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Description of key information

Acute oral toxicity (OECD TG 401), LD50 = 540 mg/kg bw

Acute dermal toxicity (OECD TG 402), LD50 > 1000 mg/kg bw.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Principles of method if other than guideline:
Groups of 5 male Sherman rats were administered doses of 126, 252, 500, 1000, and 2000 mg/kg bw by gavage. The animals were observed for lethality, changes in general appearance and demeanor and body weight gain during a 14-day post-exposure period.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sherman
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Fasting period before study: yes

ENVIRONMENTAL CONDITIONS
no details
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 10 %
Doses:
126, 252, 500, 1000, and 2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: no data
- Other examinations performed: clinical signs, body weight
Statistics:
Weil CS (1952). Biometrics 8: 249-263
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
540 mg/kg bw
95% CL:
>= 390 - <= 750
Mortality:
At the highest dose of 2000 mg/kg bw 5/5 rats died within 2-24 hrs after dosing. At the doses of 1000 and 500 mg/kg bw 2/5 rats died within 24 hrs after administration. At the two lower doses of 252 and 126 mg/kg bw, no mortality occurred.
Clinical signs:
No changes in general appearance and demeanor were observed among any of the surviving animals.
Body weight:
Except for one animal dosed with 126 mg/kg and one with 252 mg/kg bw all animals surviving until the termination of the study displayed body weight gains.
Interpretation of results:
Category 4 based on GHS criteria
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
540 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2-Hydroxyethyl acrylate
- Analytical purity: 99.1 area % (GC)
- Lot/batch No.: Beh. 11, 15 :30
- Substance No.: 98/184-1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG
- Strain: Wistar / chbb: thom (SPF)
- Age at study initiation: young adult animals
- Weight at study initiation: 200 g - 300 g (± 20 % of the mean weight)
- Fasting period before study: no fasting
- Housing: single housing
- Diet (ad libitum): Labordiaet, Klingentalmuehle AG, Kaiseraugst, Switzerland
- Water (ad libitum): tap water
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 % relative humidity
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
olive oil
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal and dorsolateral parts of the trunk (clipped)
- Application area: 50 cm2 (corresponds to at least 10 % of the body surface area)
- Type of wrap if used: The bandage consisted of four layers absorbent gauze, Ph. Eur. Lohmann GmbH & Co. KG and Fixomull stretch (adhesive
fleece), Beiersdorf AG


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with warm water
- Time after start of exposure: 24 hrs


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.36 mL/kg bw (undiluted, 400 mg/kg bw) and as an emulsion 4.0 mL/kg bw (1000 mg/kg bw)
- Concentration (if solution): 25 g / 100 mL (dose: 1000 mg/kg bw)
- Constant volume or concentration used: yes/no



VEHICLE
- Amount(s) applied (volume or weight with unit): 4.0 mL/kg bw emulsion
- Lot/batch no.: DAB 10
Duration of exposure:
24 hrs
Doses:
400 and 1000 mg/kg bw
No. of animals per sex per dose:
400 mg/kg bw: 5 males, 5 females; 1000 mg/kg bw: 5 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual body weights were determined shortly before application (day 0), weekly thereafter and at the end of the study (before fasting period). Recording of signs and symptoms was performed several times on the day of administration, and at least once each workday for the individual animals. A check for any dead or moribund animal was made twice each workday and once on saturdays, sundays and on public holidays.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology, scoring of skin findings according to Draize JH (1959) (Appraisal of the safety of chemicals in foods, drugs and cosmetics. The association of food and drug officials of the United States Austin, Texas)
Statistics:
no data
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Mortality:
No mortality occurred.
Clinical signs:
No systemic signs of toxicity were noted in any animals.
Body weight:
The expected body weight gain was observed in the course of the study with the exception of 2 male animals of the 1000 mg/kg bw dose group and 2 female rats of the 400 mg/kg bw dose group, which showed weight reduction in the first week of observation.
Gross pathology:
Necropsy findings noted in the animals sacrificed at the end of the study comprised: focal lesion with incrusted surface of the skin (400 mg/kg bw), lesion or necrosis of the skin in the region of application area (1000 mg/kg bw). Histopathological examination of 1 animal of the 1000 mg/kg bw dose group revealed focal necrosis (full thickness necrosis), perifocal hyperplasia, squamous cell and perifocal inflammation.
Other findings:
- Local skin findings: The following local effects, observed in the 400 and 1000 mg/kg bw dose groups comprised very slight, well-defined and moderate to severe erythema, very slight, slight and moderate edema, scaling, severe scaling, crust formation, bleeding (in some cases extending beyond the area of exposure), petechiae extending beyond the area of exposure, ulcer, alopecia, erosion and eczematoid skin change (in one case extending beyond the area of exposure). Visual necrosis was observed in 2 female animals of the 400 mg/kg bw dose group and in 4 male animals of the 1000 mg/kg bw dose group.

