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Administrative data

Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant guideline study (OECD)
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report date:
1990

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
adopted May 12, 1981
GLP compliance:
yes
Remarks:
CIBA-GEIGY Ltd., Experimental Toxicology, Switzerland
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 2,2'-([1,1'-biphenyl]-4,4'-diyldivinylene)bis(benzenesulphonate)
EC Number:
248-421-0
EC Name:
Disodium 2,2'-([1,1'-biphenyl]-4,4'-diyldivinylene)bis(benzenesulphonate)
Cas Number:
27344-41-8
Molecular formula:
C28H22O6S2.2Na
IUPAC Name:
disodium 2,2'-([1,1'-biphenyl]-4,4'-diyldivinylene)bis(benzenesulphonate)
Details on test material:
- Name of test material (as cited in study report): FAT 65029/G
- Physical state: light yellow powder
- Analytical purity: 89.8%
- Impurities (identity and concentrations): approximately 7% sodium chloride
- Lot/batch No.: EN 372980, Op.247/248
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animal Production, CIBA-GEIGY Limited, 4332 Stein / Switzerland
- Age at study initiation: approximately 4-5 weeks
- Weight at study initiation: 85.6 to 124.6 g in males and 70.2 to 128.6 g in females
- Housing: 5 per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±10
- Air changes (per hr): 16 - 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
FAT 65029/G was weighed on a calibrated Mettler balance. The pulverised food was then homogenously mixed with the appropriate concentrations of the test article and about 25% water was added before, pelleting to ensure the necessary pellet quality. The pellets were subsequently air dried. The animals in the control group (group 1) were fed with similarly pelleted food without the test article. Fresh diets were prepared at monthly intervals and stored in stainless steel containers at room temperature until used.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC and UV-spectrometry
Duration of treatment / exposure:
123 weeks for males and 127 weeks for females.
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 500, 5000 and 50000 ppm (= mg/kg food)
Basis:
nominal in diet
No. of animals per sex per dose:
80
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The dose levels were selected based on the results of the following previously conducted studies:
Project no. C 45324-Ba (3257 W) of September 22, 1971: acute, oral toxicity in rats: LD50 = above 6000 mg/kg bw.
and
Project no. IBT A1239 of March 24, 1972: acute, oral toxicity in rats: LD50 = 5580 mg/kg bw.
and
Project no. IBT B9451: 90-day subacute oral toxicity study in rats: NOEL = above 5000 ppm
and
Project no. IBT B 516-D: Two year chronic oral toxicity study in rats: Animals treated with 0, 40, 200 and 1000 ppm (=mg/kg feed) showed no treatment related effects.
and
Report no. 7/72 S of September 13, 1972: Metabolism in rats after oral administration of FAT 65029 the test article was found to be excreted (more than 90%) unchanged via feces. The half-life period was 8 hours in males and 14 hours in females. No residues were found in organs.
and
Report of August 11, 1976: Resorption via the skin of nude mice: Only a small amount was resorbed via the skin and excreted shortly thereafter.
and
Pretest: Project no. 854004: Administration of 0, 500, 5000 and 50000 ppm (in the diet) for 4 weeks under the conditions of this foreseen lifetime study caused no mortalities and no bodyweight depression, but a marked compensatory increase of food consumption in rats of both sexes treated with 50000 ppm of FAT 65029/G.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily (a.m. and p.m. on working days)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily (a.m. and p.m. on working days)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (midweek) for the first 3 months and monthly thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

OPHTHALMOSCOPIC EXAMINATION and hearing: Yes
-Time schedule and dose groups for examinations: male and female animals of the highest dose level and of the control group were examined before the beginning (day - 6 ), during (days 536 and 723) and towards the end (day 850 for males and 879 for females) of the treatment period. In addition, group 3 males and females were examined on day 731 and groups 2 and 3 at day 852 for males and day 879 for females.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13, week 26, week 53, week 78, week 105, week 123 (males), week 127 (females)
- Anasthetic used for blood collection: Yes (Ether anesthesia)
- Animals fasted: Yes
- How many animals: 30 per sex and group
- Parameters examined: Erythrocyte Count, Hemoglobin, Hematocrit, Mean corpuscular volume, Mean corpuscular hemoglobin, Leucocyte count, Differential Leucocyte Count, Thrombocyte Count, Prothrombin Time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13, week 26, week 53, week 78, week 105, week 123 (males), week 127 (females)
- Animals fasted: Yes
- How many animals: 30 per sex and group
- Parameters examined: Glucose, Urea, Creatinine, Total protein, Albumin, Globulins, A/G Ratio, Cholesterol, Sodium, Potassium, Calcium, Phosphorus inorganic, Aspartate aminotransferase, Alanine aminotransferase, Alkaline phosphatase

