Anhydro-D-glucitol trioleate

Repeated dose toxicity: other routes

Administrative data

Endpoint:

short-term repeated dose toxicity: other route

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given (analytical purity of test substance not specified, intravenous application).

Data source

Reference

Reference Type:

publication

Title:

Study on subacute toxicity of intravenous sorbitan trioleate (STO) in Wistar rats

Author:

Yamamoto, H. et al.

Year:

1983

Bibliographic source:

The Journal of Toxicological Sciences Vol. 8, 301-310

Materials and methods

Principles of method if other than guideline:

Subacute toxicity of the test substance in rats was investigated after intravenous injection of 12.5, 50 and 200 mg/kg bw/d.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Anhydro-D-glucitol trioleate

EC Number:

247-569-3

EC Name:

Anhydro-D-glucitol trioleate

Cas Number:

26266-58-0

Molecular formula:

C60H108O8

IUPAC Name:

1,4-anhydro-2,3,6-tri-O-oleoyl-L-iditol

Details on test material:

- Name of test material (as cited in study report): Sorbitan trioleate
- Physical state: thin yellowish and oily

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5 weeks
- Weight at study initiation: males 106-118 g, females 87-96 g
- Housing: individually
- Diet (ad libitum): commercial diet (Oriental Yeast Co. Ltd)
- Water (ad libitum): tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 10

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: hydrogenated castor oil and distilled water

Details on exposure:

The test compound was injected into the tail vein of rats.

Duration of treatment / exposure:

35 days

Doses / concentrations

Remarks:

Doses / Concentrations:
12.5, 50, 200 mg/kg bw/d

No. of animals per sex per dose:

10

Control animals:

other: animals treated with 0.4 mL/100 g of saline or with 0.4 mL/100 g of 10% HCO-60

Details on study design:

- Dose selection rationale: acute toxicity test with a single intravenous injection of the test substance

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Parameters checked: red and white blood cells, hematocrit, hemoglobin content, platelet count, prothrombin time, reticulocyte count, hemogram

CLINICAL CHEMISTRY: Yes
- Parameters checked: GOT, GPT, Al-pase, BUN, creatinine, total protein, albumin/globulin, glucose, total cholesterol, albumin, sodium, potassium, calcium, chloride

URINALYSIS: Yes
- Parameters checked: pH, protein, glucose, keton body, bilirubin, urobilinogen, occult blood, specific gravity, natrium, potassium, chloride, creatinine, colour, clearness

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all rats were necropsied and the following organs were weighed: brain, pituitary, thyroid, thymus, heart, lung, kidney, spleen, pancreas, liver, adrenal, stomach, intestine, mesenteric lymph node, submaxillary gland, testis, prostate, uterus, ovary, bladder, one marrow, eye ball and tail
HISTOPATHOLOGY: Yes, the following organs were fixed in 10% formalin and embedded in paraffin: brain, pituitary, thyroid, thymus, heart, lung, kidney, spleen, pancreas, liver, adrenal, stomach, intestine, mesenteric lymph node, submaxillary gland, testis, prostate, uterus, ovary, bladder, one marrow, eye ball and tail. The embedded sections were cut in 3-5 µm thick and stained with hematoxylin and eosin, periodic acid-Schiff, elastica Van-Gieseon, azan-Mallory, congo red and oil-red O.

Statistics:

All data were analysed statistically by the Student t-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:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

RBC, Hb and Ht decreased in the 200 mg/kg bw dose group of both sexes compared to controls

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

significant increase of total cholesterol in high dose group and both sexes; some increases and decreases in different parameters, see details on results

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

most prominent effect was an increase in spleen weights in animals of both sexes of the high dose group; some changes in weight of other organs, see details on results

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

changes in spleen and liver were observed in the highest dose group and both sexes

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

major histological changes were observed in the lung, spleen, liver, bone marrow and injection site of the tail

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No abnormalities were observed in the control as well as experimental groups.

BODY WEIGHT AND WEIGHT GAIN
No significant effect.

FOOD CONSUMPTION
No significant effect.

WATER CONSUMPTION
No significant effect.

HAEMATOLOGY
The level of RBC, Hb and Ht decreased in the 200 mg/kg bw dose group of both sexes compared to controls. The values of prothrombin time (PT) and reticulocyte count (Rec) were also significantly increased in the same dose group of both sexes, suggesting that these rats were slightly anemic. The following effects were observed in the other groups, but since there was no dose dependancy, they were not assumed to be treatment-related: signficant increase in WBC and neutrophil values in males of the 12.5 mg/kg bw dose group, signficant increase in Rec in males of the control group and 50 mg/kg bw dose group, sigfnificant decrease in neutrophils in female animals of the 50 mg/kg bw dose group.

CLINICAL CHEMISTRY
A significant increase in total cholesterol was noted in the 200 mg/kg bw dose group of both sexes. In the same experimental group, values of Alp, BUN, Alb, A/G, sodium, chloride and creatinine were significantly decreased, and females of the same group also showed significant decreases in GOT and GOP. Moreover, significant increases or decreases in Alp, total cholesterol, creatinine and chloride of male and GOT, GPT and A/G of female were also found in the other experimental groups, however, these values were all within the normal range.

URINALYSIS
Only in the males of the 12.5 mg/kg bw dose group, the levels of sodium and chloride were significantly, dose-dependant, decreased compared to controls. No abnormalities were observed in the other groups. The level of protein and/or specific gravity were increased, but no marked differences between the groups were observed.

ORGAN WEIGHTS
In the 200 mg/kg bw dose group, increased spleen weights were observed in both sexes. Moreover, there were significant increases in the weight of lung and adrenals of males, significant decreases in salivary gland weights of both sexes and an increase in ovary weights additionally in the 50 mg/kg bw dose group.

GROSS PATHOLOGY
Swelling and thickening of capsule of the spleen and discolouration of the liver were evident in the highest dose group of both sexes. In addition, various other changes were observed in each group, but since there was no qualitative and quantitative difference to the control group, they were considered as not treatment-related.

HISTOPATHOLOGY: NON-NEOPLASTIC
Major histological changes were observed in the lung, spleen, liver, bone marrow and injection site of the tail. Foreign body embolisation in small muscular artery of the lung was occasionally found in the low and mid dose as well in the control group. They consisted of foreign body mutlinucleated giant cells and granulomas that contained har of the rats. Extremely remarkable granulomas in red pulp and vacuolisation were observed in the spleen of high dose goup animals of both sexes. Vacuolisation of red pulp looked like fatty vacuole degeneration. Diffuse granuloma was seen in all groups of both sexes, but no degeneration or congestion of hepatic cells was observed. Extreamedullary hemtopoiesis or congestion were observed. The bone marrow was infiltrated by granuloma in which megakaryocytes and reticulum cells were prominent in the highest dose group of both sexes. Increase of reticulum cells was characteristic. In addition, a part of the bone marrow was replaced by delicate connective tissue, fibroblasts and samll number of plasma cells and lymphocytes were also observed.

Effect levels

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects reported up to this dose level.

Target system / organ toxicity

Critical effects observed:

not specified