Fatty acids, C8-10, oxybis(2-hydroxy-3,1-propanediyl) esters

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

12 Jul - 9 Aug 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

adopted in 1982

Deviations:

yes

Remarks:

no analytical purity reported

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

130905-60-1

EC Number:

603-445-4

Cas Number:

130905-60-1

IUPAC Name:

130905-60-1

Test animals

Species:

rat

Strain:

other: Wistar Albino rats of the Crl: Wi/Br strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga GmbH (Laboratory Animal Breeding), Sulzfeld, Germany
- Age at study initiation: about 6 weeks
- Weight at study initiation: 121-152 g (males); 123-143 g (females)
- Housing: individual in Makrolon type II cages, bedding was produced from pure soft wood, dried, freed from dust and sterilized at 180 °C.
- Diet: “Ssniff R” diet in pellet form (laboratory standard rat diet), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5 ± 1.5
- Humidity (%): 60 ±10
- Air changes (per hr): 16 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test material was diluted with corn oil to give the final concentrations. For this purpose, the test material was heated to about 70°C to liquefy the test article and appropriate amounts were weighed and mixed with corn oil in volume/volume proportions.

VEHICLE
- Concentration in vehicle: 2.0, 20.0 and 50%
- Amount of vehicle (if gavage): 10 mL

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the test material was determined in the vehicle prior to the initiation of the study. In fact a 20% suspension of the test article was analysed at preparation and 2, 4 and 24 hours thereafter.
Analytical results indicated that the dosing suspensions were stable for at least 24 hours.
These analyses provided information on the homogeneity of the test item in suspension as well.
The concentration and identity of the dosing solutions were determined at the start and at the end of the study. All values obtained were in reasonable accordance with the nominal values.

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

once daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.2 other: mL/kg bw/day

Remarks:

actual ingested

Doses / concentrations 2

Dose / conc.:

2 other: mL/kg bw/day

Remarks:

actual ingested

Doses / concentrations 3

Dose / conc.:

5 other: mL/kg bw/day

Remarks:

actual ingested

Doses / concentrations 4

Dose / conc.:

180 mg/kg bw/day (actual dose received)

Doses / concentrations 5

Dose / conc.:

1 800 mg/kg bw/day (actual dose received)

Doses / concentrations 6

Dose / conc.:

4 500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels used in the present study were chosen on the basis of results obtained during a 7-day range finding study. A dosage of 5 mL/kg bw was used and did not cause overt signs of toxicity. On the basis of these results, 5 mL/kg bw was selected as the highest dose in the present study with the purpose to get information on target organ toxicity. The low and mid doses were chosen in order to obtain a clear no adverse effect level.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical observations were conducted daily. Mortality checks were performed twice daily.
- Cage side observations checked in table [animals´ sensory and motor behaviour, coat, body orifices, urine, feces and general health status] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Special clinical examinations were conducted prior to study initiation (week 0) and thereafter on week 2 and 4.

BODY WEIGHT: Yes
- Time schedule for examinations: Measurements of body weight were made at weekly intervals.

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Time schedule for examinations: at weekly intervals
- Food conversion ratio was calculated from the change in weight and the food consumption over the same periods of time: Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: cornea, episcleral vessels, anterior chamber, pupil, lens and, if possible, retina were examined with a slit lamp and an ophthalmoscope fitted with a selection of lenses prior to study initiation (week 0) and thereafter on week 2 and 4.
- Dose groups that were examined: on male and female rats of each test group.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the administration period
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: on male and female rats of each test group
- Parameters examined: erythrocytes (RBC), leukocytes (WBC), thrombocytes, haemoglobin, hematocrit, MCV, MCH and MCHC, differential blood count, reticulocytes, inclusion bodies, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the administration period
- Animals fasted: No
- How many animals: on male and female rats of each test group
- Parameters examined: Glucose, triglyceride, cholesterol, protein (total), albumin, bilirubin (total), creatinine, urea nitrogen (BUN), uric acid, calcium, chloride, inorg. Phosphorus, iron, potassium, sodium, Na/K ratio by statistical evaluation, alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), creatinine kinase (CK), glutamate dehydrogenase (GLDH), AST/ALT ratio by statistical evaluation

URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the administration period
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters examined: color, protein, pH value, glucose, bilirubin, urobilinogen, blood, nitrite, ketones, sediment, specific gravity

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to study initiation (week 0) and thereafter on week 2 and 4.
- Dose groups that were examined: on male and female rats of each test group
- Battery of functions tested: hearing activity (tested by simple noise production)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. All animals were sacrificed at the end of the experimental phase by CO2 asphyxiation. Rapid exsanguination was carried out by cutting the A.carotis. The following organs were examined: cranial, thoracic, abdominal and pelvis cavities.

HISTOPATHOLOGY: Yes. A complete histopathological examination was performed on all male and female animals of control group and high dose group on the following organs: adrenals (2x), heart, kidneys (2x), liver, spleen, prostate.

Other examinations:

The following organ weights were determined: liver, kidneys, adrenals, spleen, prostate gland, uterus, testes (left and right) with epididymides

Statistics:

Statistical analyses were performed separately on data from male and female animals. One or two-factorial analysis of variance was conducted on weight changes and food consumption. Group means were compared by the “Scheffe´” test.
Organ weights were evaluated by analysis of covariance and the mean values were compared by the “Scheffe´” test of covariance.
Values form chemical chemistry and hematology were analysed by analysis of variance with subsequent the “Scheffe´” test of variance.

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):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

significant increase in prostate weight in high dose animals. However, this increase was not attended by any histopathologcal changes.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

HISTOPATHOLOGY
All histopathological findings noted in the study were considered to be unrelated to the administration of the test article.

CLINICAL SIGNS
There were no deviations from normal in any group. All animals showed a healthy habit and behaviour throughout the study.
Reflex, ophthalmoscopic and auditory examinations revealed no findings related to the administration of the test article.
In individual animals the righting reflex was slightly reduced. This finding was attributed to coincidence, since there was no evidence of a dose-relationship.

PRE-TERMINAL DEATHS
No pre-terminal deaths occurred during the test period.

BODY WEIGHT DEVELOPMENT, FOOD CONSUMPTION AND FOOD CONVERSION RATIO
Body weights, food consumption and food conversion ratio were comparable to the controls and there were no significant intergroup differences.

HEMATOLOGY
All mean values were within the limits of the respective normal range. Hence the test article administration did not influence hematology parameters in any group.

CLINICAL CHEMISTRY
Clinical chemistry parameters did not reveal any changes which were connected with test article administration. The only significant difference was a slightly reduced total bilirubin content in high dose male animals compared to the respective control animals. Since this slight decline was without dose-relation and within the limits of the normal range, it is not considered biologically relevant and is attributed to coincidence.

URINALYSIS
The results of urinalysis gave no indication of treatment-related changes in any group. All findings were within the respective normal range and comparable to the controls.

NECROPSY - MACROSCOPIC FINDINGS
There were no macroscopic changes which were connected with test article administration.

ORGAN WEIGHTS
The only significant finding was an increase in prostate weight in high dose males. In amendment to the original study protocol this organ was therefore subjected to histo­ pathological examination.
Since nothing abnormal was found microscopically in this organ, the weight increase of prostates in high dose males may be considered either a coincidental finding or a result of a test article induced load reaction without histopathological manifestation.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 800 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Under the experimental conditions of this study a daily oral administration of 1800 mg/kg bw/day had no adverse effects on rats after 4 weeks

Target system / organ toxicity

Critical effects observed:

no