Registration Dossier

Administrative data

Description of key information

LD50(oral, rat): >5000 mg/kg;
LD50(dermal, rat): >5000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 23, 1990 to March 15, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline test with GLP, well documented
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals and Animal Husbandry
Nine male and nine female Sprague-Dawley strain rats were supplied by Bantin & Kingman Ltd., Aldborough, Hull, U.K. At the start of the main study the males weighed 129 - 148g, and the females 120 - 154g, and were approximately five to eight weeks old. After a minimum acclimatisation period of five days the animals were selected at random and given a unique number within the study by ear punching and a number written on a cage card.
The animals were housed in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding. With the exception of an overnight fast immediately before dosing and for approximately two hours after dosing, free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1 Special Diet Services Limited, Witham, Essex, U.K.) was allowed throughout the study.
Animals and Animal Husbandry (contd)
The animal room was maintained at a temperature of 21 - 23 °C and relative humidity of 39 - 55%. On one occasion the relative humidity was outside the lower limit specified in the protocol (40%). This did not affect the purpose or integrity of the study. The rate of air exchange was approxi- mately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
a single dose: 5000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
a) Range-finding Study
In order to establish a suitable dose level for the main study groups of two rats (one male and one female) were treated once only at levels of 5000, 3000, 1000 and 500 mg/kg. Animals were observed 1 and 4 hours after dosing and then daily for five days.
Individual bodyweights were recorded on the day of dosing to allow calculation of individual treatment volumes. No necropsies were performed.
b) Main Study
A group of ten rats (five males and five females) was dosed as follows in order to confirm the findings of the range-finding study.
All animals were dosed once only by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.
Animals were observed 1 and 4 hours after dosing and subsequently once daily for 14 days. Deaths and evidence of overt toxicity were recorded at each observation.
Individual bodyweights were recorded on the day of treatment (day 0) and on days 7 and 14 or at death.

Statistics:
no data
Preliminary study:
No mortality was observed in the range finding study at doses of 500, 1000, 3000 and 5000 mg/kg bw (observation period 5 days). Using the mortaiity data given above the oral LD50 of the test materiai was considered to be greater than 5000 mg/kg bodyweight. This dose level was therefore used for the main study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No evidence of toxicity related to test article was observed.
Mortality:
There were no deaths.
Clinical signs:
No evidence of systemic toxicity or skin irritation was noted during the study.
Body weight:
No toxicologically significant effects on bodyweight gain were noted during the study period.
Gross pathology:
No abnormalities were noted at necropsy of animals killed at the end of the study.
Other findings:
no data
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 (oral, rat): >5000 mg/kg
Executive summary:

This acute study was performed to determine the acute oral median lethal dose (LD50) of the test material, administered undiluted in the Sprague-Dawley strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals (1981) No. 401 "Acute Oral Toxicity".  Following a range-finding study, a group of ten fasted animals (five males and five females) was given a single oral dose of test material preparation at a dose level of 5000 mg/kg bodyweight. There were no deaths. No evidence of systemic toxicity or skin irritation was noted during the study.  No toxicologically significant effects on bodyweight gain were noted during the study period.   No abnormal ties were noted at necropsy of animals killed at the end of the study.

Therefore, the acute oral median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat, was found to be greater than 5000 mg/kg bodyweight under the condition of this study.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 27, 1990 to March 13, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline test with GLP, detailed information
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals and Animal Husbandry
Five male and five female Sprague-Dawley strain rats were supplied by Bantin & Kingman Ltd., Grimston, Aldborough, Hull, U.K. At the start of the study the males weighed 216 - 227 g, and the females 200 - 213 g and were approximately eight to ten weeks old. After a minimum acclimatisation period of five days the animals were selected at random and given a unique number within the study by ear punching and a number written on a cage card.
The animals were housed in solid-floor polypropylene cages with sawdust bedding and allowed free access to mains drinking water and food (Rat and Mouse Expanded Diet No. 1, Special Diet Services Limited, Witham, Essex, U.K.) throughout the study.

