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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: 87/302/EWG, Annex, Part B
Deviations:
yes
Remarks:
: lack of details on test substance; lack of urine and neurological examinations.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Fatty acids, C16-18, 2-ethylhexyl esters
EC Number:
292-951-5
EC Name:
Fatty acids, C16-18, 2-ethylhexyl esters
Cas Number:
91031-48-0
Molecular formula:
C24H48O2 to C26H52O2
IUPAC Name:
91031-48-0
Details on test material:
- Name of test material (as cited in study report): 2-Ethylhexylstearat
- CAS-No. of test material (as cited in study report): 91031-48-0
- Physical state: clear liquid
- Analytical purity: no data
- Storage: at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany.
- Age at study initiation: 4 weeks
- Weight at study initiation: males: 53-76 g; females: 50 - 65 g.
- Housing:2-3 animals per Makrolon Type III cage on softwood bedding (ARWI-Center, Essen, Germany).
- Diet (e.g. ad libitum): pelleted Altromin 1324, Altromin, Lage, Germany.
- Water (e.g. ad libitum): tap water
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 48-60
- Air changes (per hr): nodata, 80-490 Lux (the cages were rotated weekly in the rack)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: March 28th, 1989 - April 28th, 1989

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The application volume was 5 mL/kg bw.
The dosing solutions were prepared daily immediately before application.
The total number of applications was 23 or 24 (depending on the day of necropsy).
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, on 5 days per week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 500 and 1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: Additionally 5 male and 5 female animals per dose were dosed with 0 and 1000 mg/kg/d to determine the reversibility of possible compound-related findings (recovery group).
- Post-exposure recovery period in satellite groups: 27 days

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day, 5 days a week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly

WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at study termination
- Dose groups that were examined: control group and highest dose group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: RBC, HCT, MCV, HGB, WBC, PLT, Differential white blood cells

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination
- Animals fasted: No data
- How many animals: all animals
- Parameters checked: Urea, Creatinine, Sodium, Potassium, Glucose, Calcium, ASAT, ALAT, AP, gammaGT, Bilirubin, Chloride, total Protein, total Cholesterol.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

ORGAN WEIGHTS:
Absolute and relative organ weights were determined for the following:
Brain, Testes, heart, liver, spleen, adrenals, kidneys, thymus.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes, animals of the control and highest dose group.
Following organs were examined microscopically:
Aorta thoracica, eyes, large and small intestinum, glandular stomach, cerebrum, urinary bladder, skin, heart, testes, pituitary, cerebellum, liver, trachea, lung, maxillary lymph nodes, mesenterial lymph nodes, spleen, epididymides, adrenal, peripheral nerv, kidney, ovaries, pancreas, prostate, vesicular gland, thymus, salivary gland, oesophagus, sceletal muscle, thymus, uterus, stomach, tongue.
Statistics:
t-tests according to Sachs and Dunnett; steel-test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
All doses applied were tolerated without lethality. No symptoms were noted as compound-related effects.

BODY WEIGHT AND WEIGHT GAIN
The total body weight gain was comparable to control in all male and female test groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The mean food consumption of all groups was comparable to the control.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
The mean water intake of the male groups 2 and 4 showed a slight increase which was not considered to be compound-related.

OPHTHALMOSCOPIC EXAMINATION
The examination of the eyes by slit lamp microscope showed no compound-related effects.

HAEMATOLOGY
The haematological examinations showed no compound-related effects.

CLINICAL CHEMISTRY
The clinical chemistry showed no compound-related effects.

ORGAN WEIGHTS
The absolute and relative organ weights showed no compound-related effects.

GROSS PATHOLOGY
The macroscopical examination of the organs displayed no compound-related effects. Some observations like hydrometra, hydronephrosis,
discolouration of the thymus and one suspicion of hydrocephalus internus (animal No. 67) were considered to be spontaneous.

HISTOPATHOLOGY: NON-NEOPLASTIC
The histological examination of the organs of all groups displayed no compound-related effects.
The histological examination of the organs of the recovery group was not performed, because in the main groups no target organ was evaluated.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
According to the described study, a daily administration of 2-Ethylhexylstearate up to 1000 mg/kg bodyweight for 28 days was not cumulative-systemic toxic to rats. The NOAEL was found to be 1000 mg/kg bw/d.
Executive summary:

2-Ethylhexylstearate was tested for systemic toxicity at repeated doses of 0 (group 1), 100 (group 2), 500 (group 3) and 1000 (group 4) mg/kg body weight. The compound was administered daily by gavage over a period of 28 days. 10 male and 10 female rats were used for each dose. In addition to the groups 1 and 4, 5 male and 5 female animals were used to determine the reversibility of possible compound-related findings (recovery group).

 

All doses applied were tolerated without lethality. No symptoms were noted as compound-related effects. The mean food consumption of all groups was comparable to the control. The mean water intake of the male groups 2 and 4 showed a slight increase which was not considered to be compound-related. The total body weight gain was comparable to control in all male and female test groups. The haematological examinations showed no compound-related effects. The clinical chemistry showed no compound-related effects. The examination of the eyes by slit lamp microscope showed no compound-related effects. The absolute and relative organ weights showed no compound-related effects. The macroscopical examination of the organs displayed no compound-related effects. Some observations like hydrometra, hydronephrosis, discolouration of the thymus and one suspicion of hydrocephalus internus (animal No. 67) were considered to be spontaneous. The histological examination of the organs of all groups displayed no compound-related effects.The histological examination of the organs of the recovery group was not performed, because in the main groups no target organ was evaluated.