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EC number: 478-250-9 | CAS number: -
- 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
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 478-250-9
- EC Name:
- -
- Cas Number:
- 62965-37-1
- Molecular formula:
- C26H42N2O4
- IUPAC Name:
- (2S)-2-{[(benzyloxy)carbonyl]amino}-3,3-dimethylbutanoic acid; N-cyclohexylcyclohexanamine
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- Batch number 25557
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD (SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 43-49 days (at the start of treatment)
- Weight at study initiation: males 253-295 g, females 168-211 g (at the start of treatment)
- Fasting period before study: overnight
- Housing: 5 of one sex/cage
- Diet: standard rodent diet
- Water: ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22°C
- Humidity (%): 23-61%
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 11.01.2007 To: 08.02.2007
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1% w/v methylcellulose in water
- Details on oral exposure:
- 1.0%w/v Methylcellulose in water for formulation
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Before treatment commenced, the suitability of the proposed mixing procedure was determined and specimen formulations were analysed at
concentrations of 1 and 100 mg/mL to assess the homogeneity and stability of the test substance in the vehicle. Samples of each formulation
prepared for administration in Week 1 of treatment were analysed for achieved concentration of the test substance.
Apparatus and instrumentation
High performance liquid chromatograph (HPLC): High performance liquid chromatograph (HPLC) fitted with a UV-Vis detector.
Chromatography data handling: Waters Empower
Balances fitted with printers: Capability of weighing to accuracies of 0.1 mg, 0.01 mg and 0.001 mg.
General laboratory apparatus and glassware. - Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
15, 150 and 300 mg/kg/day
Basis:
nominal in water
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
Examinations
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- See details on results below.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See details on results below.
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
During the entire study period there was no unscheduled mortality noted at any dose level.
Clinical signs of toxicological importance comprised partially closed eyelids, hunched
posture and piloerection, which were observed in both sexes receiving 300 mg/kg/day and
underactive behaviour which was observed in females receiving 300 mg/kg/day.
BODY WEIGHT AND WEIGHT GAIN
Lower overall bodyweight gains were evident for males at 300 mg/kg/day,
whilst females at 150 or 300 mg/kg/day showed higher weight gains.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Lower food intake was evident in males at 300 mg/kg/day,
whilst females dosed with 300 mg/kg/day had a higher than control food intake.
FOOD EFFICIENCY
No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No data
OPHTHALMOSCOPIC EXAMINATION
No data
HAEMATOLOGY
Lower than control group mean haematocrit, haemoglobin and red blood cell counts were
recorded for females receiving 150 mg/kg/day and both sexes receiving 300 mg/kg/day.
These female groups also showed lower than control MCH and MCV values. In addition
females receiving 15 mg/kg/day had a tendency to exhibit lower than control haematocrit
with males at 150 mg/kg/day also showing lower haemoglobin levels.
CLINICAL CHEMISTRY
for all treated male groups. Mean creatinine values for females receiving 300 mg/kg/day
were also lower than controls. Lower than control group mean cholesterol values were
recorded for both sexes receiving 300 mg/kg/day. In addition lower than control total protein
(due to both a lowering in albumin and globulin) was recorded for females receiving 300
mg/kg/day, with lower globulin also being apparent in males at this dose level.
URINALYSIS
No data
NEUROBEHAVIOUR
Hindlimb grip strength values for males and females receiving 300 mg/kg/day were low
when compared with controls. Additionally, when compared with controls, high beam scores
(rearing activity) and low beam scores (cage floor activity) for males and females receiving
300 mg/kg/day were low throughout most of the 1-hour recording period, with the differences
being somewhat more marked in females.
Most or all of the individual total scores for these treated animals were lower than those of
the concurrent control animals.
High beam scores and, to a lesser extent, low beam scores for males receiving 150 mg/kg/day
were also low when compared with controls, with some evidence of a dose-relationship
between these animals and the males receiving 300 mg/kg/day. Motor activity scores for
females receiving 150 mg/kg/day and both sexes at 15 mg/kg/day were, however, unaffected.
ORGAN WEIGHTS
Heavier than control group bodyweight-adjusted mean kidney weights were recorded for both
sexes receiving 150 or 300 mg/kg/day. Males dosed with 300 mg/kg/day also showed
elevated bodyweight-adjusted mean liver weight compared with controls. Heavier than
control mean adrenal weight was recorded for both sexes receiving 300 mg/kg/day.
GROSS PATHOLOGY
Enlarged adrenals were seen in 3/5 females dosed at 300 mg/kg/day.
HISTOPATHOLOGY: NON-NEOPLASTIC
Treatment with 300 mg/kg/day was associated with cortical hypertrophy and hyperplasia in
the adrenals of female rats, an increased degree of aggregations of foamy alveolar
macrophages in the lungs of male and female rats and extramedullary haemopoiesis in spleen
of female rats. Treatment with 150 mg/kg/day was associated with cortical hypertrophy in
the adrenals and extramedullary haemopoiesis in the spleen of female rats. Treatment with
15 mg/kg/day was associated with cortical hypertrophy in the adrenals of female rats. As this
alteration was only slight and seen in 5/5 females each dosed at 15 and 150 mg/kg/day but only
in 2/5 dosed at 300 mg/kg/day, the finding could not be attributed to the treatment with the test
item. Therefore it was not considered for the overall assessment concerning the NOAEL.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No data
HISTORICAL CONTROL DATA (if applicable)
No data
OTHER FINDINGS
None
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Gross pathology table
Dose Level (mg/kg/day)/Sex |
0/M |
15/M |
150/M |
300/M |
0/F |
15/F |
150/F |
300/F |
Adrenals:
|
|
|
|
|
|
|
|
|
Enlarged |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3 |
Total examined |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Histopathology table
Dose Level (mg/kg/day)/Sex |
0/M |
15/M |
150/M |
300/M |
0/F |
15/F |
150/F |
300/F |
Adrenals:
|
|
|
|
|
|
|
|
|
Cortical hyperplasia |
|
|
|
|
|
|
|
|
Minimal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
5 |
Cortical hypertrophie |
|
|
|
|
|
|
|
|
Minimal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Slight |
0 |
0 |
0 |
0 |
0 |
5 |
5 |
2 |
Moderate |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
3 |
Total affected |
0 |
0 |
0 |
0 |
0 |
5 |
5 |
5 |
Total examined |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Lungs: |
|
|
|
|
|
|
|
|
Aggregations of Foamy alveolar macrophages |
|
|
|
|
|
|
|
|
Minimal |
1 |
0 |
1 |
3 |
0 |
0 |
0 |
2 |
Slight |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
1 |
Total affected |
1 |
0 |
1 |
4 |
0 |
0 |
0 |
3 |
Total examined |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Applicant's summary and conclusion
- Conclusions:
- As toxicologically important findings were evident for both sexes dosed at 300 mg/kg/day and 150 mg/kg/day the No Observed Adverse Effect
Level (NOAEL) on this study for VRT-126017 dcha is 15 mg/kg/day.
Due to the disturbances in red blood cell parameters at all treatment levels a No Observed Effect Level (NOEL) was not established on this study.
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