Registration Dossier

Administrative data

Endpoint:
repeated dose toxicity: oral
Remarks:
other: according to method
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Directive 96/54/EC, B.7
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: Rat, HanIbm (Wistar)

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: Bidistilled water
Details on oral exposure:
Method of administration:
Gavage
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
MORTALITY:

No mortality occured during the study.


CLINICAL SIGNS:

No test item-related clinical signs were noted during the

study.


FUNCTIONAL OBSERVATIONAL BATTERY:

No treatment-related changes noted.


FOOD CONSUMPTION/BODY WEIGHTS:

There were no effects on food consumption and body weights

noted.

Laboratory findings:
HEMATOLOGY:

No test item-related changes were observed in males or
females.


BIOCHEMISTRY:

All differences noted were considered to be unrelated to the
treatement.

Effects in organs:
ORGAN WEIGHTS:

No test item-related changes on organ weights observed.


MACROSCOPIC & MICROSCOPIC FINDINGS:

No test item-related findings noted.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Classified as: Not classified
Executive summary:

GENERAL In this subacute toxicity study, ucb 22060 was administered daily by oral gavage to SPF-bred Wlstar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest and the treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing period, blood samples were withdrawn for hematology and plasma chemistry analyses, All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, bone marrow, kidneys, male thyroid gland were examined to establish a no-effect level. MORTALITY 1VIABILITY All animals survived until scheduled necropsy. CLINICAL SIGNS No test item-related clinical signs were noted during daily observations or weekly behavioral observations (weeks 1-3). FUNCTIONAL OBSERVATIONAL BATTERY No test item-related clinical signs were evident during functional observational battery (week 4). Grip Strength The mean fore- and hindlimb grip strength values of test item-treated and control animals were similar. Locomotor Activity The mean locomotor activity of the male and female rats treated with 1000 mg/kg/day were generally reduced when compared with the respective controls. These differences were considered likely to be test item-related effects. FOOD CONSUMPTION No test item-related differences in mean food consumption were noted at any dose level. BODY WEIGHT No test item-related differences in mean body weights were noted at any dose level.

CLINICAL LABORATORY INVESTIGATIONS Hematology No test item-related differences in the hematology parameters were noted at any dose level tested. Clinical Biochemistry All differences noted in the clinical biochemistry parameters were considered to be fortuitous and unrelated at the treatment with the test item. ORGAN WEIGHTS None of the slight differences in mean absolute and relative organ weights were considered to be of toxicological relevance. MACROSCOPIC / MICROSCOPIC FINDINGS At necropsy, there were no macroscopic findings indicating an effect of the test item. Microscopic examination demonstrated that the test item produced morphological alterations in the male bone marrow, kidneys and thyroid gland. The findings in the bone marrow were minimally increased fatty atrophy at 1000 mg/kg/day. The thyroid gland had increased hypertrophy of follicular cells at 1000 mg/kg/day, The kidneys of all male treated groups had higher incidence and grading of tubular hyaline change, probably due to accumulation of alpha-2-microglobulins.