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EC number: 606-396-7 | CAS number: 198904-86-8
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 23 December 1999 to 31 January
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 000
- Report date:
- 2000
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(pyridin-2-yl)benzyl]hydrazinecarboxylate
- EC Number:
- 606-396-7
- Cas Number:
- 198904-86-8
- Molecular formula:
- C32H42N4O5
- IUPAC Name:
- tert-butyl 2-{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}-2-[4-(pyridin-2-yl)benzyl]hydrazinecarboxylate
- Test material form:
- solid
- Details on test material:
- - Appearance: Off-white powder
- Storage condition of test material: At room temperature protected from light
Constituent 1
- Specific details on test material used for the study:
- yellow/off white solid; 99.15% purity
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on species / strain selection:
- Supplier: Charles River Laboratories
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Animals were aged 4 weeks on receipt and were 6 weeks at the initiation of dosing. Animals were acclimated for approximately 2 weeks prior to study start and were examined during the acclimation period to determine suitability
Weight at start:
Males mean weight 197g
Females mean weight 161g
Light/Dark Cycle
A twelve hour light/dark cycle controlled via an automatic timer was provided.
Temperature
Temperature was monitored and recorded twice daily and maintained within the specified range to the maximum extent possible. Excursions outside the specified range were not considered to have affected the integrity of the study because they
were minimal and of brief duration.
Desired: Actual:
18 to 26°C
21 to 27°C
Relative Humidity
Relative humidity was monitored and recorded once daily and maintained within the specified range to the maximum extent
possible.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Oral, via intubation
- Vehicle:
- corn oil
- Details on oral exposure:
- Animals were dosed daily with the appropriate amounts of test articel via the oral gavage route for 29 days. Test articel adminstration continued through the day prior to necrospy.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- All dose level preperations were assayed during the 4 weeks (one sample and 2 sub samples per concentration) of dosing. Analysis was conducted to determine homogenicity, stability and concentration
- Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 5 animals per sex per dose
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- The study was designed to evaluate the potential toxicity of BMS 233101-01 when administered orally, via gastric intubation, to Sprague-Dawley CD® rats (5/sex/group) at dose levels of 15, 150, and 1000 mg/kg/day for a period of 4 weeks. Control animals (5/sex) received the vehicle (Com Oil) at the same dose volume (5 mUkg) as administered to the treated animals. The dose levels were selected based on the results of a 7-day range-finding study.
- Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- Animals were removed daily from there cages and examined twice pretest and once weekly during the study period. Examinations included observations of general condition, respiration, skin and fur, eys, nose, oral cavity, abdomen and external genitalia as well as evaluations for any unusual behavioral signs and clinical signs of toxic or pharmalogical effects and palpatation for tissue masses. Behavioural assessment was performed in conjuction with the physical examinations and inlcuded changes in gait, posture, response to handling, stereotypic and abnormal behaviours. During the pretest week and week 4 this examination was replaced with a full neirobehavioral examination.
- Sacrifice and pathology:
- Euthanasia was performed with carbon dioxide inhalation at termination of the study. Necropsy was scheduled to established to ensure that examination of the animals of both sexes was performed at simlliar times of the day.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- With the exception of alopecia noted in one group III and one group IV female there was no other clinical signs of treatment related effects
- Mortality:
- no mortality observed
- Description (incidence):
- All animals survived the 4 weeks of dosing
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant differences in body weights in group in the 3 test group compared to the control
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No significant differences in food consumption in the 3 test group compared to the control
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- No significant differences in hematology values in treament groups when compared to the controls
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- No significant differences in clinical chemistry values in treament groups when compared to the controls
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No macroscopic findings attributed to the treatment with BMS 233101. Macroscopic findings seen were sporadic and of the type commonly found as incidenital finding in that species
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- No reproducible significant differences in the functional observations in groups II,III and IV compared to the controls.
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No microscopic findings attributed to the treatment with BMS 233101. MAcroscopic findings seen were sporadic and of the tpye commonly found as incidenital finding in that species
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Non-toxic at all levels tested.
- Remarks on result:
- other: Non-toxic
Target system / organ toxicity
- Key result
- Critical effects observed:
- no
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
Applicant's summary and conclusion
- Conclusions:
- In conclusion, the dose levels of 1000, 150 and 15 mg/kg/day of BMS 233101-01 were considered non-toxic levels, when administered daily for 4 weeks by the oral route. Therefore, the high dose level of 1000 mg/kg/day was considered a NOEL (No Observed Effect Level).
- Executive summary:
This study was conducted for Bristol-Myers Squibb Company. It was designed to evaluate the potential toxicity of BMS 233101-01 when administered orally, via gastric intubation, to Sprague-Dawley CD® rats (5/sex/group) at dose levels of 15, 150, and 1000 mg/kg/day for a period of 4 weeks. Control animals (5/sex) received the vehicle (Com Oil) at the same dose volume (5 mUkg) as administered to the treated animals. The dose levels were selected based on the results of a 7-day range-finding study.
Data from this study may serve as a basis for classification and labeling of the test article.
Physical observations, body weight measurements and feed consumption measurements were performed pretest and weekly during the study. Motor activity and functional observational battery were performed pretest and during the fourth week of dosing. After4 weeks of treatment, hematology and clinical chemistry evaluations were performed, all animals were euthanatized, selected organs were weighed and organ/body weight and organ/brain weight ratios calculated. Complete macroscopic postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals.
All animals survived the four weeks of dosing. There were no clinical signs of treatment noted in any group during the four weeks of dosing. There were no significant differences in body weights, feed consumption, motor activity and functional observation battery during the four weeks of dosing. There were no significant differences in hematology and clinical chemistry values. There were no significant differences in organ weights, macroscopic postmortem findings and microscopic postmortem findings.
In conclusion, the dose levels of 1000, 150 and 15 mg/kg/day of BMS 233101-01 were considered non-toxic levels, when administered daily for 4 weeks by the oral route. Therefore, the high dose level of 1000 mg/kg/day was considered a NOEL (No Observed Effect Level).
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