Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
13 October 1991 - 10 Novenber 1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted in GLP compliance andwas well described. BIBR 277 CL is the hydrochloride of BIBR 277 SE (Telmisartan, free acid). However, it is not evident from the study report which testing guideline was followed for the experiments.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The study was conducted in GLP compliance andwas well described. BIBR 277 CL is the hydrochloride of BIBR 277 SE (Telmisartan, free acid). However, it is not evident from the study report which testing guideline was followed for the experiments.
GLP compliance:
yes
Limit test:
yes

Test material

Constituent 1
Reference substance name:
BIBR 277 SE
IUPAC Name:
BIBR 277 SE
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): BIBR 277 SE
- Purity test date: 23 October 1991
- Lot/batch No.: 8110110
- Expiration date of the lot/batch: confirmed until October 31, 1992
- Stability under test conditions: guaranteed over 24 hrs

Test animals

Species:
rat
Strain:
other: albino rats
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach, Germany
- Age at study initiation: 46 days
- Weight at study initiation: 179 - 221 g
- Fasting period before study:
- Housing: housed individually in Makrolon (R) cages, Type III
- Diet (e.g. ad libitum): animals received a weekly food ration of pellets (NAFAG 8577)
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C +/- 3°C
- Humidity (%): 45 - 75 %
- Air changes (per hr): 16 / hour
- Photoperiod (hrs dark / hrs light): illumination at 100 lux from 7am - 4pm.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: suspension of hydroxycellulose (0.5%)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily in the morning
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10 mg/kg b.w. (G1)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
50 mg/kg b.w. (G2)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg b.w. (G3)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg/kg b.w. (G4)
Basis:
actual ingested
No. of animals per sex per dose:
each 10 m/10 f, and additionally 3m/3f animals per substance-treated group for toxicokinetic investigations.
An extra number of 10m /10f rats of the highest concentration group were used for a 5-weeks treatment-free recovery period.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: basing on results of a preliminary dose-finding study
- Rationale for animal assignment: random
- Rationale for selecting satellite groups: random
- Post-exposure recovery period in satellite groups: 5 weeks
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: physical signs: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: bw was determined once a week

FOOD EFFICIENCY:
- each animal was given a measured, adequate quantity of feed and water, calculated from the previous weeks consumption. Food/water intake was determined once a week, by weighing the remaining food/water.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: during weeks 4 (and 9 for additional recovery group)
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the start of administration and in week 4. recovery animals were also tested in week 9.
- Anaesthetic used for blood collection: Yes (halothane)
- Animals fasted:no
- How many animals: all
- Parameters checked in table: see attached study report.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before the start of administration and in week 4. recovery animals were also tested in week 9.
- Animals fasted:no
- How many animals: all
- Parameters checked in table : see attached study report.

URINALYSIS: Yes
- Time schedule for collection of urine: in weeks 3 and 9 (recovery animals only)
- Metabolism cages used for collection of urine: Yes (URIMAX)
- Animals fasted: No data
- Parameters checked in table : see attached study report.

NEUROBEHAVIOURAL EXAMINATION: no

BONE MARROW EVALUATION:
At termination, bone marrow from 10 m/f animals from the high dose and control groups was evaluated. Since no pathological changes were observed, the smears of the other groups were not eaxmined.

TOXICOKINETICS:
Blood samples were collected from animals used specifically for the accompanying toxicokinetic investigations on the 1st and 14th study day and during the 4th week.



Sacrifice and pathology:
PATHOLOGY:
- after sacrifice, the following organs of the animals were observed: heart/ lungs/ liver/ spleen/ thymus/ brain/ pituitary gland/ thyroid/ kidneys/ adrenals / gonads.

GROSS PATHOLOGY:
A complete autopsy was performed on all animals used in the study, all macroscopial changes were recorded, beginning on the day after the final adiminstration of the test solution.

HISTOPATHOLOGY:
the following organs and tissues were collected from all anomals, fixed in Bouin's solution or 10% buffered formalin.
heart/ lungs/ liver/ spleen/ kidneys / adrenals / esophagus/ stomach/ duodenum/ jejunum/ ileum/ colon/ cecum/ rectum/ pancreas/ brain/ pituitary/ thyroid with indent parathyroids/ thymus/ parotid gland/ submandibular salivary gland/ sublingal salivary gland/ lacrimal gland/ mesenteric lymph node/ cervical lymph node/ testes/ seminal vseicle/ epididymides/ prostate/ uterus/ ovaries/ urinary bladder/ skin/ eye and optical nerve/ mammary gland/ skeletal muscle/ tngue/ trachea/ aorta/ femur/ sternum/ bone marrow/ sciatic nerve/ spinal cord/ macroscopic lesions
Statistics:
The following statistical algorithms were used:
BARTLETT test;
one-way analysis of variance; and
NEWMAN KEUL's test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
significantly decreased in the 2 highest dose groups (males)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
significantly decreased in the 2 highest dose groups (males)
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:
effects observed, treatment-related
Description (incidence and severity):
see details below
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):
see details below
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related erosions of the stomach mucosa were observed in G2 (2m/2f), G3 (5m/2f), G4 (5m/3f).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details below
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
see details below
Details on results:
CLINICAL CHEMISTRY:
at the end of the study, the values of urea nitrogen (f/m, all groups), creatinine (only m, all groups), potassium (males: all groups, females: groups 2-4) and magnesium (groups 3-4, f/m) were increased.
Furhtermore, in the male rats, the total cholesterol (G2-G4) was increased and a decrease in the total glycerol (G1-G4) was evident.

ORGAN WEIGHTS:
The following significant differences were observed:
Increase: kidneys (females G1, G3); adrenals (males G4 recovery), pituitary (males G4 recovery).
Decrease: heart (males G3, G4, females: G1-G4), pituitary (females G1, G3, G4) and thyroids (females G4).

TOXICOKINETICS:
see attached study report for details on plasma concentrations

HISTOPATHOLOGY:
mucosal erosions and ulcers of the glandular stomach were observed in animals of all groups. The injury of the stomach was found to be dose.dependant and reversible.
In the liver, a dose.related, sex.independent change developed, consisting of a harmless, patch-like basophilic appearance of the hepatocellular cytoplasm. This finding disappeared nearly completely at 5 weeks after drug withdrawal.
Hyperplasis of the renin- producing, granular epitheloid cells of the juxtaglomerular apparatus with prominent granularity were found in the kidneys. Except of the low-dose females, animals of all dose-groups were affected. These changes were more pronounced in males than in females and regressed after drug withdrawal.

Effect levels

Dose descriptor:
NOAEL
Effect level:
< 10 mg/kg bw (total dose)
Based on:
not specified
Sex:
male/female
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No NOEL could be estimated as slight toxic signs (minore focal erosions) were already demonstrated in the lowest dosage group pf 10 mg/kg. Nevertheless, as this dosage yields plasma levels exceeding the presumed therapeutic levels by a factor of ten, the present experiment does not demonstrate any special risks for short term clinical trials in humans.