs was exposed to undiluted test substance with a gauze pad for 24 hours. The concentration test substance ranged from 5-20 mL/kg.
GLP compliance:
no
Species:
guinea pig
Strain:
not specified
Details on test animals or test system and environmental conditions:
None stated

Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 - 20 mL/kg
- Concentraion: not diluted

No additional data

Duration of treatment / exposure:
24 hours
Observation period:
None stated
Number of animals:
3
Details on study design:
TEST SITE
- Type of wrap if used: gauze pad

No additional data
Irritation parameter:
erythema score
Basis:
other: Described generically as "... up to 3 erythema."
Time point:
24 h
Score:
< 3
Max. score:
3
Reversibility:
not specified
Irritation parameter:
edema score
Basis:
other: Not attributed per animal, generally stated as "Mod.-gross edema..."
Time point:
24 h
Reversibility:
not specified
Remarks on result:
other: 24h score not specified
Irritation parameter:
erythema score
Basis:
animal: 1-3
Time point:
24/48/72 h
Remarks on result:
other: No values were calculated for 24/48/72h
Irritation parameter:
edema score
Basis:
animal: 1-3
Time point:
24/48/72 h
Remarks on result:
other: No values were calculated for 24/48/72h
Irritant / corrosive response data:
Moderate oedema, necrosis, up to 3 erythema were observed.
Eschars in patch area also along top and bottom of patch, some necrosis were observed at 1 week.
2 eschars, little to heavy scarring along top and bottom patch were observed.
Other effects:
There was possibly some evidence of toxic effects caused by skin application since the animals receiving the higher doses gained less weight than the animals receiving the lowest dose.
Additional description states "Eschars in patch area also along top & bottom of patch, some necrosis at 1 week. Secondary eschars, light to heavy scarring along top & bottom patch."
Interpretation of results:
moderately irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance was moderately irritating to the guinea-pig skin in this test.
Executive summary:

The shaved skin of guinea pigs was exposed to undiluted test substance with a gauze pad for 24 hours. The concentration test substance ranged from 5-20 mL/kg.

The test substance was moderately irritating to the guinea-pig skin in this test.

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:
other: Broadly followed OECD guideline, no GLP, very limited report, but supplemented by recent laboratory communications.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Method assignment based upon recent lab communications
Principles of method if other than guideline:
Two animals were dosed with 100 microliter of test substance in the eye and observed for 7 days.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: 3-4 kg

No additional data
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 microliter

No additional data
Duration of treatment / exposure:
Single application, no data on washing.
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
2 animals
Details on study design:
None stated
Irritation parameter:
overall irritation score
Basis:
other: Single page report with summary information only.
Time point:
24 h
Remarks on result:
probability of mild irritation
Remarks:
Described only as "Slightly irritating".
Irritation parameter:
iris score
Basis:
animal: 1-2
Time point:
24/48/72 h
Remarks on result:
other: No value calculated for 24/48/72h
Irritation parameter:
conjunctivae score
Basis:
animal: 1-2
Time point:
24/48/72 h
Remarks on result:
other: No value calculated for 24/48/72h
Irritation parameter:
cornea opacity score
Basis:
animal: 1-2
Time point:
24/48/72 h
Remarks on result:
other: No value calculated for 24/48/72h
Irritation parameter:
chemosis score
Basis:
animal: 1-2
Time point:
24/48/72 h
Remarks on result:
other: No value calculated for 24/48/72h
Irritant / corrosive response data:
Based upon the observation protocol employed at the time the study was run, the substance effects of slight irritation clearly do not warrant eye damage 2 classification. The data are however insufficient to exclude classification with eye damage 2.
Other effects:
Initial - moderate erythema with squealing and slight blinking.
1 hr - slight-moderate erythema of the conjunctiva, lids and nictitating membrane. Some odema of the upper palpebra conjuctiva and nictitating membrane.
24 hrs - rabbit anaemic in appearnce and smells of urine. Iris injected - cornea (anterior portion) hazy. Upper orbital and lower palpebra, nictitating membrane and anterior cornea stained.
48 hrs - only slight erythema of the conjunctiva and nictitating membrane.
Rabbit died on 6th day.
Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance was slightly irritating to the rabbit eye in this test.
Executive summary:

Two animals were dosed with 100 microliter of test substance in the eye and observed for 7 days.

The test substance was slightly irritating to the rabbit eye in this test.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Weight of evidence skin/eye irritation

Skin

For the test substance three limited in vivo studies are available. This concerns one company report (Thyssen, 1979) and one published study (Opdyke 1976 which contains a short summary of a study of Moreno 1973, which cannot be retrieved) and study (Sutton 1963, data from Eastman Kodak). Based on the available summary data in the first two studies the test substance is applied under occlusion, which is not according to the current guidelines, but represents a worst case. Furthermore, in the study (Thyssen, 1979) the substance is applied to the ear and not to the body (application area too small, probably < 6cm2). The exposure is 24h rather than 4h. The outcome is moderately irritating. Based on the evaluation of the study (Thyssen, 1979), taking into account test design and robustness of the study report, it is questionable if this study can fulfill the endpoint. In addition, study (Sutton, 1963) indicate that the test substance is moderately irritating, however, available summary is very concise. Andersen (2006) published a final report on the safety assessment of the test substance. In this report it is stated that the Cosmetic Ingredient Review (CIR) Expert Panel expressed concern regarding the limited irritation data available for the test substance. Therefore, the relevance of benzoic acid data was further evaluated for this endpoint. Available data indicate that benzyl alcohol is metabolized in viable skin to benzoic acid and hippuric acid, catalyzed by alcohol dehydrogenase. This conversion of benzyl alcohol presumably involves the test substance as an intermediate and the well understood conversion of the test substance to benzoic acid, followed by conjugation with glycine to form hippuric acid. However as only part of the exposure of the skin to the test substance actually will result in exposure to benzoic acid it is concluded that irritation data for benzoic acid are less relevant to cover the endpoint for the test substance.

Therefore it is concluded that based on the limited data available on the test substance, the test substance is considered irritating to skin.

Eye

For the test substance, the key eye irritation study is Thyssen 1979. This report has been supplemented by recent lab communications indicating a protocol design similar to OECD 405 was employed. This is suggestive that the substance is at most slightly irritant. Registrants have commissioned new in-vitro eye corrosion/irritation studies to enhance the robustness of data for this endpoint. For the time being the substance is classified as eye damage category 2 on a precautionary basis.

Respiratory irritation

Based on the results of the acute inhalation study with the test substance investigating sensory irritation (Steinhagen 1983) , the test substance should be considered as irritating to the respiratory tract.


Justification for selection of skin irritation / corrosion endpoint:
This study was conducted according to a reliable method using guinea pig.

Justification for selection of eye irritation endpoint:
Broadly followed OECD guideline, no GLP, very limited report, but supplemented by recent laboratory communications.

Effects on skin irritation/corrosion: moderately irritating

Effects on eye irritation: slightly irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

The test substance is classified as a skin irritant (Xi R38 and H315 according to DSD and CLP) based on data available. The test substance is classified as an eye irritant (Xi R36 and H319 according to DSD and CLP, respectively) based on data available. The test substance is classified as irritating for the respiratory system (Xi R37 and H335 according to DSD and CLP, respectively), based on the results of the sensory irritation study in rats (see section 7.2.2); 50% decrease of respiratory rate at 333 ppm (= 1.6 mg/L).