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Diss Factsheets

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:
key study
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Test procedure in accordance with national standard methods (China) with acceptable restrictions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: Section 4 of the Guidelines for the Testing of Chemicals: Health Effects (ministry of environmental protection of People´s Republic of China)
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-Propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole
IUPAC Name:
2-Propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Shanghai SLAC Laboratory Animal Co., Ltd.- Weight at study initiation: 116 to 130g- Housing: every two animals were kept in a polycarbonate box, which was disinfected with an autoclave; boxes were changed twice every week- Diet (e.g. ad libitum): no data- Water (e.g. ad libitum): ad libitum- Acclimation period: 5 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20°C to 25°C- Humidity (%): 40 to 70%- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% CMC-Na
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
once daily (volume 5 mL/kg bw)
Doses / concentrations
Remarks:
Doses / Concentrations:250, 50, 10 mg/kg bw/dBasis:
No. of animals per sex per dose:
10
Control animals:
other: yes
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No dataDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: daily (dermahemia, bruise, fluffy fur, ophthalmoptosis, blood discharge, slow breathing, rapid breathing, ached back, cahexia, unusual cry, physical agitation, unusual posture, limpness, jumping, mast tail, tremors, spasm, convulsion, unbalanced movement, retard reaction, hyper-reflexia, diarrhea, anorexia, pupil dilation, pupil reduction, salivating, tearing, dirty perineum, urine incontinence, death)BODY WEIGHT: Yes - Time schedule for examinations: weeklyFOOD EFFICIENCY: food consumption weeklyWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): NoOPHTHALMOSCOPIC EXAMINATION: NoHAEMATOLOGY: Yes - Time schedule for collection of blood: at the end of the test- How many animals: all- Parameters checked: red blood cell, hemoglobin content, white blood cell, differential leukocyte count, platelet counts, plasma prothrombin and activated partial thromboplatinCLINICAL CHEMISTRY: Yes - Time schedule for collection of blood: at the end of the test- How many animals: all- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase total protein, albumin, bilirubin total, blood urea nitrogen, creatinine, cholinesterase, cholesterol total, glucose, Na, K, Cl, Ca and P ions.URINALYSIS: Yes - Time schedule for collection of urine: at the end of the test- Parameters checked: specific gravity, pH, protein contents, blood/blood cells and glucose concentrationsNEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes HISTOPATHOLOGY: Yes (brain, heart, lung, liver, thymus, spleen, kidney, adrenal gland, testis or ovary, nervus ischiadicus, cervical, spinal cord, thyroid, stomach, duodenum, jejunum, ileum, colon, rectum, mesenteric lymph node, prostate, epididymides, urinary bladder and uterus)
Statistics:
ANOVA, t-test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
additional high dose males/females = additional group tested with 250 mg/kg bw/d with additional 14-day recovery periodadditional control group males/females = additional control group with additional 14-day recovery periodCLINICAL SIGNS AND MORTALITYNo obvious clinical signs or death in any group during the whole experimental periodBODY WEIGHT AND WEIGHT GAINThere were significant decreases of body weights of males of high dose group from 2nd to 13th week. The body weights of the additional high dose males (250 mg/kg bw/d with additional 14-day recovery period) were significantly decreased from 2nd to 15th week.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)FOOD EFFICIENCYThere were significant decreases of total food efficiency of males of high dose group from 2nd to 13th week. The total feed efficiency of the additional high dose females (250 mg/kg bw/d with additional 14-day recovery period) was significantly decreased. The total feed efficiency of the additional high dose males (250 mg/kg bw/d with additional 14-day recovery period) was significantly decreased from 2nd to 15th week.WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)OPHTHALMOSCOPIC EXAMINATIONHAEMATOLOGYA significant decrease of WBC in females of high dose group was noted. Furthermore, values of RBC in females of additional high dose group were significantly decreased. Despite the statistical differences, these changes were not clinically meaningful.CLINICAL CHEMISTRYOn serum biochemical examination, values of CHOL, K, Ca and P in high dose females were significantly decreased, and values of Ca in mid dose females were significantly increased. Values of Ca and P were significantly increased and values of TP were significantly decreased in high dose males. Values of ALB were significantly decreased in additional high dose females and values of ALT, AST and K were significantly decreased in additional high dose males.URINALYSISThere was no abnormality of the specific gravity, color, pH, glucose, crypt-blood and protein contain.NEUROBEHAVIOURORGAN WEIGHTSA significant increase in absolute weights of kidneys and relative organ weights of heart, liver, spleen and kidneys in high dose females were noted. Significant increases