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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study (OECD 408)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
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): Laromin C 260
- Analytical purity: >99 %
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: 42 days
- Weight at study initiation: males: 178 (168 - 193) g; females: 147 ( 139 - 157) g
- Housing: single
- Diet: Kliba-Labordiaet Ratte/Maus/Hamster Haltung GLP 343 Mehl, ad libitum
- Water: ad libitum
- Acclimation period: 8 days

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5 % CMC (carboxymethyl cellulose)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gas chromatography
Duration of treatment / exposure:
3 month
Frequency of treatment:
each working day (5 days/week)
Doses / concentrations
Remarks:
Doses / Concentrations:
2.5, 12, 60 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
test group: 30;
control group: 10
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before and after the application period
- Dose groups that were examined: control and high dose

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 29 and 85
- Anaesthetic used for blood collection: No data
- Animals fasted: yes, overnight
- How many animals: all
- Parameters examined: Erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), thrombocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 29 and 85
- Animals fasted: Yes
- How many animals: all
- Parameters examined: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, sodium, potassium, chloride, inorganic phosphorus, calcium, bilirubin total, creatinine, glucose, urea, total protein, albumin, cholesterol, triglycerides.

URINALYSIS: Yes
- Time schedule for collection of urine: day 23 and 79
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: Nitrite, pH-Value, hemoglobin, protein, glucose, ketone bodies, bilirubin, urobilinogen, sediment, volume.

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
blood was sampled from all surviving animals of both sexes for immunological determinations after about 8 and 13 test weeks.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
60 mg/kg bw : On day 71 one male was sacrificed moribund. Deteriorated general state of health with differently discolored regions of various localizations in the animals of both sexes was observed.

BODY WEIGHT AND WEIGHT GAIN
60 mg/kg bw: Significantly retarded body weight gain in both sexes.
12 mg/kg bw: Significantly retarded body weight gain in the female animals, which was present in the males only as a trend.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
60 mg/kg bw: Reduced feed consumption in the males and females.
12 mg/kg bw: Slight reduction of the feed consumption in the females.

OPHTHALMOSCOPIC EXAMINATION
No abnormalities

HAEMATOLOGY
60 mg/kg bw: Increase of the lymphocyte values with changed nuclear structure in both sexes. Increase of the monocyte and neutrophilic polymorphonuclear granulocytes in the females. Decrease of the mean cell volume, mean hemoglobulin content of the individual erythrocyte, of the chloride and creatinine values in both sexes. Decrease of the total protein, albumin, globulins and triglyceride levels in the males. Increased inorganic phosphate in the females.

CLINICAL CHEMISTRY
60 mg/kg bw: Increase of the alanine aminotransferase, aspartate aminotransferase, leukocyte and lymphocyte values in both sexes.
12 mg/kg bw: Increase of the aspartate aminotransferase values in the males.

URINALYSIS
60 mg/kg bw: Increase of the erythrocyte and leukocyte values, of renal and round-cell epithelias, bacterias and roundcell epithelias without nucleus in the urine of both sexes.
12 mg/kg bw: Increase of bacterias and round-cell epithelias without nucleus in the urine of both sexes. Increase of erythrocytes in the urine of the males and single renal and round-cell epithelias in both sexes

ORGAN WEIGHTS
60 mg/kg bw: Increase of the absolute liver weights in the females. Increase of the relative liver weights in the males and females. Increase of the relative kidney weights of the males and females. Increase of the absolute adrenal weights of the males and females. Increase of the relative adrenal weights of the males and females.
12 mg/kg bw: Increase of the relative liver weights in the males. Increase of the absolute kidney weights in the males. Increase of the relative kidney weights in the males and females.

HISTOPATHOLOGY: NON-NEOPLASTIC
60 mg/kg bw: Histopathology revealed microvacuolar degeneration of the liver of most animals. The lesion was qualitatively more distinct in the female than in the male animals. Vacuolar tubulopathy was seen in the kidneys of all animals that were sacrificed at the end of the study. Vacuolar myocardial degeneration was observed in the heart of all male and female animals. The adrenal glands of all male and female animals showed the picture of a progressive transformation.
12 mg/kg bw: Histopathology revealed vacuolar tubulopathy in the kidneys of some male and female animals. The heart of most animals was found to show vacuolar myocardial degeneration

OTHER: The immunological examinations elicited no adverse effects on the humoral parameters examined.

Effect levels

Dose descriptor:
NOAEL
Effect level:
2.5 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In conclusion, it may be stated that the 3-month administration of Laromin C 260 to male and female rats at a dose of 60 mg/kg b.w. each working day by gavage led to clear toxic findings, such as reduced feed consumption, retarded body weight gain, impaired general state of health, changes of the hematologic (white and red blood counts), enzymatic, clinicochemical and urinanalytical parameters as well as hepato and nephrotoxic, myocardially toxic and adrenotoxic (progressive transformation) effects.

12 mg/kg b.w. led in the female animals to a reduced feed consumption, in the animals of both sexes to a retarded body weight gain, and to an increase of the aspartate aminotransferase values in the male animals. Urinalysis detected in both sexes an increased number of bacterias, of round-cell epithelias with and without nucleus, and of renal epithelias and in the male animals an increase of erythrocytes. The pathological examinations exhibited hepato and nephrotoxic and myocardially toxic findings.

  

2.5 mg/kg b.w. caused no differences when compared with the control .

 

Applicant's summary and conclusion