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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:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Acute (Mouse and Rat) and Short-term (Rat) Toxicity Studies on Blue VRS
Author:
D. E. Hall and I. F. Gaunt, Madge Farmer and P. Grasso
Year:
1967
Bibliographic source:
Fd Cosmet. Toxicol Vol. 5, pp. 165-170, 1967

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Data is from Journal with permission
Principles of method if other than guideline:
Chronic repeated dose toxicity was studied for Blue VRS in rats orally.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Blue VRS- Molecular formula: C27H31N2O6S2.Na- Molecular weight: 566.672g/mole - Substance type: Organic- Physical state: Solid- Impurities: 5.5 %

Test animals

Species:
rat
Strain:
other: SPF Carworth Farm E
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animalTEST ANIMALS- Source: No data available- Age at study initiation: No data available- Weight at study initiation: No data available- Fasting period before study: No data available- Housing: 5/cage- Diet (e.g. ad libitum): Spillers Small Laboratory Animal diet, ad libitum- Water (e.g. ad libitum): Water ad libitum- Acclimation period: No data availableENVIRONMENTAL CONDITIONS- Temperature (°C): No data available- Humidity (%):No data available- Air changes (per hr): No data available- Photoperiod (hrs dark / hrs light): No data availableIN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: Spillers Small Laboratory Animal diet
Details on oral exposure:
Details on oral exposurePREPARATION OF DOSING SOLUTIONS: No data availableDIET PREPARATION- Rate of preparation of diet (frequency): Daily - Mixing appropriate amounts with (Type of food): Spillers Small Laboratory Animal food - Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): Spillers Small Laboratory Animal diet - Concentration in vehicle: 0.0, 0.3, 0.75, 1.5 and 3.0% - Amount of vehicle (if gavage): No data available- Lot/batch no. (if required): No data available- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:0.0, 0.3, 0.75, 1.5 and 3.0 % (0, 150, 375, 750 and 1500 mg/kg/day)Basis:nominal in diet
No. of animals per sex per dose:
Total : 1800 % : 15 male and 15 female 0 % : 15 male and 15 female003 % : 15 male and 15 female0.75 % : 15 male and 15 female1.5 % : 15 male and 15 female3.0 % : 15 male and 15 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequencyCAGE SIDE OBSERVATIONS: Yes - Time schedule: Daily - Cage side observations checked in table [No.?] were included: Mortality were observed DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: Daily BODY WEIGHT: Yes - Time schedule for examinations: WeeklyFOOD 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: 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 data available WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available - Time schedule for examinations: No data available OPHTHALMOSCOPIC EXAMINATION: No data available - Time schedule for examinations: No data available - Dose groups that were examined: No data available HAEMATOLOGY: Yes- Time schedule for collection of blood: Weekly At 6 week and on terminally - Anaesthetic used for blood collection: Cardiac puncture No data available - Animals fasted: No data- How many animals: All the treated animals were examined. - Parameters checked in table [No.?] were examined: Erythrocytes, Packed cell volume, Hemoglobin concentration in all teeated animals and total and Dtfferentlal Leucocytes count in 0, 1.5 and 3.0 % dose groups were examined. CLINICAL CHEMISTRY: Yes - Time schedule for collection of blood: At 6 week and on terminally - Animals fasted: No data available - How many animals: All the treated animals were examined. - Parameters checked in table [No.?] were examined: Serum urea was examined. URINALYSIS: Yes - Time schedule for collection of urine: at week 12, a 6-hr period of water deprivation and during a 4-hr period beginning 16 hr after a water load of 25 ml/kg. - Metabolism cages used for collection of urine: : No data available - Animals fasted: : No data available - Parameters checked in table [No.?] were examined: pH, Specific gravity and Volume were examined. NEUROBEHAVIOURAL EXAMINATION: No data available - Time schedule for examinations: No data available - Dose groups that were examined: No data available - Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available OTHER:Absolute and relative organ weights were examined.Organ examined. Liver, Left and Right Kidneys, Brain, Heart, Spleen, Adrenals and Gonads were examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes Gross abnormalities were examined. HISTOPATHOLOGY: YesOrgan examined. Liver, Left and Right Kidneys, Brain, Heart, Spleen, Adrenals and Gonads were examined.
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mortality: No effect on servival were observed in treated rat as compared to control. Clinical signs: No effect were observed on health of treated rat as compared to control.
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality: No effect on servival were observed in treated rat as compared to control. Clinical signs: No effect were observed on health of treated rat as compared to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Impairment of growth was observed in male rats during the first 4 weeks in 1.5 and 3.0 % dose group.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption: Reduced food intake was observed in 1.5 and 3.0 % treated rats. Compound intake: Reduced in compound intake was observed in 1.5 and 3.0 % treated rats.
Food efficiency:
not specified
Description (incidence and severity):
Reduced
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
No departure from normality was observed; red cell morphology was also unaffected.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
No effect on kidney function investigated during the last week of treatment or on serum urea nitrogen determined terminally
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
The urine of all the animals receiving Blue VRS in the diet was bluish-green and slightly more acid than that of the controls. Proteinurea was comparable in test and control groups and no reducing substances were detected in the urine of any group.
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
No effect on the absolute or relative (g/100 g body weight) organ weights was observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Fatty changes in the liver of 1.5 and 0.3 % treated female rat were observed.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Histopathology:Increase number of active acini in the thyroids of 1.5 & 0.3% treated male and female rats were observed. Blue material in the lumen of convoluted tubules associated with a coloured line observed at the cortlcomedullary junction of kidney in male of 3.0% treated dose group. Retardation of growth in males at the 1.5 and 3.0 % dose group and occasional fatty change in the livers of some of the females at the 3.0 % dose group. Increase in the number of active follicles in the thyroids of both males and females of the treated groups but this is not necessarily attributable to Blue VRS. Histological changes associated with acinal activity occur in response to stress of various kinds.

Effect levels

Dose descriptor:
NOAEL
Effect level:
375 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight, food consumption, compound intake, haematology, clinical chemistry, organ weights, gross pathology and histopathology.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be 375 mg/kg/day (0.75 %) when SPF Carworth Farm E male and female rats were treated with Blue VRS.
Executive summary:

In a Chronic repeated dose toxicity study, SPF Carworth Farm E male and female rats were treated with Blue VRS at a concentration of 0.0, 0.3, 0.75, 1.5 and 3.0 % (0, 150, 375, 750 and 1500 mg/kg/day) orally. Impairment of growth, Reduction in food consumption, compound intake and bluish-green and slightly more acid urine were observed in 1.5 and 3.0 % treated male and female as compared to control. In addition, Fatty changes in the liver of female rat and increase number of active acini in the thyroids of male rat of 1.5 and 3.0 % treated animals. Blue material in the lumen of convoluted tubules associated with a coloured line observed at the cortcomedullary junction of kidney in male of 3.0 % treated dose groups but this was not necessarily attributable to Blue VRS. Histological changes associated with acinal activity occur in response to stress of various kinds were noted. Therefore, the no observed adverse effect level (NOAEL) was considered to be 375 mg/kg/day (0.75 %) when SPF Carworth Farm E male and female rats were treated with Blue VRS orally for 90 days.