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Diss Factsheets

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedures cannot be subsumed under a testing guideline, nevertheless they are well documented and scientifically acceptable.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1972
Report date:
1972

Materials and methods

Principles of method if other than guideline:
A subchronic test of 13 weeks was performed in rats. Groups of 15 males and 15 females were administered by oral gavage with 30, 100 and 300 mg/kg bw/day of test substance in water emulsion (Cremophor).
GLP compliance:
no
Remarks:
pre GLP
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tetrasodium 4,4'-bis[[4-[bis(2-hydroxypropyl)amino]-6-[(4-sulphonatophenyl)amino]-1,3,5-triazin-2-yl]amino]-stilbene-2,2'-disulphonate
EC Number:
267-097-1
EC Name:
Tetrasodium 4,4'-bis[[4-[bis(2-hydroxypropyl)amino]-6-[(4-sulphonatophenyl)amino]-1,3,5-triazin-2-yl]amino]-stilbene-2,2'-disulphonate
Cas Number:
67786-25-8
Molecular formula:
C44H48N12Na4O16S4
IUPAC Name:
tetrasodium 2,2'-ethene-1,2-diylbis[5-({4-[bis(2-hydroxypropyl)amino]-6-[(4-sulfonatophenyl)amino]-1,3,5-triazin-2-yl}amino)benzenesulfonate]

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: males 114 and females 120 g.
- Housing: in groups of 5 in Macrolon cages (type 3).
- Diet: ad libitum, Altromin-R-Food.
- Water: ad libitum, tap water.

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2 °C.
- Photoperiod: from the 7.00 a.m. to 7.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
water emulsion (Cremophor).
Duration of treatment / exposure:
91 days.
Frequency of treatment:
Daily.
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 100 and 300 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
15 males and 15 females x dose x treated group.
30 males and 30 females in the control group.
Control animals:
yes, concurrent vehicle
Details on study design:
Control group dosed with 5.0 ml/kg of vehicle.

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS
The animals were inspected daily.

BODY WEIGHT
The body weight was measured weekly.

HAEMATOLOGY
The following blood tests were performed in 5 rats pre dose after 13 weeks: hemoglobin as cyanmethemoglobin, counting the erythrocytes and leukocytes, platelet count, hematocrit determination, calculation of Färbe-coefficient, calculation of the corpuscular volume, assessment of complete blood count based on smears.

CLINICAL CHEMISTRY
In 5 rats of all groups, the following determinations were carried out after 13 weeks: activity of serum glutamate pyruvate Transeminase (GPT), serum glutamic-oxaloacetic transaminase, serum sorbitol dehydrogenase, glutamate dehydrogenase. In addition, the bilirubin concentrations were determined in serum.
In 5 rats of all groups, the concentration of urea and creatinine were determined after 13 weeks in the serum.

URINALYSIS
The urine were examined for albumin, sugar and blood; bile pigments: Ehrlich's reagent, Schlesinger's reagent; microscopic sediment analysis; specific gravity.
Sacrifice and pathology:
After 13 weeks, the rats were anesthetized and killed by exsanguination.
The internal organs (thyroid, heart, Lungs, liver, spleen, kidneys, adrenals, testes and Ovarian) were macroscopically evaluated and weighed.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
no difference from the control group
Mortality:
no mortality observed
Description (incidence):
no difference from the control group
Body weight and weight changes:
no effects observed
Description (incidence and severity):
compatible with the control group
Haematological findings:
no effects observed
Description (incidence and severity):
all values ​​found were within the physiological range
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
no pathological findings
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
absolute and relative organ weights did not differ fron control
Gross pathological findings:
no effects observed
Description (incidence and severity):
no changes were recorded
Details on results:
CLINICAL SIGNS AND MORTALITY
During the three month test period the rats of the treated groups did not differ from those of the control group.

BODY WEIGHT AND WEIGHT GAIN
The body weight increase in the treated groups was compatible with that recorded in the control group.

HAEMATOLOGY
All values ​​found were within the physiological range.

CLINICAL CHEMISTRY
No indication of liver damage. For the kidney functionality evaluation, the values ​​found were all in the normal range.

URINALYSIS
Also in the urine no pathological findings were observed.

ORGAN WEIGHTS
The average values ​​of the absolute and relative organ weights of the groups of rats treated with the drug did not differ significantly from those of the control group.

GROSS PATHOLOGY
The internal organ macroscopically analysis showed no changes.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL ≥ 300 mg/kg bw/day (nominal).
Executive summary:

Method

A subchronic test of 13 weeks was performed in rats. Groups of 15 males and 15 females were administered by oral gavage with 30, 100 and 300 mg/kg bw/day of test substance in water emulsion (Cremophor).

Results

During the three month test period the rats of the treated groups did not differ from those of the control group. The body weight increase in the treated groups was compatible with that recorded in the control group.

No treatment related findings were recorded in the hematological, clinical chemestry analysis and urinalysis. The internal organ macroscopically analysis showed no changes.

Conclusion

NOAEL ≥ 300 mg/kg bw/day (nominal).