Under the conditions of this study the acute dermal median lethal dose (LD50) of 2 -Hydroxyethyl acrylate was found to be greater than 1000 mg/kg body weight for the male animals. Due to animal welfare reason (necrosis of the skin) the other sex was not tested. In a study performed in parallel with the similar test substance Hydroxypropyl acrylate (Project-No. 11A0185/981043) no mortality occurred after application of 1000 mg/kg body weight to 5 female animals. Therefore the acute dermal median lethal dose (LD50) of 2 -Hydroxyethyl acrylate is considered to be greater than 1000 mg/kg body weight for the male and female animals.

Body weights [g]:

Dose [mg/kg bw]

400

1000

male

female

male

Day 0

250

230

270

Day 7

270

232

273

Day 13

302

248

305

Interpretation of results:
Category 4 based on GHS criteria
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
Please see for more information the read-across justification in Section 13.
Reason / purpose:
read-across source
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 mg/kg bw
Remarks on result:
other: Result read-across CAS 25584-83-2
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
1 000 mg/kg bw

Additional information

Oral exposure route:

There are several valid studies available that are acceptable for assessing the acute oral toxicity of 2-hydroxyethyl acrylate in rats.

The key acute toxicity oral study was performed with Sherman rats (Dow Chem. Co., 1980). Groups of 5 male Sherman rats were administered doses of 126, 252, 500, 1000, and 2000 mg/kg bw by gavage. The animals were observed for lethality, changes in general appearance and demeanor and body weight gain during a 14-day post-exposure period. No data were given concerning clinical signs or necropsy findings and LD50 was determined to be 540 mg/kg bw with 95 % confidence limits of 390 to 750.

In another acute toxicity study conducted by BASF (1974) according to an internal protocol comparable to the OECD TG 401 groups of 5 Sprague-Dawley rats/sex/dose were administered doses of approx. 202, 404, 809, 1137, and 1618 mg/kg bw by gavage and observed for 7 days for lethality and clinical signs of intoxication. The mortality rate was 0/10, 0/10, 3/10, 7/10, and 10/10 in the low, mid and high dose groups, respectively. The LD50 was found to be approx. 960.5 mg/kg bw. Clinical symptoms were unspecific: dyspnoea, slight apathy, closed eyes, and squatting posture. In the surviving animals, reduction of body weight as compared to weights determined at test start was noted. At necropsy acute dilatation of the right heart chamber, acute congestive hyperemia of the heart, and stomach dilatation with distinctly injected vessels were recorded in the deceased animals. The sacrificed animals of the mid dose group showed at necropsy dilatation of the gastro-oesophageal vestibule, adhesion to the peritoneum, and alterations of the epithelium of the glandular stomach (epithelial foldings plump and irregular). These data indicate, that the substance causes local skin damage in the GI-tract due its corrosivity, which might at least partially be responsible for the effects noted (BASF AG, 1974).

Similar LD50 values were observed in three other studies (Union Carbide Corporation (1966), Smyth et al (1951), and The Dow Chemical Company (1962)).

Based on these test results (LD50 > 500 - < 1000 mg/kg bw), 2-hydroxyethyl acrylate is assessed to be of moderate toxicity after a single ingestion, which might be at least partially due to the local tissue damage.

Dermal exposure route:

The key acute dermal toxicity study of the test substance was a GLP-compliant study according to OECD Guideline 402 (BASF, 1999a). A group of 5 male and 5 female Wistar rats (400 mg/kg bw) and a second group of 5 male rats (1000 mg/kg bw) were tested. The test material was applied in undiluted form (400 mg/kg bw) or as an emulsion in olive oil DAB 10 (1000 mg/kg bw) to the clipped epidermis (dorsal and dorsolateral parts of the trunk) of each animal and was covered by a semi-occlusive dressing for 24 hours. No systemic signs of toxicity were noted in all animals. Local effects, observed in the 400 and 1000 mg/kg bw dose groups comprised very slight, well-defined and moderate to severe erythema, very slight, slight and moderate edema, scaling, severe scaling, crust formation, bleeding (in some cases extending beyond the area of exposure), petechiae extending beyond the area of exposure, ulcer, alopecia, erosion and eczematoid skin change (in one case extending beyond the area of exposure). Visual necrosis was observed in 2 female animals of the 400 mg/kg bw dose group and in 4 male animals of the 1000 mg/kg bw dose group. Although the skin barrier was almost completely destroyed under the given test conditions and severe local skin damage was noted, no mortality occurred. Under the conditions of this study the acute dermal median lethal dose (LD50) of 2-hydroxyethyl acrylate was found to be greater than 1000 mg/kg body weight for the male animals. Due to animal welfare reason (necrosis of the skin) the other sex as well as higher doses were not tested.

In a supporting study performed in parallel with the structural analogue hydroxypropyl acrylate (CAS 25584 -83 -2) no mortality occurred after application of 1000 mg/kg body weight to 5 female animals. Therefore the acute dermal median lethal dose (LD50) of 2-hydroxyethyl acrylate is considered to be greater than 1000 mg/kg body weight for the male and female animals (BASF, 1999).

