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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
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
- Toxic effect type:
- dose-dependent
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Justification for type of information:
- Intertnal method in accordance with SOPs.
- Qualifier:
- according to guideline
- Guideline:
- other: Internal method in accordance with standard operating procedures.
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Composition:
98.4% L-654,969 - Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- 15 females and 15 males
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- dosed twice daily for 91 days males and 92 days females.
- Duration of treatment / exposure:
- Test duration: 90 days
- Frequency of treatment:
- Dosing regime: 7 days/week
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- control
- Dose / conc.:
- 2 mg/kg bw/day (nominal)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- Male: 15 animals at 0 mg/kg bw/day
Male: 15 animals at 2 mg/kg bw/day
Male: 15 animals at 10 mg/kg bw/day
Male: 15 animals at 20 mg/kg bw/day
Female: 15 animals at 0 mg/kg bw/day
Female: 15 animals at 2 mg/kg bw/day
Female: 15 animals at 10 mg/kg bw/day
Female: 15 animals at 20 mg/kg bw/day - Control animals:
- yes, concurrent vehicle
- Clinical signs:
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No drug-related mortality was observed. A moribund rat in the low dose group was sacrificed in Week 1. Gross examination revealed that the cause of death was due to an intubation accident.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The was no difference in the bodyweight gain of control and treated female rats. There was a decrease in bodyweight gain of high dose males (8%, p=0.018) and a slight, but not statistically significant decrease (4%, p=0.57) in bodyweight gain of middle dose males as compared to controls.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There was no difference in the food consumption between control and treated rats.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in haematology in control and treated rats.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in serum biochemistry in control and treated rats.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related differences in urinalysis in control and treated rats.
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In addition, increased liver weights were seen (absolute and relative to brain and bodyweight) in the middle and high dosage group females; no similar changes were observed in males. Histologically, the only liver changes apparent were cellular atypia and bile duct proliferation in 2 females in the high dose group. No other animals in this study showed similar changes.
There was a non-significant but dose-related trend towards increased thyroid weights in females in all 3 treatment groups and in males in the middle and high dose groups. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At necropsy, grossly thickened non-glandular mucosa was observed in the stomachs of rats in all treated groups.
Microscopically, this appeared as very slight to moderate hyperkeratosis and acanthosis with submucosal oedema and cellular infiltration present. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- < 2 mg/kg bw/day (nominal)
- Based on:
- not specified
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- gross pathology
- organ weights and organ / body weight ratios
- Remarks on result:
- other: due to the increased incidence of changes in the stomachs of all treated rats, a NOEL could not be specifically established; NOEL therefore defined above as < the lowest dose given.
- Critical effects observed:
- not specified
- Conclusions:
- No no-effect level was established. The changes observed in the nonglandular mucosa of rats are similar to those observed in studies with structurally-related compounds.
Although the pathogenesis of the changes is not clearly understood, it appears to be related to the inhibition of HMG-CoA reductase caused by the substance. No similar gastric epithelium is found, nor in the dog oesophagus, where similar squamous epithelium is found. Since the effect appears to be specific to the rat, it is not considered to be relevant to human exposure.
The notifier thus considers, despite the fact that no "no-effect level" has been established, that the substance should be classifed as STOR RE 1 and labelled with H372. The Irish CA considers that the substance should be classified as "Toxic".
This 90-day study has been compared with Annex V and also the OECD 90-day Guideline No. 408.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEL
- 2 mg/kg bw/day
- Study duration:
- subchronic
- Experimental exposure time per week (hours/week):
- 13
- Species:
- rat
- Quality of whole database:
- 1
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for classification or non-classification
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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