in relative organ weights of lung and kidneys in high dose males and a significant increase in relative organ weight of lung in mid dose (50 mg/kg bw/d) males were noted. The relative organ weights of brain, spleen, lung, kidneys and testes in additional high dose males (250 mg/kg bw/d with 14-day recovery period) were significantly increased while absolute weights of heart, liver and adrenal glands were significantly decreased. There was a significant increase in absolute weights of adrenal glands in additional high dose females.GROSS PATHOLOGYUneven appearance of the kidneys of high dose animals and additional high dose animals was noted during macroscopical observation.HISTOPATHOLOGY: NON-NEOPLASTICThe histopathological results under optic microscope were described as follows:Control group (10 female animals): no overt abnormalities.High dose group (10 female animals): light-grade hydropic degeneration/ negrosis of the renal tubule epithelium with light grade interstitial inflammatory cell infiltration in one case; mid-grade hydropic degeneration/necrosis of the renal tubule epithelium with mid-grade interstitial inflammatory cell infiltration in 3 cases; light-grade hydropic degeneration of the renal tubule epithelium in 4 cases; light-grade hydropic degeneration of the renal tubule epithelium with light-grade interstitial inflammatory cell infiltration in 1 case; mid-grade hydropic degeneration/necrosis of the renal tubule epithelium, mid-grade renal tubular dilatation and light-grade renal tubular cast with light-grade interstitial inflammatory cell infiltration in 1 case.Control group (10 male animals): focal necrosis of the myocardial cells with light-grade infiltration of inflammatory cells in the subepicardial layer in 1 case; light-grade hepatocyte fatty degeneration in 3 cases; mid-grade hepatocyte fatty degeneration in 1 case; light-grade infiltration of inflammatory cells of interstitial tissue of prostate in 3 cases.High dosage group (10 male animals): focal necrosis of the myocardial cells with light-grade infiltration of inflammatory cells in the subepicardial layer in 1 case ; light –grade hepatocyte fatty degeneration in 3 cases; mid-grade hepatocyte fatty degeneration in 1 case; light-grade hydropic degeneration of the renal tubule epithelium in 2 cases; mid-grade hydropic degeneration of the renal tubule epithelium in 2 cases; light-grade hydropic degeneration/necrosis of the renal tubule epithelium in 1 case, light-grade infiltration of inflammatory cells of interstitial tissue of prostate in 3 cases Mid dosage group (10 female animals): light-grade hydropic degeneration of the renal tubule epithelium in 2 cases; mid-grade hydropic degeneration of the renal tubule epithelium in 1 case.Mid dosage group (10 male animals): light-grade hydropic degeneration of the renal tubule epithelium in 3 cases.Low dosage group (10 female animals): light-grade infiltration of inflammatory cells beneath the mucosa of the pelvis in 1 case.Low dosage group (10 male animals): no overt abnormalities.Additional control group (10 female animals): no overt abnormalities.Additional high dosage group (10 female animals): mid-grade hydropic degeneration/necrosis of the renal tubule epithelium with mid-grade interstitial inflammatory cell infiltration and light-grade dilatation of collecting tube in the renal papillae in 1 case; light-grade hydropic degeneration/necrosis of the renal tubule epithelium with light-grade interstitial inflammatory cell infiltration in 2 case; light-grade hydropic degeneration/necrosis of the renal tubule epithelium with mid-grade interstitial inflammatory cell infiltration in 2 cases, mid-grade hydropic degeneration/necrosis of the renal tubule epithelium with mid-grade interstitial inflammatory cell infiltration in 2 cases; light grade hydropic degeneration of the renal tubule epithelium in 2 cases.Additional control group (10 male animals): light-grade hepatocyte fatty degeneration in 3 cases; mid-grade hepatocyte fatty degeneration in 1 case: light –grade infiltration of inflammatory cells of interstitial tissue of prostate in 3 cases.Additional high dosage group (10 male animals): light-grade hepatocyte fatty degeneration in 2 cases; light-grade hydropic degeneration/necrosis of the renal tubule epithelium with light-grade interstitial inflammatory cell infiltration in 1 case; high-grade hydropic degeneration/necrosis of the renal tubule epithelium and light-grade renal tubular cast with high-grade interstitial inflammatory cell infiltration in 1 case; high-grade hydropic degeneration/necrosis of the renal tubule epithelium with high-grade interstitial inflammatory cell infiltration and mid-grade renal tubular dilatation in 1 case; mid-grade hydropic degeneration/necrosis of the renal tubule epithelium with mid-grade interstitial inflammatory cell infiltration in 3 cases; mid-grade hydropic degeneration/necrosis of the renal tubule epithelium and mid-grade renal tubular cast with mid-grade interstitial inflammatory cell infiltration in 1 case.HISTOPATHOLOGY: NEOPLASTIC (if applicable)HISTORICAL CONTROL DATA (if applicable)OTHER FINDINGS

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effectsbody weight; food efficiency; clinical chemistry; gross pathology; organ weights; histopathology;

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no observed adverse effect level (NOAEL) of the substance is considered to be 10 mg/kg bw/d for rats under the conditions of this study.