In addition, there are several older studies with 2-HEA conducted in rabbits which demonstrate without exception a higher toxicity of 2-HEA in rabbits in comparison to rats with LD50 values > 50 - < 200 mg/kg bw (Dow Chemical Company 1980 and 1981, BASF 1979, Union Carbide Corporation 1966). However, 2-hydroxyethyl acrylate is a corrosive substance and is classified and labelled as Skin Corrosion Category 1B, H314. More recent experimental experience has shown that rabbits are quite susceptible to stress, e. g. caused by local skin damage due to the application of corrosive substances like 2-HEA. Emotional stress and intense pain can lead to cardiac failure in rabbits. Therefore it is unclear if death was due to stress as a response to severe local effects, or due to systemic toxicity of the compound.

Lethality was also observed after an exposure period of 4 hours in skin irritation studies with rabbits if undiluted material was tested, whereas no systemic effects were noted if a 10 % solution was applied (Dow, Chemical Company, 1980).

However, assumed that bioavailability after dermal application of 2-HEA was 100 % due to damage of the skin barrier a LD50 value comparable to that after oral administration (100 % bioavailability has been demonstrated (BAMM, 1992)) would be expected. Since there are no indications for interspecies differences in the toxicological profile of 2-HEA (as can been seen in the sections for repeated dose toxicity) the lower LD50 values from rabbit studies are assessed to be a secondary reaction due to severe local effects. Moreover, bioavailability after dermal application of non-corrosive test substance concentrations has been shown to be definitively lower than after oral administration (BAMM, 1992).

Although evaluation and classification of a test substance should be based on the most sensitive species, rabbits are assessed to be hypersensitive towards corrosive test substances causing severe skin damage and do not adequately reflect the acute dermal toxicity potential of such substances. Therefore, rabbits are considered to be inappropriate for the evaluation of dermal toxicity of 2-HEA and the respective studies are considered invalid (reliability 3).

In contrast, based on data from rats, even under test conditions at which the skin barrier is compromised and severe local tissue damage is noted, however in the absence of mortality, this species is assessed to be the most appropriate one for the evaluation of acute dermal toxicity of 2-HEA. Furthermore, the rat is one of the recommended test species according to OECD TG 402. It should be noted, that even in rats, the noted effects at necropsy (rather unspecific toxicity) might at least partially due to severe local skin damage caused by 2-HEA.

A retrospective analysis of data from acute oral and dermal toxicity testing, performed on pesticide active substances and new chemical entities has demonstrated that there is a relationship between dermal acute toxicity and oral acute toxicity, and there are no significant numbers of compounds that are classified as a potential hazard only via the dermal route (Creton et al. 2010). Thus, a comparable acute oral and dermal hazard can be expected.

This assessment is supported by data from acrylic acid (AA), one of the main metabolites of 2-HEA. For AA the situation regarding skin effects and acute dermal toxicity is comparable: skin corrosivity and pronounced acute dermal toxicity noted in rabbits based on results with undiluted material. A recently performed acute dermal toxicity study with diluted acrylic acid in rabbits shows however, that all animals survived exposure to the test substance up to the limit dose of 2000 mg/kg bw. At 2000 mg/kg (20% dilution) all animals survived and gained body weight as expected. From Day 1 through Day 14, animals were observed with areas of brown discoloration, blanching, edema, erythema, eschar, fissuring, mechanical damage and/or small areas of necrosis. Besides clear skin damage, no gross abnormalities were noted during the gross necropsy. These results clearly show that the pronounced toxic effects of acrylic acid and in consequence also 2-HEA are due to local corrosion/tissue damage, but not or only to a minor degree due to systemic toxicity (BAMM, 2011).

Inhalation exposure route:

Data on acute toxicity of 2-hydroxyethyl acrylate by the inhalation route are limited. There are several inhalation hazard tests available where groups of rats were exposed to vapour atmospheres saturated with the volatile parts of the substance. In one study groups of 3 rats/sex were exposed for 8 hrs to a vapour atmosphere and observed for a post-exposure period of 7 days. No mortality occurred, clinical signs of toxicity were dyspnoea and irritation of mucous membranes (nose, respiratory tract) (BASF, 1974).

Inhalation exposures to 333 and 394 ppm (corresponding to approx. 1.58 and 1.87 mg/L exceeding by far the saturated vapour concentration, indicating a vapour / aerosol mixture) for 8 and 4 hours respectively caused irritation and were in the threshold area for lethality. In both trials 1/6 rats died within 24 hrs of exposure to a saturated vapour atmosphere (Union Carbide Corporation, 1966a).

A 7-hour exposure to a saturated vapour atmosphere of approx. 300 ppm (corresponding to approx. 1.45 mg/L; exceeding by far the saturated vapour concentration, indicating a vapour / aerosol mixture) at room temperature had no lethal effect on 5 female Sherman rats. No signs of toxicity were observed. In parallel, 5 female rats were exposed to an atmosphere saturated with test substance vapours at 100 °C. 5/5 rats died within 5 hrs of exposure (Dow Chem. Co., 1980). Similar results were observed in another study by The Dow Chemical Company (1962).


Justification for classification or non-classification

Based on the available information the substance is classified as Acute Tox. 4 H302: Harmful if swallowed and Acute Tox. 4 H312: Harmful if in contact with skin, in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.