2-Propenoic acid, 2-propylheptyl ester

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1985-04-02 to 1985-07-18

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP and guideline study with acceptable restrictions. Read across was performed with 2-ethylhexyl acrylate. Please refer to IUCLID section 13 for read across justification.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

Version / remarks:

1981

Deviations:

yes

Remarks:

Food consumption was not recorded, lung tissues were not perfused, and laryngopharynx was not examined.

Principles of method if other than guideline:

The study was conducted according to OECD guideline 413 (1981). Compared to the actual version of the test guideline, validity is restricted in that food consumption was not recorded, lung tissues were not perfused, and laryngopharynx was not examined.

GLP compliance:

yes

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

IUPAC Name:

2-ethylhexyl acrylate

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): 2-ethylhexyl acrylate (CAS: 103-11-7)
- Physical state: liquid
- Analytical purity: 99.7 %
- Substance No.: 85/81
- Stability under test conditions: The stability of the test substance during the study period was assessed by reanalysis (BASF AG, ZHU Report from 02 Sep 1985).
- Storage condition of test material: refrigerator

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, D-7950 Biberach, Germany
- Age at study initiation: approximately 8-weeks old
- Weight at study initiation (mean): male rats: 223 g (213 - 234 g); female rats: 158 g (150 - 164 g)
- Housing: single
- Diet (ad libitum): Kliba Labordiaet Ratte/Maus A 343 10 mm Pellet, Klingentalmuehle AG, CH-4303 Kaiseraugst, ad libitum
- Water (ad libitum): tap water, ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12 h dark / 12 h light

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation chambers (glass/steel inhalation chambers) with a capacity of approx. 1.3 m^3
- Method of holding animals in test chamber: animals in wire cages
- Temperature, humidity in air chamber: 22.8-23.6 °C, 36-41 %

TEST ATMOSPHERE
- Brief description of analytical method used: The test substance concentrations were checked intermittently (10 and 30 ppm) or continuously (100 ppm) by total hydrocarbons analyzers (THCA)/GC/FID.
- Samples taken from breathing zone: yes

EXPOSURE SYSTEM
The test and control animals were exposed to the test substance vapors and control air in a whole-body exposure system, respectively. All air streams, supply air and exhaust air of all test groups were adjusted by air flow meters (rotameters), measured continuously and recorded approximately every 2 hours. The air temperatures in the exposure systems were measured continuously with multipurpose thermometers (Diehl GmbH & Co) and recorded approximately every 2 hours. The pressures in the exposure systems were measured continuously (slanting tube pressure gage) and recorded once a day.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Measured test substance concentrations were within ± 5% of the nominal concentrations (see table below).

Duration of treatment / exposure:

90 days

Frequency of treatment:

6 h/day; 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
10; 30; 100 ppm (corresponding to approx. 0.075; 0.226; 0.753 mg/L)
Basis:
nominal conc.

No. of animals per sex per dose:

Groups of 10 male and 10 female rats per test concentration were exposed to test substance vapors in a whole-body exposure system on 6 hours per day, 5 days per week at 10, 30, and 100 ppm (corresponding to approximately 0.075 mg/L, 0.226 mg/L or 0.753 mg/L).

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale:
In order to obtain preliminary information about the profile of action of 2-EHA vapor, the maximum concentration during the 90-day study was to be within the saturation range of the test substance (estimated by extrapolation of the vapor-pressure curve: T = 20°C; p= 0.13 mbar = 130 ppm). For technical reasons (e.g. condensation phenomena and hence poor reproducibility with slight temperature fluctuations), the maximum concentration which could be reliably maintained under the study conditions was chosen to be 100 ppm. The minimum concentration of 10 ppm was based on the applicable MAK value (maximum occupational exposure concentration) for methyl acrylate (1984). The intermediate concentration was established between these two concentrations as 30 ppm in order to obtain a concentration-response relationships.

- Post-exposure period: none

- Control: An air control with 10 male and 10 female rats was run in parallel.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Mortality and clinical signs were checked each day.


BODY WEIGHT: Yes
- Time schedule for examinations: Body weight determinations were conducted once a week.


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of the animals in the control group and the high dose group were checked with a focusable hand-held slit lamp for changes in the refracting media at the beginning of the pre-flow period (day -8) and at the end of the study (day 83).
- Dose groups that were examined: high-dose, control


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- Anaesthetic used for blood collection: No
- How many animals: 10
- Parameters were examined:
The following hematological examinations were carried out on 10 animals per test group and sex at the end of the exposure period: Hemoglobin, erythrocytes, hematocrit, mean hemoglobin content per erythrocyte, mean cell volume, mean corpuscular hemoglobin concentration, platelets, leukocytes.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the exposure period
- How many animals: 10 animals per test group and sex
- Parameters were examined:
The following clinicochemical examinations were carried out on 10 animals per test group and sex at the end of the exposure period: Total bilirubin, creatinine, urea, sodium, potassium, total protein, glucose, inorganic phosphate, calcium, chloride, triglycerides, cholesterol, albumine, globulins.
The following enzyme activities were determined: - Glutamic-pyruvic transaminase - Alkaline phosphatase - Glutamic-oxalacetic transaminase. Clotting analyses were performed: Prothrombin timne (Hepato Quick's test).


