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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Registered substance
IUPAC Name:
Registered substance

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distd.
Details on oral exposure:
daily dose;
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
UV/VIS spectrometry
Duration of treatment / exposure:
Test duration: 28 days; at the end of the treatment period five animals/sex were maintained untreated for two weeks;
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 10 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: 10 animals at 1000 mg/kg bw/day
Female: 10 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: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle
Positive control:
no

Examinations

Observations and examinations performed and frequency:
clinic examinations: twice daily
body weight: weekly and on the day preceding termination;
food consuption: per group per week;
food efficieny: no
water consumption: no;
Ophthaloscopic examination: yes
Haematology: yes
clinical chemistry: yes
Urinalysis: yes
Neurobehavioural Examination: yes
Sacrifice and pathology:
All animals necropsied as scheduled were weighed on the day of necropsy and descriptions of all macroscopic abnormalities were recorded. Necropsies were
performed by experienced prosectors supervised by an experienced veterinary pathologist. At the end of the treatment or recovery period the animals were
anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
Samples from all animals at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution;

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
males treated at 1000 mg/kg/d
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
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:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
MORTALITY
No unscheduled deaths occurred during the course of the study in animals of either sex treated with Bthe substance at a daily dose level of 50 mg/kg, or in
females treated at 200 mg/kg.
One male treated daily at 1000 mg/kg died on day 23 of the treatment period. A further male and one female in this group, both of which were designated as
recovery group animals, died on day 29 and day 28 (respectively).
One male animal treated at 200 mg/kg died on day 5 of the treatment period. A post mortem examination revealed bluish colored fluid in the thoracic cavity. This
finding is suggestive of mechanical damage due to the dosing procedure, although no evidence of traumatic injury was noted at necropsy. Therefore, the evidence
for test article-induced death is equivocal.
All other animals survived the scheduled treatment period, and the treatment-free period where applicable.
CLINICAL SIGNS
Daily clinical examinations revealed treatment-related effects at all dose levels employed. Blue colored feces occurred in all animals treated with the substance at
all dose levels. All other clinical signs were restricted to the group treated with the substance at a daily dose level of 1000 mg/kg. Sedated behavior and ruffled fur
occurred in animals surviving the treatment period, but multiple clinical signs occurred in animals that died prematurely.
BODY WEIGHT AND WEIGHT GAIN
There were no treatment-related effects on the body weight development of animals of either sex treated with the substance at 50 or 200 mg/kg, or in females
treated at 1000 mg/kg.
The overall body weight gain of males treated at 1000 mg/kg was lower than the controls. There was no effect on body weight gain during the recovery period.
FOOD CONSUMPTION
There were no treatment-related effects on the absolute and relative food consumption of animals of either sex treated with the substance at 50 or 200 mg/kg, or
in females treated at 1000 mg/kg.
The overall mean food consumption of the male group treated at 1000 mg/kg was 8% lower than the controls. There was no effect on food consumption during the
recovery period.
OPHTHALMOSCOPIC EXAMINATION
No ocular abnormalities attributable to the administration of the test article occurred in either sex at any dose level, up to and including the highest daily dose level,
1000 mg/kg.
HAEMATOLOGY
There were no treatment-related changes in the hematological profile of either sex treated at a daily dose level of 50 or 200 mg/kg.
Red blood cell count was slightly reduced and circulating reticulocyte numbers and neutrophil / lymphocyte ratio were increased in males treated at 1000 mg/kg.
Hemoglobin and methemoglobin concentrations of the female group treated at 1000 mg/kg were elevated after 4 weeks of treatment.
No treatment-related effects were apparent at the end of the treatment-free period in either males or females.
CLINICAL CHEMISTRY
There were no treatment-related changes in the clinical biochemistry parameters of either males or females treated daily at 50 or 200 mg/kg.
Plasma ALAT activities were significantly higher in both sexes after 4 weeks of treatment. The male group also showed a significantly higher uric acid concentration
and calcium ion concentration than the control group. The female group also showed significantly higher plasma triglyceride concentration, higher GGT activity and
significantly lower total protein, albumin and globulin concentrations than the controls. The albumin / globulin ratio was unaffected.
No other treatment-related clinical biochemistry effects were apparent after 4 weeks of treatment and none were apparent at the end of the treatment-free period in
either males or females.
URINALYSIS
There were no treatment-related changes in urinalysis parameters in either males or females treated daily at 50 mg/kg or in males treated at 200 mg/kg.
Animals of both sexes treated at 1000 mg/kg showed significantly higher urine volumes than the control groups and significantly lower specific gravity and
osmolality. Urine pH was also significantly higher than the controls in female animals.
In the female group treated at 200 mg/kg, urine osmolality was significantly lower and pH was significantly higher than the control values.
All other measured physiological parameters and all urine cellular or chemical constituents of the treated groups were similar to, and not significantly different from
the control values.
No treatment-related effects were apparent at the end of the treatment-free period in either males or females.
NEUROBEHAVIOUR
Quantitative assessment of locomotor activity revealed consistently lower activity in both male and female animals treated at 1000 mg/kg.
Quantitative measurement of forelimb and hindlimb grip strength revealed no statistically significant differences from the control groups at any of the dose levels
employed.
ORGAN WEIGHTS
There were no treatment-related changes in the organ weights or ratios of male and female groups treated daily at 50 or 200 mg/kg, or in males treated at 1000 mg/
kg.
The adrenal weight and both ratios of the female group treated at 1000 mg/kg were significantly higher than the control group values after 4 weeks of treatment.
There were no other treatment-related effects on organ weights after 4 weeks of treatment.
At the end of the treatment-free period, female adrenal weights and all other organ weights and ratios in males and females, with the exception of ovary weight,
were not significantly different from the control values. Group mean ovary weight and ratios were significantly lower than control group values at this time. In the
absence of an effect on this parameter after 4 weeks of treatment and in the absence of any histological findings in the ovary, the lower ovary weight is considered
to be of no toxicological consequence.
GROSS PATHOLOGY
At the end of the treatment-free period, a bluish discoloration remained in some tissues and organs of animals treated at 1000 mg/kg. The kidneys and lymph
nodes of all animals remained bluish in color. Occasional animals also showed a persistence of a bluish color in the lungs, stomach and small and large intestine.
HISTOPATHOLOGY: NON-NEOPLASTIC
At 1000 mg/kg the treatment-related lesions persisted during the recovery period in the kidneys, urinary bladder, liver and lung. Treatment-related lesions also occurred in the spleen of male animals previously treated at 1000 mg/kg.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the findings of reduced urine osmolality, elevated urine pH and renal pelvic dilation in some animals treated at 200 mg/kg/day.
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on the findings of reduced urine osmolality, elevated urine pH and renal pelvic dilation in some animals treated at 200 mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Classified as: Not classified