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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:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Principles of method if other than guideline:
Method: other: Directive 84/449/EEC, B.7 (1984) and Japanese MHW guideline (1986)/MITI (1987)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Basazol Gelb 8511
- Physical state: powder
- Analytical purity: 96%
- Lot/batch No.: 6123, Study 6781

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae GmbH
- Age at study initiation: 42 days
- Weight at study initiation: males 183 (176 - 193) g; females 154 (145 - 161) g
- Housing:Dk III stainless steel wire cages; Becker & Co. Castrop- Rauxel
- Diet :ad libitum
- Water ad libitum
- Acclimation period: 7 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:
olive oil
Details on analytical verification of doses or concentrations:
The test substance preparations were prepared in intervals, for which the stability was demonstrated. Before the beginning of the study, the stability of the test substance in the vehicle was requested over a period of 4 hours and 4 days. At the start of the study, samples were sent to the analytical laboratory for determination of the homogeneity and of the correctness of the concentration of the test substance preparations.
The stability of the test substance in the vehicle over a period of 4 hours and 4 days was verified analytically. The homogeneity of the test substance preparations and the correctness of the concentrations had been confirmed.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 60, 180 mg/kg bw.
Basis:
actual ingested
No. of animals per sex per dose:
5 in the lowest and intermediate dose group
10 in the highest dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 day recovery period for vehicle control and highest dose group

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
All animals showed no abnormalities which could be related to the test substance
administration.During the administration period and during the recovery period no
animal died prematurely.

BODY WEIGHT AND WEIGHT GAIN
There were no differences (application and recover -period) between body weights of
male and female rats receiving the test substance and body weights of the control rats
with exception of a marginal decrease in body weight of the highest dose group in the males

FOOD CONSUMPTION
Throughout the study (application and recovery period),the amount of food consumed by
the males and females of dose groups 20, 60 and 180 mg/kg body weight did not differ
substantially from that consumed by untreated control animals.

HAEMATOLOGY
No substance-induced changes were observed.

CLINICAL CHEMISTRY
At the end of the administration period statistically significantly decreased total protein and
globulin concentrations were found in the serum of the male animals of test group
3 (180 mg/kg). In the course of the recovery period the total protein and globulin levels
returned to normal . This latter observation and the very slight, not statistically significant
decrease in body weight (about 3%) at the end oft he administration period may indicate a
substance-related effect. However, the decrease in protein and globulin concentrations was
observed in one sex only and the reducedprotein parameters were not accompanied by
commensurate changes in biochemical or pathology results. Therefore, the decrease in
protein levels may also be an incidental finding.In the remaining clinicochemical parameters no substance-induced changes were detected.

URINALYSIS
In the urine of the male and female animals of allt reatment groups (20, 60 and 180 mg/kg)
a dose-dependentdiscoloration of the samples, from yellow to orange and red-brown, was
observed at the end of the administration period. The discoloration of the urine is a finding
without any pathological relevance, because the renal elimination of the test substance is a
physiological process. At the end of the recovery period the color in the urines of the
animals of the highest dose group was normal . Furthermore, after 4 weeks of test substance
adminstration the reagent-strip tests showed positive results for blood in the urine of the
males in test group 3 (180 mg/kg) and in the females of test group 2 and 3 (60and
180 mg/kg) and positive results were also found for bilirubin in the females of test group 1
and 2 (20 and60 mg/kg). However, no red blood cells were seen in the urine sediments of
the animals of the treatment groups, which would support the finding of a possible
hematuria and in the serum of both sexes no increase in total bilirubin concentrations was
noted. It is supposed, that the findings in the urine of the male and female animals are
caused by an interference of the analytical tests with the excreted test substance itself or
with one of its metabolites. Therefore, all changes observed in the urine of the male and
female animals are toxicologically not relevant.

GROSS PATHOLOGY
At necropsy animals from the dose groups 2 and 3 showed coloration but this was not
associated with any histopathological changes and was considered to be of no toxicological significance.

Effect levels

Dose descriptor:
NOAEL
Effect level:
60 - 180 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No effects on food consumption, drinking water consumption and mortality. No treatment-related changes of organ-weights and in histopathology. There was a dose-related red coloration of the urine of all animals in the test groups which was seen beginning from day 14 of the treatment. Urine analysis gave no indication of any toxicologically relevant deviations. A decrease in total protein and globulins was noted for the male animals of the high dose group at the end of the administration period. The coloration of urine and gut mucosa as well as of the mesenteric lymph nodes does not represent a toxic effect but proves that Basazol Gelb 8511 or one of its metabolites is resorbed by the organism. The disappearance of the coloration demonstrates that the test substance is eliminated from the organism during the treatment-free period.

The NOAEL is between 180 mg/kg bw and 60 mg/kg bw.

Applicant's summary and conclusion