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EC number: 404-520-2 | CAS number: 139893-43-9 SIMVASTATIN AMMONIUM SALT
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
Description of key information
in an initial carcinogenicity study in rats, there was a treatment-relatedincrease in thyroid follicular cell adenomas (benign tumors) in female rats at a dosage of 25mg/kg/day that was considered secondary to enhancement ofthyroid hormone clearance. Therewas no increase in tumor incidence in mice up to 25mg/kg/day.Epithelial hyperplasia of the forestomach was observed in both studies.Simvastatin caused an increasedincidence in hepatocellular adenomas and carcinomas, pulmonary adenomas and harderian glandadenomas(NOAEL = 25 mg/kg/day). In rats, an increased incidence of hepatocellularneoplasms was observed (NOAEL = 25 mg/kg/day)
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26th June 1989 to 2nd July 1991
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- CRL:CD (SD) BR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Inc., Wilmington, MA
- Age at study initiation: 29 days
- Weight at study initiation: 58 - 102g
- Housing: one animal per cage in suspended steel cages, environmentally controlled clean air rooms
- Diet: Purina certified rodent chow ad libitum
- Water: Tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Photoperiod: 12hrs dark / 12hrs light) - Route of administration:
- oral: gavage
- Vehicle:
- other: Methylcellulose 0.5%
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test item was suspended in 0.5% aqueous methylcellulose and appropriate dilutions made with methylcellulose for the remaining dose groups
VEHICLE
- Concentration in vehicle: 50, 100, 250 and 500 mg/kg/day
- Amount of vehicle (if gavage): 5ml/kg dose volume - Duration of treatment / exposure:
- 106 weeks
- Frequency of treatment:
- Daily
- Post exposure period:
- None
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Treatment groups consisted of approximately 50 rats/sex/group and included 2 control groups which received the vehicle and 4 drug treated groups which received the test item at 50, 100, 250 and 500 mg/kg/day. Due to the severity of the top two doses, these groups were terminated and discarded without examination after 5 doses of 500 mg/kg/day and 21-22 doses of 250 mg/kg/day.
- Positive control:
- None
- Observations and examinations performed and frequency:
- CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during weeks 1-4 and weekly thereafter
PALPATATION FOR MASSES
- Time schedule: Weekly during weeks 1-60 and monthly thereafter
BODY WEIGHT: Yes
- Time schedule: Twice weekly during weeks 1-12 and weekly thereafter
FOOD CONSUMPTION
- Food consumption was measured weekly through week 60 on a 3 day intake period
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Weeks 13, 26, 52, 77 and 104
- Dose groups that were examined: All control groups and 50 and 100 mg/kg day groups.
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Weekly up to Week 61 from all moribund animals
Then a revision was made whereby blood samples were taken at time of necroscopy (early sacrifice or terminal necroscopy) from only those animals that showed enlargement of spleen, lymph nodes and/or liver. - Sacrifice and pathology:
- Complete necroscopies were carried out on all rats from the control groups and from the 50 and 100 mg/kg/day groups. This included microscopic examination of a detailed set of formalin-fixed, paraffin-embedded and hematoxylin-and-eosin stained slides.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg/day dose groups.
Clinical signs observed in the first few days of dosing. Rats had morbidity, severe weight loss, decreased food consumption, decreased activity, pilo-erection, fecal/urine staining, hind limb weakness, sternal recumbency and alopecia.
250 mg/kg/day dose groups.
Clinical signs observed in the first few days of dosing. Rats had morbidity, weight loss and/or markedly decreased weight gain (50-80% below control in first 2 weeks), decreased activity, pilo-erection, hind limb weakness and alopecia.
The severity necessitated the termination of the 500 and 250 mg/kg/da dose groups after 5 days and 4 weeks respectively.
50 and 100 mg/kg/day dose groups.
Excessive pre and/or post dose salivation - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 500 mg/kg/day dose groups.