URINALYSIS: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

The animals were sacrificed at the end of the 3-month inhalation period and each animal was necropsied. Histopathologic examination was carried out on 31 organs/tissues of high dose and control animals. The lungs, nasal cavity, thyroid and parathyroid glands, trachea and liver from all animals/all test groups were subjected to histopathology examination.

Statistics:

A T-test according to Williams was performed.

WILLIAMS DA (1971 ). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics 27: 103 - 117
WILLIAMS DA (1972 ). The comparisdn of several dose levels with a zero dose control. Biometrics 28: 519 - 531

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no deaths during the study.

- 100 ppm (0.753 mg/L): Mild lethargy, eyelid closure during exposure.
- 30 ppm (0.226 mg/L): Mild lethargy and eyelid closure during exposure.
- 10 ppm (0.075 mg/L): As compared to control animals, no toxic effects which could be interpreted as being related to the test substance.


BODY WEIGHT AND WEIGHT GAIN
- 100 ppm (0.753 mg/L): Retarded body weight gain in both sexes on determination of the body weight change; retarded body weight gain in male animals only on determination of body weight.
- 30 ppm (0.226 mg/L): Slight retardation in body weight gain of the female animals.
- 10 ppm (0.075 mg/L): As compared to control animals, no toxic effects which could be interpreted as being related to the test substance.


OPHTHALMOSCOPIC EXAMINATION
- 100 ppm (0.753 mg/L): No findings.
- 30 ppm (0.226 mg/L): No findings.
- 10 ppm (0.075 mg/L): No findings.


HAEMATOLOGY
- 100 ppm (0.753 mg/L): No findings.
- 30 ppm (0.226 mg/L): No findings.
- 10 ppm (0.075 mg/L): No findings.


CLINICAL CHEMISTRY
- 100 ppm (0.753 mg/L): Increase in glutamic-pyruvic transaminase activity and alkaline phosphatase activity of female rats; reduction of total proteins in female animals and very slightly in male rats; slightly reduced albumin concentrations in both sexes (not statistically significant); reduction of glucose level in female animals.
- 30 ppm (0.226 mg/L): Reduced total protein and albumin levels in both sexes; only a tendency to a reduction in albumin levels in female animals.
- 10 ppm (0.075 mg/L): As compared to control animals, no toxic effects which could be interpreted as being related to the test substance.


ORGAN WEIGHTS
- 100 ppm (0.753 mg/L): No findings.
- 30 ppm (0.226 mg/L): No findings.
- 10 ppm (0.075 mg/L): No findings.


GROSS PATHOLOGY
- 100 ppm (0.753 mg/L): Reduction in body weight resulted in darker coloration of liver parenchyma with indistinct lobular marking (decrease in liver lipids).
- 30 ppm (0.226 mg/L): No findings.
- 10 ppm (0.075 mg/L): No findings.


HISTOPATHOLOGY: NON-NEOPLASTIC
Nasal cavity:
Degeneration of olfactory mucosa was diagnosed. This degeneration was characterized by a reduction of cellular layers, reduction or loss of apical cytoplasmic structures such as olfactory knobs and microvilli, and by necrosis. Identification of the remaining olfactory mucosa cells was not possible. Occasional mitoses were present.
Level I: Degeneration of olfactory mucosa was diagnosed in all rats of 100 ppm group and in 4 males and 4 females each of 30 ppm group. In 100 ppm group, the degeneration affected the olfactory mucosa diffusely in the dorsal and dorsolateral area, and the severity was mainly moderate. In 30 ppm group, the degeneration affected only small areas of the dorsolateral olfactory mucosa and was minimal in severity.
Level II: Degeneration of olfactory mucosa was diagnosed in all rats of 100 ppm group, 1 male of group 2, 2 males and 1 femaLe of 10 ppm group 1, and 1 male of control group. In 100 ppm group, the degeneration was diffuse (dorsal, dorsolateral), whereas in the other groups, the degeneration was focal. The severity was minimal to marked in 100 ppm group, and mainly minimal in the other groups.
Level III: Degeneration of olfactory mucosa was only diagnosed in one male and one female each of the 100 ppmgroup. The severity was slight.
Level IV: No degeneration of the olfactory mucosa was noted.

Liver
Fatty change, characterized by micro- to macrovesicular hepatocellular fat deposits was diagnosed in rats of all groups including controls.
The fatty change was mainly localized in zones 1 (periportal zone) and 2 (intermediate zone). In 5 males of 30 ppm group and in one male of 100 ppm group, fatty change was noted also in zone 3 (zone surrounding terminal hepatic venule). Generally, the severity of fatty change was higher in males than in females. In females, the severity of fatty change was similar in all groups. In males, the severity of fatty change was less in 100 ppmgroup when compared with the rats of the other groups.

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

0.075 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local effects: degeneration of the olfactory epithelial layer in the cranial part of the nasal cavity

2

Dose descriptor:

LOAEC

Effect level:

0.226 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local effects: degeneration of the olfactory epithelial layer in the cranial part of the nasal cavity

3

Dose descriptor:

NOAEC

Effect level:

0.226 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic effects: Clinical chemistry: elevated activities of transaminase and alkaline phosphatase

4

Dose descriptor:

LOAEC

Effect level:

0.753 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic effects: Clinical chemistry: elevated activities of transaminase and alkaline phosphatase

Target system / organ toxicity

Critical effects observed:

not specified