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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
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity in Non-Rodents)
Version / remarks:
-reliability scoring based on 1998 guideline
Deviations:
yes
Remarks:
-purity and source/origin of test article not provided; deviations continued in Materials and Method Section
GLP compliance:
no
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): LYCASIN 80/55
- Physical state: Not reported
- Analytical purity: Not reported
- Lot/batch No.: 462B
- Stability under test conditions: Not reported
- Storage condition of test material: Cold room (4°C)

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CERM, 63201 RIOM, France
- Age at study initiation: 8 months (except for 1 dog, which was 6 months old).
- Weight at study initiation: Not reported
- Fasting period before study: Not reported
- Housing: Animals were housed in 1.35 square meters wired boxes (2 animals of the same sex/box)
- Diet (e.g. ad libitum): Commercial compound granulated feeds
- Water (e.g. ad libitum): Adequate drinking water; ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.3 ± 1.2
- Humidity (%): relative humidity of 40 ± 20
- Air changes (per hr): 8 to 9
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: December 21, 1981 To: June 16, 1982

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Product was warmed up at 40°C just before each administration in order to reduce the viscosity.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Actual dose administered was reported as 4.95 g/kg bw; however, details on the analytical verification of the dose was not provided.
Duration of treatment / exposure:
13 weeks (93 days)
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
4.95 g/kg body weight (4.87 mL/kg body weight)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
5.00 g/kg body weight (4.87 mL/kg body weight)
Basis:
other: nominal
No. of animals per sex per dose:
4/sex/group
Control animals:
other: yes, treated concurrently with tap water
Details on study design:
- Dose selection rationale: Decision made by owner company
- Post-exposure recovery period in satellite groups: Animals were sacrificed after 13 weeks of treatment (no recovery period was tested).
Positive control:
None used.

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily observations (diarrhea occurrence was recorded on a weekly basis)

BODY WEIGHT: No (only body weight gain data was provided)
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Weeks 0, 2, 4, 8, and 13
- Dose groups that were examined: all animals


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Weeks 0, 4, and 13
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Weeks 0, 4, and 13
- Animals fasted: No data
- How many animals: all animals

URINALYSIS: Yes
- Time schedule for collection of urine: Weeks 0, 4, and 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Para aminohippurate (PAH) clearance was determined on all animals at the end of the study period.
Sacrifice and pathology:
All of the animals were sacrificed at the end of the 13 weeks and macroscopic and microscopic examinations of various organs were evaluated.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
One animal was found dead on the 21st day with lesions of pneumonia. The authors reported that this death was due to incorrect intubation and not compound-related. No clinical symptoms appeared following the administration of Lycasin, except for intermittent diarrhea reported in all test animals. The onset of diarrhea was not related to the time of compound administration.

BODY WEIGHT AND WEIGHT GAIN
The control animals and the test animals had comparable growth. One female animal lost weight regularly in small amounts from the 8th week of treatment and had an increased serum triglyceride level, and an increased serum alkaline phosphatase level, which correlated with the presence of dark bile on autopsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The control animals received a normal food intake. Male dogs in the test group had their food intake reduced by 30% and all females had a normal food intake, except for 2 animals at the end of the study. Food intake in the test animals was slightly decreased throughout the entire study, without any effect on the animals’ weight progression.

OPHTHALMOSCOPIC EXAMINATION
Ophthalmologic examinations did not reveal any compound-related abnormalities.

HAEMATOLOGY
No hematological disturbances were reported to be related to the administration of Lycasin, except for increased erythropoiesis in 1 female animal in the test group. The increased erythropoiesis was suggested by the authors to be correlated with the tubular dilation of the nephron (stimulation of erythropoietin production).

CLINICAL CHEMISTRY
Biochemical laboratory tests revealed an increase in the level of circulating triglycerides in 3 female animals in the test group. This modification became abnormal for 1 female animal at 13 weeks. The authors suggested this animal was more sensitive than the other animals to the sugar-rich diet. The predominant oxidation of the glucids (glycolysis and krebs cycle) slowed down the oxidation of fatty acids resulting from lipolysis. Thus, the free fatty acids and those “formed” from glucids are reused for the synthesis of triglycerides. This animal also had a higher alkaline phosphatase level than the other animals, which correlated with the presence of dark bile upon autopsy. No biologically significant modification was reported for the other parameters.

URINALYSIS
Urinary analyses did not reveal any abnormalities related to the administration of the test compound.

ORGAN WEIGHTS
No significant compound-related changes in organ weight were reported.

GROSS PATHOLOGY
Following macroscopic examination, no compound-related abnormalities were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histological examinations revealed dilated kidney tubules (intensity was minimal) in 2 male dogs and 3 female dogs of the test group. Other lesions or abnormal findings are common and frequently observed in the beagle dog under the experimental conditions of the tests.

OTHER FINDINGS
Clearance determination of PAH did not show a decreased value.

Effect levels

Dose descriptor:
NOAEL
Basis for effect level:
other: The authors did not report a NOAEL.
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion