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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
Study period:
13 Sep 1983 to 11 July 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
"See additional information"
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
Disodium 1-amino-4-(4-benzenesulfonamido-3-sulfonatoanilino)anthraquinone-2-sulfonate
EC Number:
400-350-8
EC Name:
Disodium 1-amino-4-(4-benzenesulfonamido-3-sulfonatoanilino)anthraquinone-2-sulfonate
Cas Number:
85153-93-4
Molecular formula:
C26H17N3Na2O10S3
IUPAC Name:
disodium 1-amino-4-(4-benzenesulfonamido-3-sulfonatoanilino)anthraquinone-2-sulfonate
Specific details on test material used for the study:
Code no: FAT 20297/C
Batch no: HS 11029/16
Description: Blue powder
Received: January 25, 1983
Validity: about 30 years

Test animals

Species:
rat
Strain:
other: Tif: RAIf (SPF)
Details on species / strain selection:
Recommended by the guideline.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Production, CIBA-GEIGY LTD., 4332 Stein / Switzerland
- Age at study initiation: approx. 4-5 weeks
- Weight at study initiation: 105-111 g in males; 105-107 g in females
- Housing: In group of 5 in macrolon cages type 4 with standardised granulated soft wood bedding (Société Parisienne des sciures Pantin).
- Diet: Pelleted, certified standard diet Nafag No. 890 Tox, ad libitum
- Water: Tap water ad libitum
- Acclimation period: 8 days

DETAILS OF FOOD AND WATER QUALITY:
Food: All batches of diet were assayed for composition and contaminant levels by the manufacturer. Analytical results are available at the animal supply office (CIBA-GEIGY LTD., Pharmaceuticals Division PH 2.162).
Water: Results of the routine chemical examination of water at source (Grundwasserfassung Stein) as conducted periodically by the water authority (Baudepartement des Kantons Aargau, Abteilung Gewaesserschutz) are available to CIBA-GEIGY LTD., as well as the results of inhouse chemical analysis by the analytical laboratories of the Pharmaceuticals Division, CIBA-GEIGY LTD.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 55 ± 10 %
- Air changes: 16-20 air changes/hour
- Photoperiod:12 hrs light per day

IN-LIFE DATES: From: August 30, 1983; To: October 5 - 6 , 1983

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
FAT 20297/C was weighed on a calibrated Mettler balance. The pulverised diet was then homogeneously mixed with the appropriate concentrations of the compound and about 25% water was added before pelleting to ensure the necessary pellet quality. The pellets were subsequently airdried. The animals in the control group (group 1) were fed with similarly pelleted feed without the test substance..PREPARATION OF DOSING SOLUTIONS:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Prior to the initiation of the study, pretest feed samples were analysed for concentration, homogeneity and stability of FAT 20297/C.
- The mean concentration of active ingredient during the study according to the chemical analysis * was 96.6 - 104.6 % of the added amount.
- These analysis were carried out in the Analytical Laboratories of CIBA-GEIGY Ltd., Basier / Switzerland.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group Males
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Control group (females)
Dose / conc.:
104 mg/kg bw/day (actual dose received)
Remarks:
low dose for males
Dose / conc.:
297 mg/kg bw/day (actual dose received)
Remarks:
mid dose for males
Dose / conc.:
1 050 mg/kg bw/day (actual dose received)
Remarks:
high dose for males
Dose / conc.:
102 mg/kg bw/day (actual dose received)
Remarks:
low dose for females
Dose / conc.:
282 mg/kg bw/day (actual dose received)
Remarks:
mid dose for females
Dose / conc.:
1 090 mg/kg bw/day (actual dose received)
Remarks:
high dose for females
Dose / conc.:
1 000 ppm
Remarks:
low dose for males and females
Dose / conc.:
3 000 ppm
Remarks:
mid dose for males and females
Dose / conc.:
10 000 ppm
Remarks:
high dose for males and females
No. of animals per sex per dose:
10 males and 10 females per group
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (midweek)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
Animals of the highest dosage group and of the control group were examined before (day -6) and towards the end (day 27) of the treatment period.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All animals


