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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:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
12 Nov 1984 - 21 Jan 1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions. Lack of test material details, no analysis of urine and neurobehaviour.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
yes
Remarks:
lack of test material details, no analysis of urine and neurobehaviour
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
lack of test material details, no analysis of urine and neurobehaviour
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): only trade name given
- Chemical denomination: Glyceride, C16-18 und C18 mono- und dihydroxyfettsäuren
- Physical state: white, solid, waxy particles
- Analytical purity: no data
- Batch No.: 4026-3
- Storage: at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River WIGA, Sulzfeld, Germany.
- Age at study initiation: 4 weeks
- Weight at study initiation: 52-69 g (males) and 54-67 g (females)
- Housing: animals were housed in groups of 2-3 animals in Makrolon type III cages on soft wood bedding
- Diet: Altromin 1324 DK (Altromin GmbH, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 59-67.5
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 12 Nov 1984 To: 19 Dec 1984

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared freshly on the day of application. The test substance was grind with a mortar before adding peanut oil.

VEHICLE
- Purity: DAB 7
- Amount of vehicle: 5 mL/kg bw
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 500 and 1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10 (main study)
5 (satellite low and mid-dose groups)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Yielding of a high security range.
- Post-exposure recovery period in satellite groups: 33 days

Examinations

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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice a day

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: on Day 28
- Dose groups that were examined: all animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on Day 28
- How many animals: all animals
- Parameters checked: erythrocytes, haematocrit, haemoglobin concentration, mean cell volume, leukocyte count, thrombocyte count and differential leukocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on Day 28
- How many animals: all animals
- Parameters checked: urea, creatinine, sodium, potassium, glucose, calcium, alkaline phosphatase, glutamate oxalacetate transaminase, glutamate pyruvate transaminase, gamma-glutamyl transferase, cholesterol, total protein, chloride, bilirubin

ORGAN WEIGHTS:
- Thyroid gland, adrenal gland, thymus, spleen, heart, kidneys, brain, testes, liver
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals. Liver, thyroid gland, kidneys, adrenals, testes, uterus, ovaries, thymus, spleen, brain and heart were examined.
HISTOPATHOLOGY: Yes, from animals of vehicle control and highest dose group: Aorta thoracica, eyes, small and large intestine, glandular stomach, brain, urinary bladder, skin, heart, testes, liver, trachea, lung, maxillary lymph nodes, mesenterial lymph nodes, spleen, epididymis, adrenal gland, peripheral nerv, kidneys, ovary, pancreas, prostate, vesicular gland, thyroid gland, salivary gland, oesophagus, sceletal muscle, thymus, uterus, stomach, tongue. Target organs of digestive tract were histopathologically analysed from all animal groups.
Statistics:
t-test, U-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:
effects observed, treatment-related
Description (incidence and severity):
high-dose: reduction of HT-value (m), reduction of stab leucocytes (f); mid-dose: reduction of HT-value and reduction of leucocyte count (m), low-dose: increase of thrombocyte and leucocyte count (m), increase leucocyte count (f); non-adverse
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
see Table 1 under "Any other information on results incl. tables".
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
see Table 2 under "Any other information on results incl. tables".
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see Table 3 under "Any other information on results incl. tables".
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All animals survived the foreseen number of applications without substance-related symptoms. There were a few individual observations, which appeared at different phases of the study and were considered to be not treatment-related: one male in the control group and one female in the high-dose group showed alopecia, one female in the mid-dose group showed chromodacryorrhoea.
One male in the high-dose group died during narcosis for blood sampling at the end of the exposure period.

BODY WEIGHT AND WEIGHT GAIN
No effects were observed in group mean body weight (gain) over the whole study period.

FOOD CONSUMPTION
During the first week, a slight but statistically significant decrease in mean group food intake was observed in females of the low-dose group compared to the control group (17 vs. 18 g/rat/day), which was considered to be not toxicologically relevant. No further effects were observed in mean group food intake.

WATER CONSUMPTION
No effects were observed in group mean water intake over the whole study period.

OPHTHALMOSCOPIC EXAMINATION
No effects were observed.

