Registration Dossier
Registration Dossier
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EC number: 404-520-2 | CAS number: 139893-43-9 SIMVASTATIN AMMONIUM SALT
Repeated dose toxicity: other routes
Administrative data
- Endpoint:
- repeated dose toxicity: other route
- Adequacy of study:
- other information
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Title:
- Unnamed
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: Internal company method in accordance with standard operating procedures.
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
- EC Number:
- 404-520-2
- EC Name:
- Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
- Cas Number:
- 139893-43-9
- Molecular formula:
- C25 H43 O6 N
- IUPAC Name:
- ammonium 7-{8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5-dihydroxyheptanoate
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- Composition:
98.4% L-654,969
Test animals
- Species:
- rabbit
Administration / exposure
- Vehicle:
- methylcellulose
- Remarks:
- 0.5% aqueous methylcellulose
- No. of animals per sex per dose:
- Female: 3 animals at 0 mg/kg bw/day
Female: 10 animals at 90 mg/kg bw/day
Results and discussion
Results of examinations
- Clinical signs:
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One rabbit was found dead prior to dosing on the last day of the study, while another animal appeared moribund.
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption was markedly reduced in 8/10 test animals from day 1 onwards, complete anorexia being seen in 7/10 by day 4 of the study.
- Food efficiency:
- effects observed, treatment-related
- Description (incidence and severity):
- Low or no output of faeces and urine correlated closely with the reductions in food and water consumption.
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced or no water intake was observed in 7/10 test animals by day 4 of dosing.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Serum aspartate aminotransferase (AST) and alanine aminotranferase (AST) were mildly elevated (2-4 times above the control group average) in most test animals by day 3 of the study. By day 6 values of AST in 3/8 surviving animals were over 2000 u/l. Increases were particularly marked in the animal found dead on day 6 and in the moribund animal.
AST levels tended to be higher than ALT, and serum alkaline phosphatase levels were also elevated, although the increases were not as marked.
Serum creatinine and urea nitrogen level were increased (2-3 fold over controls) by day 6 of the study. No treatment-related effects on arterial pH, pCO2, HCO3 and serum electrolytes (Na+, K+, cl+) were observed on days 3-6. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathological examination was limited to liver, kidneys, and any macroscopic abnormalities, Treatment - related yellow-red reticulation of the liver was seen in 8/10 treated animals, pale kidneys in 7/10, and 3/10 had occasional small red foci on the stomach mucosa.
Centrilobular necrosis (slight) was seen in the 8 rabbits showing macroscopic liver changes, with a proportion also showing centrilobular congestion and hepatocellular vacuolation. 6/10 test animals had moderate to marked choleocystitis of the gallbladder. Slight to moderate proximal tubular vacuolation was present in 7/10 animals, with a proportion also showing tubular necrosis, focal tubular basophilia, tubular distension and presence of proteinaceous casts. 2/3 rabbits showing macroscopic abnormalities in the stomach had small erosions in the pyloric mucosa. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
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