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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 20th January 1986 to 13th February 1986
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 986
Materials and methods
Test guideline
- Guideline:
- other: In accordance with standard operating procedures
- 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
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- crl:CD [SD] BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: 14.5 wks
- Weight at study initiation: 218 - 317g
- Housing: females housed singly in metal cages
- Diet: Purina Certified Rodent Chow #5002
- Water: Tap Water
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-27
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: aqueous methyl-cellulose
- Details on exposure:
- Suspension of MK-0733 in 0.5% aqueous methyl-cellulose prepared daily.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of suspensions for oral dosing were collected during the first and last weeks of dosing and assayed for concentration.
- Details on mating procedure:
- Each female was housed with one untreated male of the same strain. Females were selected for study when daily vaginal lavage revealed the presence of spermatozoa (Day 0 of gestation).
- Duration of treatment / exposure:
- Days 6 through 17 of gestation
- Frequency of treatment:
- Animals were dosed twice daily with a minimum of 4 hours between each dose.
- Duration of test:
- 11 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 3.125 mg/kg bw/day (nominal)
- Dose / conc.:
- 6.25 mg/kg bw/day (nominal)
- Dose / conc.:
- 12.5 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent no treatment
Examinations
- Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: animals were observed for physical signs at dosing, 5 hours post-dosing and once daily thereafter
BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 8, 10, 12, 14, 16, 18 and 20 of gestation.
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Measured every third day, starting Day 3 of gestation.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: skin, haircoat, thoracic and abdominal viscera.- Ovaries and uterine content:
- The uterus was examined to determine the reproductive status (pregnant/non-pregnant).
- Fetal examinations:
- Fetuses were examined and classified as live, dead or resorption. Gross necropsy was carried out.
All fetuses were weighed and examined externally. Approximately one third of fetuses from each litter were given a visceral examination by dissection. - Statistics:
- Statistical analyses were based on analysis of variance or covariance using a Least Significant Difference (LSD) procedure after normalising for non-parametric data by the Rankit method.
Parameters:
Maternal body weight changes
Percent preimplantation loss (litter mean)
Implants per pregnant female
Resorptions plus dead fetuses / implants (litter mean)
Live fetuses / pregnant female
Live fetal weight (litter mean) adjusted for litter size by covariant analysis
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Dead fetuses:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 6.25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a significant (P<0.05) decrease of 0.21g (5.4% less than control) in the mean fetal weight of the 12.5 mg/kg bw group.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 6.25 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- fetal/pup body weight changes
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
- Treatment related:
- no
Applicant's summary and conclusion
- Conclusions:
- There was no evidence of a teratogenic effect at dose levels up to 12.5 mg/kg b.i.d in rats receiving MK-0733 orally. A slight but significant (P<0.05) decrease in mean fetal body weight occurred in the 12.5 mg/kg b.i.d. group. This effect is considered probably treatment related but it is clear that no other indications of embryotoxicity were apparent.
Maternal toxicity was not seen in this study. Based on this data, the no-effect level for maternal and embryotoxicity in rats given MK-0733 is 6.25 mg/kg b.i.d - Executive summary:
The objective of the study was to assess the teratogenic effect of MK-0733 when adminstered to rats orally from Day 6 through 17 of gestation. A suspension of MK-0733 in 0.5% aqueous methyl-cellulose was prepared to give dose rates of 3.125, 6.25 and 12.5 mg/kg b.i.d. Rats were treated twice daily by oral gavage. Animals were observed for physical signs and body weights were recorded at 6, 8, 10, 12, 14, 16, 18 and 20 days gestation. Food consumption was recorded every third day.
On day 20, animals were sacrificed and their reproductive status determined. Fetuses were examined and classified as live, dead or resorption. Gross necropsy was carried out. All fetuses were weighed and examined externally. Approximately one third of fetuses from each litter were given a visceral examination by dissection.
Maternal body weight changes, Percent preimplantation loss (litter mean), Implants per pregnant female, Resorptions plus dead fetuses / implants (litter mean), Live fetuses / pregnant female, and Live fetal weight (litter mean) were measured.
There was no evidence of a teratogenic effect at dose levels up to 12.5 mg/kg b.i.d in rats receiving MK-0733 orally. A slight but significant (P<0.05) decrease in mean fetal body weight ocurred in the 12.5 mg/kg b.i.d. group. This effect is considered probably treatment related but it is clear that no other indications of embryotoxicity were apparent.
Maternal toxicity was not seen in this study. Based on this data, the no-effect level for maternal and embryotoxicity in rats given MK-0733 is 6.25 mg/kg b.i.d
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