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EC number: 433-730-7 | CAS number: 23926-51-4 L-THREONINETHYLESTER
- 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
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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:
- September 18, 2007 to December 12, 2007
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: The study was performed in accordance with GLP standards and with testing guidelines. No major deviations from the protocol. Minor deviations did not affect the integrity or outcome of the study.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- minor deviations
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- yes
- Remarks:
- minor deviations
- Principles of method if other than guideline:
- NA
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Test material form:
- solid: particulate/powder
- Remarks:
- migrated information: powder
- Details on test material:
- - Name of test material (as cited in study report): L-Threonine Ethylester
- Analytical purity: no data
- Purity test date: 99.6%
- Lot/batch No.: 0706H013
- Expiration date of the lot/batch: 1 February 2009
- Stability under test conditions: considered to be stable under test conditions
- Storage condition of test material: in a sealed container, frozen
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: recognised supplier
- Age at study initiation: The preliminary study animals: 34 to 36 days old; The main study animals: 48 to 50 days old.
- Weight at study initiation: The preliminary study animals: 106.0 to 138.0 g (males), 113.0 to 124.1 g (females); The main study animals: 179.5 to 236.5 g (males), 140.4 to 173.2 g (females).
- Fasting period before study: no data
- Housing: single exclusive room during each set of assessments, otherwise the main study animals were housed in groups of five, and the preliminary study animals were housed in groups of three.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The preliminary study animals: 7 days; The main study animals: 21 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 40 to 70% (on a few occasion the relative humidity was outside the ranges, highest recording was 80%)
- Air changes (per hr): 15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light (0600h to 1800h) and 12 hours dark
IN-LIFE DATES: No data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Purified water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations were prepared daily and used within 4 hours of preparation.
DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: refrigerated
VEHICLE
- Amount of vehicle (if gavage): a dose volume of 10mL/kg was used. Individual dose volumes were based on individual bodyweight. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis was performed weekly on the main study. The normal target range for the results was 90% to 110% (liquid formulations) of nominal concentration.
- Duration of treatment / exposure:
- Preliminary study, Test duration: 7 days
Main study, Test duration: 28 days - Frequency of treatment:
- The preliminary study animals were dosed once daily for seven days, excluding the day of termination.
The main study animals were dosed once daily for 28 days excluding the day of necropsy.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
250, 500 and 1000 mg/kg/day (prelimary study)
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
0, 250, 500 and 1000 mg/kg/day (main study)
Basis:
actual ingested
- No. of animals per sex per dose:
- Preliminary study: 3 males and 3 females per dose
Main study: 5 males and 5 females per dose - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
For the preliminary study:
The limit dose of 1000 mg/kg/day was selected as the high dose level for the preliminary study based on the results of the acute rat oral toxicity study (Covance study number 0665/349). In this study the acute median lethal oral dose was found to exceed 2000 mg/kg. For the preliminary study, a descending sequence of dose levels (250 and 500 mg/kg/day) were selected to aid in the selection of dose levels for the main study.
For the main study:
In the preliminary study, dose levels of 250, 500 or 1000 mg/kg/day were well tolerated following 7 days of repeated administration. The dose level of 1000 mg/kg/day was chosen as the high dose level for the main study because this is the maximum dose level (limit dose) required by the regulators. A descending
sequence of dose levels (250 and 500 mg/kg/day) were selected to further characterise the toxicity of the test article and/or to establish a No-Observable-Effect-Level (NOEL) and/or No-Observable-Adverse-Effect-Level (NOAEL).
- Rationale for animal assignment (if not random): randomisation procedure
- Rationale for selecting satellite groups: NA
- Post-exposure recovery period in satellite groups: NA
- Section schedule rationale (if not random): NA - Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All main study and preliminary animals were observed daily for signs of ill health or overt toxicity after dosing (0.5, 1, 2 and 4 hours).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly, each animal was given a detailed physical examination.
BODY WEIGHT: Yes
- Time schedule for examinations: Day-7, the first day of the dosing, weekly intervals and on the day of necropsy
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g /animal/day (for the preliminary study) and g/animal/week (for the main study).
