Registration Dossier

Administrative data

Description of key information

It is concluded that no skin irritation was caused by the pure test substance in rabbits. No relevant effects were observed when the undiluted test article  was instilled into the eyes of rabbits, supported by a study using 50% solution of the test substance, also showing negative results. 

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:
16-29 May 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant OECD404 guideline study without significant deviations
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Sex, species, strain: male New Zealand White rabbits.
Breeder: Grimaud freres selection S.A.S., La Corbiere, Roussay, France.
Number: three animals were used, as recommended by the international guidelines.
Age/weight: on the day of treatment, the animals were 2 to 4 months old and had a mean body
weight istandard deviation of2.6 i0.1 kg.
Acclimation: at least 5 days before the beginning ofthe study.
Identication: individual metal ear tag.
The conditions in the animal room were set as follows:
. temperature: 18 ± 3° C
. relative humidity: 30 to 70%
. light/dark cycle: 12 h/12 h
. ventilation: approximately 12 cycles/hour ofltered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and led. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were veried and calibrated at regular intervals.
The animals were housed individually in Pajon cages (50 cm x 57 cm x 75 cm).
Each cage was equipped with a food container and a water bottle.
During the study, the animals had free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France). Food was analyzed regularly by the supplier for composition and contaminant levels. Drinking water ltered by a FG Millipore membrane (0.22 micron) was provided ad libitum. Bacteriological and chemical analyses ofwater are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines). No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome ofthe study.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: The untreated skin served as control.
Amount / concentration applied:
Doses of 0.5 mL of the undiluted test item were placed on a dry gauze, which was then applied to an area of approximately 6 cm2 of the anterior left ank (application for 3 minutes), the anterior right ank (application for l hour) or the posterior right ank (application for 4 hours) of the animals. The gauze pad was held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.
The untreated skin served as control. No residual test item was observed on removal ofthe dressing.
Duration of treatment / exposure:
3 minutes on anterior left ank, 1 hour on anterior right ank and 4 hours on posterior right ank
Observation period:
The skin was examined approximately 1 hour, 24, 48 and 72 hours after removal of the dressing. Since there were persistent irritation reactions (dryness) at 72 hours in animal No. 697 (anterior left ank), the observation period was extended up to their complete reversibility (Le. day 14).
Number of animals:
3 male animlas
Details on study design:
Criteria for irritation
A substance or a preparation is considered to be irritating to the skin if, when it is applied to healthy intact animal skin for up to 4 hours, significant inammation is caused and which persists for 24 hours or more after the end of the exposure period.
Criteria for corrosion
A substance or a preparation is considered to be corrosive if, when it is applied to healthy intact animal skin, it produces full thickness destruction of skin tissue on at least one animal during the test for skin irritation, or if the result can be predicted (for example: from strongly acid or alkaline reactions).
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 24 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible
Remarks on result:
other: 4 hours exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 48 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: 4 hours exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: 4 hours exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 24 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: 4 hours exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 48 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: 4 hours exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
of three animals
Time point:
other: 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
other: 4 hours exposure
Irritant / corrosive response data:
A well defined erythema (grade 2) was noted 1 h after removal of patches but reversed to grade 0 within 24 hours in 2 animals and within 48 hours in one animal.
Other effects:
Following 3 minutes exposure dryness of the skin was noted from day 4 up to day 13.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under these experimental conditions, the test item SALICYLATE D'OCTYLE was slightly irritant when applied topically to rabbits. A classification according to CLP/DSD however is not required.
Executive summary:

In this study 3 animals were exposed topically to 2-ethylhexyl salicylate over a period of 3 minutes, 1 hour and 4 hours respectively. One hour following removal of the patches slight erythrema were noted at the sites exposed to 3 minutes and 1 hour wereas the erythema were well-defined (grade 2) where exposed for 4 hours. However, all erythema fully reversed within 24 hours and onyl in one animal following 48 hours. No Edema were recorded in any of the animals at any time. Dryness of skin was noted in one animal following 3 minutes exposure but this fully reversed within 14 days. Thus, the test item was considered non-irritant following the CLP (Regualtion EC No 1272/2008) classification system

