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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:
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: secondary source
Title:
OPINION ON PHENYLBENZIMIDAZOLE SULFONIC ACID AND ITS SALTS
Author:
HEALTH AND CONSUMER PROTECTION DIRECTORATE GENERAL
Year:
2006
Bibliographic source:
OPINION ON PHENYLBENZIMIDAZOLE SULFONIC ACID AND ITS SALTS- SCCP/1056/06

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
The objective of this study was to evaluate the subchronic toxicity of the given test substance in Wistar rats.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid
Details on test material:
- IUPAC name:Phenylbenzimidazole Sulfonic Acid
- Molecular formula: C13H10N2O3S
- Molecular weight: 274.299g/mol
- Substance type: organic
-Physical state: solid

Test animals

Species:
rat
Strain:
Wistar
Remarks:
W.74 (SPF)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 5% aqueous tylose
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): 5% aqueous tylose
- Concentration in vehicle: 0, 100, 330 and 1000 mg/kg bw
- Lot/batch no. (if required): 414 512

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg body weight.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
7 days/week
Doses / concentrations
Remarks:
Dose levels: 0, 100, 330 and 1000 mg/kg bw
No. of animals per sex per dose:
Test: 30 animals [15♂, 15♀]/ dose group)
Control: 30 animals [15♂, 15♀]
Control animals:
yes
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations were carried out daily on all animals.
- Cage side observations checked: Mortality was observed.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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: Not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified
- Food consumption were recorded weekly.

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: Not specified

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

OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations: Not specified
- Dose groups that were examined: Not specified

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 6 and at termination of the study
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 5 males and 5 females of each group.
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 6 and at termination of the study
- Animals fasted: Not specified
- How many animals: 5 males and 5 females of each group.
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: Yes
- Time schedule for collection of urine: week 6 and at termination of the study
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined.No data available

NEUROBEHAVIOURAL EXAMINATION: Not specified
- Time schedule for examinations:Not specified
- Dose groups that were examined:Not specified
- Battery of functions tested: sensory activity / grip strength / motor activity / other:Not specified

IMMUNOLOGY: Not specified
- Time schedule for examinations: Not specified
- How many animals: Not specified
- Dose groups that were examined: Not specified
- Parameters checked in table [No.?] were examined.Not specified

OTHER: No data available
Sacrifice and pathology:
Anatomic pathology examinations comprised organ weights, necropsy, histopathology.
GROSS PATHOLOGY: Yes
Organ weights (thymus, thyroid, heart, lung, liver, spleen, kidneys, adrenals, testes,ovaries) were determined for all animals. All animals were also subjected to macroscopic inspection after necropsy.

HISTOPATHOLOGY: Yes
Histopathological examination was carried out in 5 male and 5 female animals of the control- and the 1000 mg/kg-group. The organs looked at were:heart, lung, liver, pancreas, spleen, kidneys, pituitary, thyroid, thymus, adrenals,testes/epididymes, prostate gland, seminal vesicles, ovaries, uterus, salivary gland (head),oesophagus, stomach, intestines (duodenum, jejunum, ileum, olon), lymph nodes, bladder, brain, eyes, aorta, trachea, skeletal muscles, bones, bone marrow).
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were seen in any group.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Three mortalities (1♂, week 5, control group; 1♀, week 13, 330 mg/kg-group; 1♀, week 6, 1000 mg/kg-group) occurred intercurrently but were not substance related.
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was the same in test and control groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Water consumption was the same in test and control groups.
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
Haematology results (total and differential blood count) of test animals did not differ from controls throughout the experiment.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Clinico-chemical parameters of test animals did not differ from controls throughout the experiment except for protein content in serum in females of the 1000 mg/kg-group, which was increased as compared to controls.However, the level found was within the biological variability range on record for female rats of this age and was therefore not considered substance related.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Differences in organ weights, if observable at all (e.g. spleen in ♀'s), were small and not dose dependent.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Necropsy-findings in the animals which had died intercurrently, revealed no pathological changes attributable to the test substance. Neither did the animals which were sacrificed pursuant to protocol at the end of the study exhibit any such changes.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Histopathology did not reveal any organ change or –damage in any one of the dose groups.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
food consumption and compound intake
water consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No toxic effect were observed

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
On the basis of the parameters examined, the NOAEL value was considered to be 1000 mg/kg/day in male and female rats for 13 weeks study by oral gavage.
Executive summary:

The sub-chronic toxicity study was conducted by using the given test chemical as per OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) in male and female Wistar rats at the concentration of 0, 100, 330 and 1000 mg/kgbw/day for 13 weeks via oral gavage route. The given test chemical was dissolved in 5% aqueous tylose and administered as 10 ml/kg bw via oral gavage route. Control animals received vehicle only. Animals were treated as given above and examined with respect to in-life-observations, clinical pathology and anatomic pathology. In-life-observations were carried out daily on all animals for mortalities and clinical signs of toxicity. Body weight and food-/water consumption were recorded weekly. Clinical pathology, viz. haematology, clinical chemistry and urinalysis, was performed in week 6 and at termination of the study using 5 males and 5 females of each group. Anatomic pathology examinations comprised organ weights, necropsy, histopathology. Organ weights (thymus, thyroid, heart, lung, liver, spleen, kidneys, adrenals, testes, ovaries) were determined for all animals. All animals were also subjected to macroscopic inspection after necropsy. Histopathological examination was carried out in 5 male and 5 female animals of the control- and the 1000 mg/kg-group. The organs looked at were: heart, lung, liver, pancreas, spleen, kidneys, pituitary, thyroid, thymus, adrenals, testes/epididymes, prostate gland, seminal vesicles, ovaries, uterus, salivary gland (head), oesophagus, stomach, intestines (duodenum, jejunum, ileum, olon), lymph nodes, bladder, brain, eyes, aorta, trachea, skeletal muscles, bones, bone marrow).

Three mortalities (1♂, week 5, control group; 1♀, week 13, 330 mg/kg-group; 1♀, week 6, 1000 mg/kg-group) occurred intercurrently but were not substance related. No clinical signs of toxicity were seen in any group. Food- and water consumption were the same in test- and control groups. Haematology results (total and differential blood count) of test animals did not differ from controls throughout the experiment. The same holds for clinico-chemical parameters, except for protein content in serum in females of the 1000 mg/kg-group, which was increased as compared to controls. However, the level found was within the biological variability range on record for female rats of this age and was therefore not considered substance related. Necropsy-findings in the animals which had died intercurrently, revealed no pathological changes attributable to the test substance. Neither did the animals which were sacrificed pursuant to protocol at the end of the study exhibit any such changes.

Differences in organ weights, if observable at all (e.g. spleen in ♀'s), were small and not dose dependent. Histopathology did not reveal any organ change or –damage in any one of the dose groups.

Based on the above study, the toxicologically no adverse effect amount by repetitive oral administration of test substance for 13 weeks was observed and hence under this test condition NOAEL was considered to be1000 mg/kg bw/day.