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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary literature

Data source

Reference
Reference Type:
other:
Title:
Repeated dose oral toxicity of the test chemical
Author:
HERA risk assessments
Year:
2003
Bibliographic source:
HERA targeted risk assessment

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: FWA5
- Molecular formula: C28H20O6S2.2Na
- Molecular weight: 562.572 g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): 7% NaCl and 7% water

Test animals

Species:
rat
Strain:
other: Tif:RAIf, SPF
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
No data

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
No data
Vehicle:
other: Feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose level of 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females).

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Feed
- Concentration in vehicle: 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chemical analysis of the feed was done
Duration of treatment / exposure:
Chronic
Frequency of treatment:
No data
Doses / concentrations
Remarks:
0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females)
No. of animals per sex per dose:
No detailed data available
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- Cage side observations checked in table [No.?] were included. Mortality, appearance and behavior

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- 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: No data

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 data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
The test substance did not affect appearance and behavior and was similar in all groups of test.
Mortality:
no mortality observed
Description (incidence):
Mortality was unaffected by the test chemical
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
10% decrease in body weight were observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Increased food consumption was observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Water consumption showed a dose-related increase in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day)
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Hematology did not show treatment-related effects.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical blood chemistry parameters did not show treatment-related effects.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
An increase in urine output was observed in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day)
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, significantly increased organ-to-body weight ratios for liver (p<0.01) were seen in males (2300 mg/Kg/day), and in males and females for kidney (p<0.05) (2300 mg/Kg/day for males and 2620 mg/Kg/day for females). The test substance did not adversely affect other parameters.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Macroscopic examinations at necropsy revealed an increased incidence of pancreateic nodules and masses in the 2300 mg/kg/day males and 2620 mg/Kg/day females.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathology revealed statistically significant test article-related neoplastic effects to the pancreas of high dose males and females. Nodular hyperplasia of the exocrine pancreas was observed in 51 of 78 (p<0.001) high dose (2300 mg/Kg/day) males versus 6 of 78 control group males, and in 10 of 79 (p<0.05) high dose (2620 mg/Kg/day) females versus 1 of 78 control group females.

Other non-neoplastic lesions seen in the dosed animals were not related to treatment with FWA-5.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Exocrine pancreas adenoma, a benign tumor, was observed in males of the 5,000 and 50,000 ppm dose groups at an incidence of 2/79 and 18/78 (p<0.05), respectively, compared with 0/78 in control. Pancreatic carcinoma, a malignant tumor, was also observed in 2/78 high-dose males and although not statistically significantly increased, the rarity of this tumor and the treatment-related finding of adenomas in this group suggest the carcinomas could be related to the treatment. In females, adenomas in exocrine pancreas occurred only in the high dose (2620 mg/Kg/day) group (2/79) and were within the historical control range; carcinomas were not observed in any of the females.
Other effects:
no effects observed

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: No significant effects were noted at the mentioned dose level
Dose descriptor:
NOAEL
Effect level:
226 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The No observed adverse effect level (NOAEL) for the test chemical is considered to be 190 mg/kg/day for males and 226 mg/kg/day for females when they were exposed to the test chemical during the chronic exposure period.
Executive summary:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male and female Tif:RAIf, SPF strain rats. The test chemical was mixed with feed at dose levels of 0, 500, 5000, or 50,000 ppm (19, 190, and 2300 mg/kg/day in males and 21, 226, and 2620 mg/kg/day in females). During the chronic study period, the test animals were observed for mortality, clinical signs, changes in body weight, food and water consumption, urinanalysis, hematology and clinical chemistry parameters.The test substance did not affect appearance and behavior and was similar in all groups of test. Mortality was unaffected by the test chemical. 10% decrease in body weight were observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Increased food consumption was observed in 2300 mg/Kg/day dose group in males and 2620 mg/Kg/day dose group in females. Water consumption showed a dose-related increase in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day) and was associated with corresponding urine output. Hematology and chemistry parameters did not show treatment-related effects. An increase in urine output was observed in the two highest dose groups (190 and 2300 mg/Kg/day and 226 and 2620 mg/Kg/day). In the high dose group, significantly increased organ-to-body weight ratios for liver (p<0.01) were seen in males (2300 mg/Kg/day), and in males and females for kidney (p<0.05) (2300 mg/Kg/day for males and 2620 mg/Kg/day for females). The test substance did not adversely affect other parameters. Macroscopic examinations at necropsy revealed an increased incidence of pancreateic nodules and masses in the 2300 mg/kg/day males and 2620 mg/Kg/day females. Histopathology revealed statistically significant test article-related neoplastic effects to the pancreas of high dose males and females. Nodular hyperplasia of the exocrine pancreas was observed in 51 of 78 (p<0.001) high dose (2300 mg/Kg/day) males versus 6 of 78 control group males, and in 10 of 79 (p<0.05) high dose (2620 mg/Kg/day) females versus 1 of 78 control group females. Other non-neoplastic lesions seen in the dosed animals were not related to treatment with FWA-5. Exocrine pancreas adenoma, a benign tumor, was observed in males of the 5,000 and 50,000 ppm dose groups at an incidence of 2/79 and 18/78 (p<0.05), respectively, compared with 0/78 in control. Pancreatic carcinoma, a malignant tumor, was also observed in 2/78 high-dose males and although not statistically significantly increased, the rarity of this tumor and the treatment-related finding of adenomas in this group suggest the carcinomas could be related to the treatment. In females, adenomas in exocrine pancreas occurred only in the high dose (2620 mg/Kg/day) group (2/79) and were within the historical control range; carcinomas were not observed in any of the females. Based on the observations made, the No observed adverse effect level (NOAEL) for the test chemical is considered to be 190 mg/kg/day for males and 226 mg/kg/day for females when they were exposed to the test chemical during the chronic exposure period.