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:
May - December 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: valid guideline study performed under GLP
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Breeder: Grimaud frères selection S.A.S., La Corbière, Roussay, France.
Number: three animals were used, as recommended by the international guidelines.
Age/weight: on the day of treatment, the animals were 2 to 4 months old and had a mean body weight ± standard deviation of 2.8 ± 0.1 kg.
Acclimation: at least 5 days before the beginning of the study. Identification: individual metal ear tag.
The conditions in the animal room were set as follows:
• temperature: 18 ± 3 °C
• relative humidity: 30 to 70%
• light/dark cycle: 12 h/12 h
• ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment were verified and calibrated at regular intervals.
The animals were housed individually in Pajon cages (50 cm x 57 cm x 75 cm). Each cage was equipped with a food container and a water bottle.
During the study, the animals had free access to 110C pelleted diet (SAFE, Villemoisson, Epinay-sur-Orge, France).
Food is analyzed regularly by the supplier for composition and contaminant levels. The diet formula is presented in the report.
Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
Bacteriological and chemical analyses of water are performed regularly by external laboratories.
These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines).
No contaminants were known to have been present in the diet or drinking water at levels which may be expected to have interfered with or prejudiced the outcome of the study.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 ml of undiluted test item per eye
Duration of treatment / exposure:
The lower and upper eyelids were held together for about one second to avoid any loss of test item. The right eye, which remained untreated, served as control. The eyes were not rinsed after administration of the test item.
Observation period (in vivo):
The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test item.
The study was ended on day 4 in the absence of persistent ocular reactions.
Number of animals or in vitro replicates:
3 animals in total
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0.6
Max. score:
3
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 1 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0.1
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 1 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Irritant / corrosive response data:
A slight or moderate chemosis (grade 1 or 2) and a slight or moderate redness of the conjunctiva (grade 1 or 2) were observed in all animals on day 1. A slight chemosis was still observed on day 2 in 1/3 animals. Slight redness was noted until day 3 in 2/3 animals. No ocular reactions were observed on day 4.
Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.0 and 0.0 for
chemosis, 0.7, 0.3 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0,
0.0 and 0.0 for corneal opacity.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the experimental conditions, the test item 2-ethylhexyl salicylate (SALICYLATE D'OCTYLE) was slightly irritant when administered by ocular route to rabbits. The criteria for classification according to CLP (regulation EC No 1272/2008) were not met.
Executive summary:

A slight or moderate chemosis and a slight or moderate redness of the conjunctiva were observed in all animals on day 1; A slight chemosis was noted on day 2 in one rabbit and slight redness of the conjunctivae persisted until day 3 in 2 animals. By day 4 all scores were down to zero, indicative of full reversibility. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.3, 0.0 and 0.0 for chemosis, 0.7, 0.3 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. Thus, the substance 2 -ethylhexyl salicyclate is not subject to classification acording to CLP (Regulation EC No 1272/2008).

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In a GLP compliant OECD404 guideline study with rabbits using 99.8% pure 2-ethylhexylsalicylate applied over 3 minutes, 1 hour and 4 hours respectively well-defined erythema were noted directly following removal of the test item but the skin fully recovered within 24 hours (in one animal within 48 hours). No edema were observed at any time. In a second study (Test No. 1989132) the potential primary skin irritation of test article at different concentrations was investigated. Six female rabbits were administered dermally at 4 different concentrations of 100%, 25%, 5% and 1% of test article and a vehicle control on each animal. The mean scores for erythema and edema at 100% test concentration were 2.5 and 1.7, respectively, and not fully reversed within 14-day observation period. The mean scores for erythema and edema at 25% test concentration were 1.7 and 0.9, respectively. The mean score for erythema at 5% test concentration was 0.1, as well as 1% test concentration, and fully reserved within 72 hours. On day 7, edema, erythema and a layer of scales were observed on the test sites of four of the rabbits, treated with 100% test concentration. Scales were seen on the test sites of all the rabbits, treated with 25% test concentration, along with erythema on two rabbits. On day 14, scattered to thick layer of yellow scales were seen on the test sites of five of the rabbits, treated with 100% test concentrations. Scattered scales were seen on the test sites of two of the rabbits, treated with 25% test concentration. However, as the purity of test material was not recorded in the test report and the results do contradict the first study when comparing results for neat substance, the effects seen in this second study may have been attributable to impurities present in the test item and thus this study was disregarded and not used for classification and risk assessment.