8 rats in first five days of dosing. (4/sex)
250 mg/kg/day dose groups.
2 rats dead in the first 12 days of dosing. (Day 9 and 12)
8 rats sacrificed in moribund condition in the first 3 weeks of dosing. (6 female, 2 male) - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 500 mg/kg/day dose groups.
Average weight loss - 12.4g in females and 11.8g in males after 3 days of treatment.
250 mg/kg/day dose groups.
Average weight loss - 3.8g in females and 4g in males.
After 2 weeks of treatment weight gain began to improve and by week 3 the body weight of females began to approximate those of the control animals, while that of males remained 34% below the controls.
50 and 100 mg/kg/day dose groups.
A statistically significant decreasing trend in body weight gain was determined for females at both doses and for males at 100 mg/kg/day - Ophthalmological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg/day dose groups.
Increase in lenticular opacities after 103 weeks - 25.4% versus 14.8% in controls
posterior polar cataracts (PPC) - 2 animals
posterior subcapsular cataracts (PSC) - 7 animals
complete cataracts (CC) - 7 animals
50 mg/kg/day dose groups.
Similar to control at 103 weeks - however, the incidence of complete cataracts was 4/100 compared to 1/200 in controls - Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 100 mg/kg/day dose groups.
Hepatocellular adenoma females x 13, males x 12
Hepatocellular carcinoma females x 11, males x 12
50 mg/kg/day dose groups.
Hepatocellular adenoma females x 13, males x 6
Hepatocellular carcinoma females x 5, males x 4
Thyroid Gland
apparent increased incidence but not statistically significant - Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Hepatic and gastric changes:
Centrilobular, acidophilic and hypertrophy, focal cystic degeneration, eosinophilic and basophilic, focal cellular alteration of the liver, acanthosis, hyperkeratosis, cellular infiltration, and edema of the forestomach. - Key result
- Dose descriptor:
- NOEL
- Effect level:
- 25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical signs
- histopathology: neoplastic
- mortality
- ophthalmological examination
- Conclusions:
- At doses of 200 and 500 mg/kg/day, MK-0733 produced severe toxicity in rats necessitating early termination of these two treatment groups within the first 4 weeks of study initiation. Treatment related findings included loss of weight and/or marked depression in body weight gain accompanied by marked decrements in food intake, decreased activity, hind limb weakness/paralysis, morbidity and death.
In the 50 and 100 mg/kg/day treatment groups, MK-0733 was well tolerated. Treatment related changes included slight statistically significant decrements in body weight gain in females at both doses and in males at 100 mg/kg/day. In addition, an increased incidence of lenticular opacities occurred in both the 50 and 100 mg/kg/day dose animals after 103 weeks. An increased incidence of hepatocellular neoplasms was observed in both the 50 and 100 mg/kg/day dose groups.
In an initial carcinogenicity study in rats, there was a treatment-relatedincrease in thyroid follicular cell adenomas (benign tumors) in female rats at a dosage of 25mg/kg/day that was considered secondary to enhancement ofthyroid hormone clearance. Therewas no increase in tumor incidence in mice up to 25mg/kg/day.Epithelial hyperplasia of the forestomach was observed in both studies.Simvastatin caused an increasedincidence in hepatocellular adenomas and carcinomas, pulmonary adenomas and harderian glandadenomas(NOAEL = 25 mg/kg/day). In rats, an increased incidence of hepatocellularneoplasms was observed (NOAEL = 25 mg/kg/day). Therefore, the NOEL for carcinogenesis remains at 25 mg/kg/day (as established in this previous study). In addition, an increase in the incidence of thyroid hyperplastic lesions was also observed. The hyperplastic response induced by MK-0733 in the rat thyroid is a species specific response, directly related to the liver enlargement caused by MK-0733 in rats and has no implications for man.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 25 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
- Quality of whole database:
- 1
- Organ:
- liver
- lungs
- stomach
- thyroid gland
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Additional information
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