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: All animals

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

OTHER: Hearing test: Animals of the highest dosage group and of the control group were examined before (day -6) and towards the end (day 27) of the treatment period.
Sacrifice and pathology:
At the end of the test period all control and test animals which survived were bled under ether anaesthesia and subjected to detailed autopsy.
Besides the weight of the exsanguinated body the organs weights were also recorded.
After the fixation organ samples from each control and test rat were taken, embedded in paraplast, sectionned at 3-5 micron, stained with haematoxylin and eosin and subjected to microscopic examination.
Statistics:
For each time point and parameter a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system, parameter free methods were applied. Each treated group was compared to the control group in respect of dispersion and displacement. In addition a trend test was applied considering all groups.
Statistical analysis is performed to draw attention to distinct values. A statistically significant difference between two values does not necessarily imply biological relevance of that deviation and is not conclusive for a treatment related effect.
Hence, the responsible scientist may not comment on statistically significant values lying within the physiological range and on the other hand may comment on statistically not significant values, which differ substantially from the expected normal values.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical symptoms and no signs of local and/or systemic toxicity were observed.
Mortality:
no mortality observed
Description (incidence):
No death occurred during the course of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight of all treated male and female groups was similar to that of the respective controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption was slightly higher in both treated male and female animals of group 4 (10000 ppm) compared to the respective control. The mean food consumption of the other treated male and female groups was similar to that of the respective control groups.
Food efficiency:
no effects observed
Description (incidence and severity):
The mean food conversion of female group 4 (10000 ppm) was higher than the respective control ratio, thus indicating spillage of food due to reduced palatability of the medicated diet.
Specific food consumption in relation to body weight - addressed as food conversion ratio - of the other treated animals was similar to the control ratios.
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
The mean water consumption showed a tendency to increased intake in both treated male and female groups 3 and 4 (3000 and 10000 ppm). However, since water consumption was measured only by cage, the number of values (n = 2) does not allow for a definite judgement about the relevance of this finding. The toxicological significance of this deflection is however in doubt.
The mean water consumption of treated male and female group 2 (1000 ppm) was similar to that of the respective control groups (the low value of the female control at week 4 is considered unreliable).
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmic inspections and hearing examinations performed before (day -6) and towards the end (day 27) of the application period revealed no evidence of a reaction to the treatment.
Haematological findings:
no effects observed
Description (incidence and severity):
No difference, which could be related to the test compound was found between treated and control animals in the hematological values.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Throughout the treated groups, no changes were observed, which could be related to the substance administration.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative mean liver weight of both treated male and female groups 4 (10000 ppm) were significantly depressed. Additional statistically significant differences in organ weights, attributed to spontaneous variation rather than to the treatment were also observed.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment related gross pathological findings were observed. All other gross and histopathological lesions seen in some control and test animals were only incidental in nature and not due to the application of the tested compound.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopical examination revealed slightly more pronounced fatty changes of the hepatocytes in female and male animals of group 4 (10000 ppm).
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
3 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOEL
Effect level:
297 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Key result
Dose descriptor:
NOEL
Effect level:
282 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

Dosage Levels: The amount of test material in the diet was determined analytically during the study. The results of these analyses revealed a concentration of 96.6 - 104.6% of the nominal value.

According to the analytical results the calculated mean daily intake of FAT 20297/C was approximately 104, 297 and 1050 mg/kg bw. in males and 102, 282 and 1090 mg/kg bw in females.

Applicant's summary and conclusion

Conclusions:
"No observed effect level" for FAT 20297/C when offiered to rats continuously in their feed over a period of 28 days is 3000 ppm, corresponding to a mean daily intake of FAT 20297/C of 297 mg/kg body weight for males and 282 mg/kg bw for females.
Executive summary:

The repeated dose toxicity of Acid Blue 344 was investigated in this study conducted according to OECD Guideline 407. In this study a total of 80 RAIf (SPF) rats, 10 males and 10 females per dose group were used. The test article FAT 20297/C was administered in the diet for 28 days at dosages of 1000, 3000 and 10000 ppm ( = mg/kg feed). According to the analytical results the calculated mean daily intake of FAT 20297/C was approximately 104, 297 and 1050 mg/kg bw in males and 102, 282 and 1090 mg/kg bw in females. After 28 days of daily dose administration, no mortality or clinical symptoms/ systemic toxicity were observed at any dose levels. No treatment related effect on body weights, food and water consumption, food conversion, eyes, hearing capability, hematology and blood chemistry was observed. However, absolute and relative mean liver weights of both treated male and female groups 4 (10000 ppm) were significantly depressed. Microscopical examination revealed slightly more pronounced fatty changes of the hepatocytes in female and male animals of group 4 (10000 ppm). Based on these findings, "No observed effect level" for FAT 20297/C is 3000 ppm, corresponding to a mean daily intake of 297 mg/kg bw for males and 282 mg/kg bw for females.