Therefore, pure test article is considered to be not a skin irritant under the condition of an OECD404 test protocol according to CLP (Regulation EC No 1272/2008).

Eye irritation:

Two eye irritation studies are available, one testing undiluted material and another supporting study using 50% solution of test item. Under the conditions of the first study using undiluted material (Report No 31722 TAL) , the test item 2-ethylhexyl salicylate (SALICYLATE D'OCTYLE) was slightly irritant when administered by ocular route to rabbits, when 0.1 ml of neat material was applied to rabbit eyes. The criteria for classification according to CLP (regulation EC No 1272/2008) were not met. Another study (Test No. 1989133) was conducted to investigate the primary eye irritant effect of test article in a 50% solution. About 0.1 ml of the diluted test article was placed in the left eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test substance was dropped. The eyes were examined and the grade of ocular reaction was recorded 1 hour later. 24 hour later an examination was performed before and after installation of oculoguttao flouresceini. After the examined the eyes were rinsed with 20 ml of a 0.9% sodium chloride solution. The eyes were also examined 48 and 72 hours after the treatment. Slight reactions of conjunctiva (redness) were seen in one rabbit at the 1- and 24-hour reading. No reactions of the conjunctiva, iris or cornea were observed in any of the rabbits at the 48- and 72-hour readings.

It is concluded that the test article in neat form and as 50% solution did not cause positive eye response in rabbits.


Justification for selection of skin irritation / corrosion endpoint:
OECD TG and GLP compliant study

Justification for selection of eye irritation endpoint:
OECD TG and GLP compliant study, Substance was tested undiluted whereas supportive study only 50% conc. was applied

Justification for classification or non-classification

In an OECD404 guideline study according to GLP the pure test substance (99.8% purity) was found to be non-irritant according to the criteria in CLP (Regulation EC No 1272/2008) and only slight, respectively well-defined, erythema were observed directly after removal of the patches which full reversed within 24 respectively 48 hours. In another primary skin irritation/corrosion test in 6 rabbits with 2-ethylhexyl salicylate, the individual mean of scores 1, 2 and 3 days after treatment were 3.0, 2.0, 1.67, 2.33, 3.0, 3.0 for edema and 2.33, 1.0, 1.3, 1.67, 1.67, 2.33 for erythema. However, in the study report no purity was provided and it cannot be excluded that effects seen were caused by impurities. Thus this study was disregarded for classification and classification is based on the first study with 99.8% purity. Therefore, 2-ethylhexyl salicylate is not to be classified for skin irritation/corrosion according to the criteria laid down in the EU Dangerous Substances Directive (67/548/) and according to the criteria of the EU Classification Labelling and Packaging Regulation (1272/2008/EC).

In guideline-compliant acute eye irritation/corrosion test in rabbits, neat and 50% 2-ethylhexyl salicylate caused no corneal opacity, iridial irritation and no irritation of the conjunctivae consisting chemosis or discharge at levels triggering classification. Therefore, 2-ethylhexyl salicylate does not have to be classified according to the criteria laid down in the EU Dangerous Substances Directive (67/548/) and according to the criteria of the EU Classification Labelling and Packaging Regulation (1272/2008/EC).

No conclusion on classification and labeling regarding respiratory tract irritation can be derived due to lack of data.