HAEMATOLOGY
Low-dose males showed a slight increase in thrombocytes and lymphocytes; low-dose females showed a slight increase in leukocytes. A slight decrease in haematocrit and leukocytes and a slight increase in lymphocytes were observed in males of the mid-dose group; no effects were observed in mid-dose females. In the high-dose group, haematocrit and rod-shaped leukocytes were slightly decreased in males, and leukocytes were slightly increased in females.
Overall, haematological parameters, group and individual values did not allow the identification of a substance-related toxic effect.

CLINICAL CHEMISTRY
In low-dose males, GOT and GPT values were decreased and bilirubin values were increased; no effects on females were observed. Males in the mid-dose group showed a slight decrease in GOT and GPT as well as a decrease in calcium, while females presented a slight increase in protein and cholesterol and slight decrease in chloride. In males of the high-dose group, there was a decrease in GOT, an increase in sodium without concomitant increase in chloride, and a slight decrease in bilirubin. High-dose females showed a slight decrease in GOT and a decrease in chloride.
Overall, none of the above mentioned changes in biochemical parameters could be attributed to the test substance, since there was no dose-dependency and individual values were (with a few not dose-dependent exceptions) within the normal ranges for this species and age.

ORGAN WEIGHTS
Absolute organ weights:
Males in the low-dose group showed a slight decrease in adrenals weight. No effects were observed in low-dose females. In the mid-dose group, males showed a slight decrease in thymus weight and females showed a slight increase in brain weight. A slight decrease in thymus weight was also observed in high-dose males. High-dose females showed no effects in absolute organ weights.
Relative organ weights:
There was only a slight decrease in thymus weight in the mid-dose males.
Overall, no substance- and dose-dependent effects were observed.

GROSS PATHOLOGY
There were no substance- and dose-dependent findings. Sporadic findings included hydrometra, hydronephrosis, kidney cysts, slight redness of the stomach mucosa and inflammation of the forestomach mucosa.

HISTOPATHOLOGY: NON-NEOPLASTIC
Sporadic findings across control and treatment groups included slight interstitial inflammation in the lung, prostate inflammation, slight changes in the forestomach mucosa and increased haematopoiesis in the liver parenchyma.
In the mid- and high-dose groups, non-inflammatory dilatation of lymph vessels in the small intestine as well as foreign body giant cells and vacuolization were found in Peyer Plaques. This observed dilation of lymph vessels and foreign body giant cells (fused macrophages) in the small intestine can be interpreted as adaptive responses to a high dose of triglycerides, as the upper intestinal tract is responsible for triglyceride resorption. The histopathological findings indicated an incomplete enteral resorption. Other parts of the gastrointestinal tracts including the mesenteric lymph nodes were without treatment-related findings.
No other treatment related abnormalities were observed.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

 Table 1. Results of the haematological and biochemical examination.

Dose group

HAT

leucocyte

lymphocyte

thrombocyte

GOT

GPT

Na

Cl

Ca

bilirubin

protein

cholesterol

 [mg/kg bw/day]

Males

100

-

-

-

-

-

-

-

500

-

-

-

-

-

-

1000

-

-

 

-

-

-

-

 

Females

100

-

-

-

-

-

-

-

-

-

-

-

500

-

-

-

-

-

-

-

-

-

1000

-

-

-

-

-

-

-

-

-

 /↓: slight increase/reduction

Table 2. Results of absolute/(relative) organ weight examination.

Dose group

thyroid gland

brain

adrenal gland

 [mg/kg bw/day]

males

100

-

-

500

-

- /(↓)

1000

-

-

 

females

500

-

-

 /↓:slight increase/reduction

Table 3. Results of histopathological examination. Dilation of lymph vessels in the duodenum and jenunum (number of animals with findings and grading/total number of animals in group).

Main group

Duodenum

Jejunum

 [mg/kg bw/day]

 

control

Male

0/5

Female

0/5

Male

0/5

Female

0/5

100

0/5

0/5

0/5

0/5

500

0/5

1+/5

5+/5

4+/5

1000

0/5

2+/5

0, 1+, 3++, 1+++/5

5+/5

Satellite group

Duodenum

Jejunum

 [mg/kg bw/day]

 

 

Male

Female

Male

Female

500

1+/5

3+/5

3+, 1++/5

2+/5

+,++,+++: slight, moderate, severe findings

Applicant's summary and conclusion