URINALYSIS: Yes
- Time schedule for collection of urine: week 13, week 26, week 53, week 78, week 105, week 123 (males), week 127 (females)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: Urine Volume, urine relative densitiy, pH, Protein, Glucose, Ketones, Blood, Bilirubin and Urobilinogen, Urine Sediment.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
For each time point and parameter an univariate statistical analysis is performed. Non parametric methods were applied, to allow for non normal as well as normal data distribution. Each treated group is compared to the control group by Lepage's two-sample test. This test is a combination of Wilcoxon and Ansari-Bradley statistics, i.e. a combined test for location and dispersion. The Lepage test has a good power against the more general alternative that the distributions differ not only in location but also in dispersion. In addition, monotone increasing trends from control to the highest dose group are tested by Jonckheere's test for ordered alternatives. Survival analysis was performed by the regression model (partial likelihood) introduced by Cox in order to compare survival experience of treated animals with the control and versus treated group 2. Statistical analysis is performed to draw attention to distinct values. Mean values differing from the control by combined location and/or variation are marked by an asterisk. 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

Details on results:
CLINICAL SIGNS AND MORTALITY: The appearance and behaviour of treated rats were similar to those of the control group. Treatment had no effect on mortality.

BODY WEIGHT AND WEIGHT GAIN: Mean bodyweights for males and females of group 4 (50000 ppm) became progressively lower than control values, attaining a 10% difference after 2 years of treatment. Mean bodyweights of other treated males were not disturbed by treatment, whereas for females of groups 2 and 3 (500 and 5000 ppm) slightly higher mean bodyweights were consistently recorded.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): The overall food intake for males and females of group 4 (50000 ppm) was 14% higher than that of the control group. The food intake of other treated males was not disturbed by treatment, whereas for females for groups 2 and 3 (500 and 5000 ppm) slightly higher intakes were recorded.

FOOD EFFICIENCY: The food consumption ratios for males and females of group 4 (50000 ppm) were higher than control values. Ratios for other treated groups were similar to those of the control group thus indicating that the slightly higher bodyweights recorded for females of groups 2 and 3 (500 and 5000 ppm) were directly related to their slightly increased food intake.

WATER CONSUMPTION: A dose related increase in water intake was recorded for males and females of groups 3 and 4 (5000 and 50000 ppm).

OPHTHALMOSCOPIC EXAMINATION: Eye examinations and hearing tests revealed no evidence of a treatment related effect.

HAEMATOLOGY: Apart from a tendency towards higher platelet counts in some females of group 4 (50000 ppm), values for all other parameters in treated rats were not influenced by treatment.

CLINICAL CHEMISTRY: The blood chemistry profile of treated rats showed no evidence of a treatment related disturbance.

URINALYSIS: Males and females of group 4 (50000 ppm) excreted larger volumes of more alkaline and mainly more dilute urine than did the controls, although at the preterminal investigation these, differences were no longer apparent.

ORGAN WEIGHTS: Kidneys weights relative to bodyweight were significantly higher than control values at weeks 53 and 105 for males and females of group 4 (50000 ppm) and at termination for group 4 males. In addition, for group 4 males, liver weights relative to bodyweight were significantly higher at week 105 and at termination. However, no common pathology was seen to account for these changes.

GROSS PATHOLOGY: Macroscopical examination revealed an increased incidence of pancreatic nodules and/or masses in rats of both sexes from group 4 (50000 ppm).

HISTOPATHOLOGY: Histological examination revealed an increased incidence of nodular hyperplasia of the exocrine pancreas in animals of both sexes from group 4 (50000 ppm) and increased incidence (18/78) of exocrine pancreatic adenomas in male animals from group 4 (50000 ppm). These changes accounted for the majority of pancreatic nodules and/or masses found at autopsy. In 2/78 male rats from group 4 (50000 ppm) a carcinoma of the exocrine pancreas was recognised. The same type of lesion was also diagnosed in one control female.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
190 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: organ weights: higher liver and kidney weights; histopathology: pancreas
Dose descriptor:
NOAEL
Effect level:
226 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: organ weights: higher liver and kidney weights; histopathology: pancreas
Dose descriptor:
LOAEL
Effect level:
2 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: organ weights: higher liver and kidney weights; histopathology: pancreas
Dose descriptor:
LOAEL
Effect level:
2 620 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: organ weights: higher liver and kidney weights; histopathology: pancreas

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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