2-ethylhexyl acrylate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19 Nov 1984 - 19 Feb 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Principles of method if other than guideline:

Since the epicutaneous application of 86.5 and 21 % 2-Ethylhexyl acrylate in a chronic study on male C3H mice had led to the development of papillomas and carcinomas, the present study was conducted in order to investigate whether this was an effect specific to that strain or not.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexyl acrylate

EC Number:

203-080-7

EC Name:

2-ethylhexyl acrylate

Cas Number:

103-11-7

Molecular formula:

C11H20O2

IUPAC Name:

2-ethylhexyl acrylate

Details on test material:

- Test substance: 2-ethylhexyl acrylate
- Chemical name: 2-propenoic acid, 2-ethylhexyl ester
- Analytical Purity: > 99 %
- Impurities: stabilised by means of 15 ppm monomethylhydrochinone

Test animals

Species:

mouse

Strain:

other: C3H and NMRI

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany and Jackson Laboratories, Bar Harbor, USA
- Age at study initiation: 6 weeks
- Housing: single
- Diet (ad libitum): Standard-Haltungsdiaet Nr . 1324 der Fa . Altromin, Lage/Lippe, BRD
- Water (ad libitum): tap water
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1 °C
- Humidity (%): 59 ± 9
- Photoperiod (hrs dark / hrs light): 12 h light : 12 h dark

Administration / exposure

Type of coverage:

open

Vehicle:

acetone

Details on exposure:

Route of Administration: dermal

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Test solutions were prepared once per month. They were analysed at the start and end of the treatment period by gas chromatography.

Duration of treatment / exposure:

3 months

Frequency of treatment:

3 times a week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

4.5 mg/cm² per day (nominal)

Remarks:

21.0 % w/w

Doses / concentrations 2

Dose / conc.:

19.2 mg/cm² per day (nominal)

Remarks:

86.5 % w/w

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: none

Positive control:

no

Examinations

Observations and examinations performed and frequency:

Body weight was determined before test start and then once weekly. Mortality, appearance and behavioural abnormalities were checked twice on workdays and once daily on weekends. Clinical symptoms of intoxication were recorded once daily. Skin changes at the application sites were recorded in detail.

Sacrifice and pathology:

At the end of the 3-month test period all surviving animals were sacrificed and subjected to gross-pathological examination. Animals that had died during the course of the study were also necropsied. The skin areas from the application site and organs which showed abnormalities were fixated in 10 % formalin. Samples from 5 animals/group were examined histopathologically. Three microscopical slices were prepared from every application area and stained with hematoxylin-eosin.

Statistics:

Due to the small number of animals scheduled for histopathlogical examination, no statistical evaluation was performed.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no significant differences in body weight development between control and treatment groups. Concerning general appearance and behaviour there were no abnormalities noted amongst the animals of the treatment groups.
One C3H mouse died during the 7th week of treatment. This death was probably not test substance-related. All other animals survived until the end of the study.

BODY WEIGHT AND WEIGHT GAIN
No abnormalities were reported as compared to the historical control.

GROSS PATHOLOGY (macroscopic skin reactions)
The NMRI mice treated with 21 and 86.5 % solutions of the test material in acetone did not show any skin changes or abnormalities at the application site, except for two high dose animals with slight erythema. In contrast, the C3H mice that had been treated with a 86.5 % solution of the test material in acetone showed eschar formation at the application sites already during the 2nd week of treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
Due to the skin changes that had been observed on 10/10 C3H mice treated with the high dose, the application site of all 10 animals were examined histopathologically. Eschar formation, condensation of the subcutis, and pigment loaded hair follicles were recorded. Epidermal hyperplasia was found in 4/10 C3H mice. The 5 high dose NMRI mice which had also been subjected to necropsy and histopathological examination, showed condensation of the subcutis, but only in one animal eschar formation at the application sites. No epidermal hyperplasia were found. The skin samples of the 5 low dose NMRI mice and the 5 control mice did not reveal any abnormalities upon histopathological examination.

Effect levels

Dose descriptor:

NOAEL

Effect level:

4.5 mg/cm² per day (nominal)

Sex:

male

Basis for effect level:

other: Local skin effects

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In a study on the skin effects of 2-EHA on two mice strains after 3-month epicutaneous application it was shown that skin irritation was more severe in C3H than in NMRI mice (BASF, 1986). 10 male C3H mice and 5 male NMRI mice were administered to 25 µl 2-EHA solution (86.5% 2-EHA in acetone) on the clipped dorsal skin (approximately 1,081 mg/kg bw/day, based on mouse body weight of 20 g) at three days per week, additionally 5 NMRI mice were treated with a 21% solution of 2-EHA in acetone (approximately 262 mg/kg bw/day), 10 male NMRI mice treated with acetone served as controls. Clinical symptoms, mortality and body growth were recorded. Macroscopic skin effects were reported from all C3H mice and five of the NMRI mice of all other groups. Histopathological examinations were restricted to the skin of the application area and of tissues with macroscopic abnormalies of 5 animals of each group.

No other clinical abnormalities other than crust formation in 10/10 C3H mice and reddening in 2/5 NMRI mice at the application site at 2-EHA concentration of 86.5% were observed. Epidermal hyperplasia was found in some C3H mice but not in the NMRI strain at 2-EHA concentrations of 86.5%. A condensation of the subcutis was reported for both strain at this concentration. No clinical or microscopic lesions were observed in NMRI mice treated with 21% 2-EHA and in vehicle control mice. With respect to local effects on the skin, a NOAEL of 25 µl of a solution containing 21% 2-EHA in acetone (170 mg/kg bw/day) administered on three days/week during 3 months was delivered for the NMRI mice. No conclusion on a systemic NOAEL can be drawn from this study.