Animals and Animal Husbandry (contd)
The animal room was maintained at a temperature of 21 - 23 °C and relative humidity of 39 - 50%. On one occasion the relative humidity was outside the upper limit specified in the protocol (40%). This did not affect the purpose or integrity of the study. The rate of air exchange was approximately 15 changes per hour and the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
 A group of ten animals (five males and five females), was given a single, 24-hour, semi-occluded dermal application of the test material to intact skin, at a dose level of 5000 mg/kg bodyweight. The appropriate amount of the undiluted test material, as received, was applied uniformly to an area of shorn skin approximating to 10% of the total body surface area using a graduated syringe. A piece of surgical gauze measuring 7 cm x 4 cm was placed over the treatment area and semi-occluded with a piece of self-adhesive bandage (HYPERTIE). The bandage was further secured with a piece of BLENDERM wrapped around each end.
Shortly after dosing the dressings were checked. After the 24-hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test material.
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
Approximately twentyfour hours prior to the commencement of the test the back and flanks of each animal were clipped free of hair using veterinary clippers to expose a skin area of approximately 5 cm x 4 cm.
A single group of animals was treated.
Observations
All animals were observed for overt signs of toxicity and death 1 and 4 hours after dosing and subsequently at least once daily for fourteen days.
Individual bodyweights were recorded on the day of treatment (day 0) and on days seven and fourteen.
All animals were subjected to a gross necropsy examination for any macroscopic abnormalities. No tissues were retained.

Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No adverse effects were observed in test article treated rats.
Mortality:
There were no deaths.
Clinical signs:
No evidence of systemic toxicity or dermal irritation was noted during the study.
Body weight:
Two females showed slight bodyweight loss during the first week. All other animals showed expected gain in bodyweight during the study period.
Gross pathology:
No abnormalities were noted at necropsy of animals killed at the end of the study.
Other findings:
no data
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 (dermal, rat, 24h): > 5000 mg/kg
Executive summary:

This study was performed to assess the acute dermal toxicity of test article with the method described in the OECD Guidelines for Testing of Chemicals (1981) No. 402 "Acute Dermal Toxicity".A group of tenrats (five malesand five females), was given a single, 24-hour, semi-occluded dermal application of the test material tointact skin, at a dose level of 5000 mg/kg bodyweight.  There were no deaths. No evidence of systemic toxicity or dermal irritation was noted during the study. Two females showed slight bodyweight loss during the first week. All other animals showed expected gain in bodyweight during the study period. No abnormalities were noted at necropsy of animals killed at the end of the study.

Therefore, based on the results of this study, the acute dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was considered to be greater than 5000 mg/kg body­weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

An acute oral toxicity study is available selecting the limit dose of 5000 mg/kg in rats based on the results of range-finding assay, which followed OECD guideline.There were no deaths. No evidence of systemic toxicity or skin irritation was noted during the study.No toxicologically significant effects on bodyweight gain were noted during the study period. No abnormal ties were noted at necropsy of animals killed at the end of the study.

In a dermal toxicity study, rats were given a single, 24-hour, semi-occluded dermal application of the test material to intact skin, at a dose level of 5000 mg/kg body weight.There were no deaths. No evidence of systemic toxicity or dermal irritation was noted during the study. Two females showed slight bodyweight loss during the first week. All other animals showed expected gain in bodyweight during the study period.No abnormalities were noted at necropsy of animals killed at the end of the study.

Therefore, based on the results of this study, the acute oral and dermal median lethal dose (LD50) of the test material in the Sprague-Dawley strain rat was considered to be greater than 5000 mg/kg body weight.


Justification for selection of acute toxicity – oral endpoint
Only key study available

Justification for selection of acute toxicity – dermal endpoint
Only key study available

Justification for classification or non-classification

Under the experimental condition, test article failed to cause acute toxicity by oral and dermal application. Therefore, it is concluded that test article is not to be classified according to CLP (Regulation EC No.1272/2008) and DSD (Directive 67/548/EEC).

According to regulation (EC) 1907/2006 Annex XI (weight of evidence), testing for acute inhalation toxicity is not considered to be required, for the following reasons: - 2-ethylhexyl salicylate has a negligible vapour pressure. Thus an acute 4-hour inhalation study would be carried out at the limit dose of 5 mg/L aerosol. Assuming a very conservative value of 100% bioavailability, a rat would receive a systemic dose of 0.8 L/min/kg x 240 min x 5 mg/L aerosol = 960 mg/kg. - Since the acute oral LD50 was higher than this value, it is considered unlikely that mortality would be observed in an acute inhalation study. In the acute oral toxicity study no effects were observed at the limit dose of 5000 mg/kg. - With regard to possible local respiratory effects, 2-ethylhexyl salicylate is not classified for eye irritation and showed no irritation effects on the mucosal membranes of the eyes. Upon occluded application to the skin, 2-ethylhexyl salicylate showed irritative effects to the skin. In conclusion, 2-ethylhexyl salicylate is considered unlikely to exert a relevant local irritative effect on respiratory mucosal membranes. Therefore, performance of an acute inhalation study is considered not necessary for scientific reasons and 2-ethylhexyl salicylate is considered unlikely to exert effects upon inhalation that would require classification according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No. 1272/2008.

2-ethylhexyl salicylate does not have to be classified for specific target organ toxicity – single exposure according to Regulation (EC) No 1272/2008, as no specific toxic effects were observed after acute exposure.