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: NA
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations: NA
- Dose groups that were examined: NA
HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection:No data
- Animals fasted: No data
- How many animals: 4 males, 4 females
- Parameters examined: hæmoglobin concentration, packed cell volume, mean cell volume, mean cell hæmoglobin concentration, red cell distribution width, platelet crit, platelet distribution width, red blood cell count, reticulocytes, mean cell hæmoglobin, hæmoglobin distribution width, platelet count, mean platelet volume, total and differential white cell count, prothrombin time, activated partial thromboplastin time.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals:
- Parameters examined: aspartate aminotransferase, alkaline phosphatase, potassium, inorganic phosphorus, total protein, globulin, total cholesterol, urea, creatinine, alanine aminotransferase, sodium, calcium, chloride, albumin, albumin/globulin ratio, glucose, total bilirubin.
URINALYSIS: No
- Time schedule for collection of urine: NA
- Metabolism cages used for collection of urine: NA
- Animals fasted: NA
- Parameters examined: NA
NEUROBEHAVIOURAL EXAMINATION: Yes, a battery of behavioral tests was performed (FOB). Observational measurements were evaluated before and upon removal from the home cage. The animal was also placed into a circular arena for 2 minutes. During this time, behavior was evaluated as indicated in the Open Field section.
- Time schedule for examinations: Week 4 (end of study)
- Dose groups that were examined: All groups
- Battery of functions tested: sensory activity to stimuli, grip strength and motor activity - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes. Gross lesions from all main study animals and tissues from control and high dose animals were examined microscopically by the study pathologist. Due to treatment related effects in the kidneys of females receiving 1000mg/kg/day the kidneys of females receiving 250 or 500 mg/kg/day were examined by microscopy by the study pathologist.
HISTOPATHOLOGY: Yes. Gross lesions from all main study animals and certain tissues from control and high dose animals were embedded in paraffin was BP, sectioned at a nominal 5 µm and stained with hæmatoxylin and eosin. Liver, spleen and kidney from low and intermediate dose animals were processed to the slide stage. - Statistics:
- ANOVA, Levene's test
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- no unsheduled deaths in the preliminary and main study
- Mortality:
- no mortality observed
- Description (incidence):
- no unsheduled deaths in the preliminary and main study
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- absence of any dose relationship
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- similar to control
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- A slightly higher mean activated partial thromboplastin time (APTT) in both sexes at 1000 mg/kg/day. A slightly higher mean prothrombin time for males at 1000 mg/kg/day. All treated female groups , higher WBC count.
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean hindlimb grip strength was lower than control for males receiving 500 or 1000 mg/kg/day and higher than the control for females receiving 1000 mg/kg day.
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- higher kidney weight for both sexes at 1000 mg/kg/day
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- very minor corticomedullary mineralisation in the kidney of all treated female groups.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There were no unscheduled deaths in the preliminary or main study. All clinical signs observed in the preliminary or main study were considered typical of laboratory maintained rats.
BODY WEIGHT AND WEIGHT GAIN
There were no treatment related effects on Week 1-4 mean body weight gains in all treated groups. Mean body weight gains for males receiving 250 mg/kg/day and both sexes receiving 500 mg/kg/day were lower than contols. But this was considered to be of no relationship to treatment as the females receiving 250 mg/kg/day and both sexes receiving 1000 mg/kg/day were similar to the control.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Mean food consumption (Week 1-4) for all treated groups were similar to the control.
FOOD EFFICIENCY
Not examined
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Not examined
OPHTHALMOSCOPIC EXAMINATION
Not examined
HAEMATOLOGY
Haematology investigations on Day 29 revealed a slightly higher than control mean activated partial thromboplastin time (APTT) in both sexes receiving 1000 mg/kg/day. The mean prothrombin time for males receiving 1000 mg/kg/day was slightly higher than control. All treated female groups were noted with a slightly higher than control mean lymphocyte count (and concomitantly higher mean WBC count), with a dose related trend evident. All other differences from control were either generally within the concurrent control range and/or showed no dose- relationship and were therefore considered to be unrelated to treatment.
CLINICAL CHEMISTRY
All differences from control were either generally within the concurrent control range, were attributable to one outlying value and/or showed no dose-relationship and were therefore considered to be unrelated to treatment.
URINALYSIS
Not examined
NEUROBEHAVIOUR
The mean hindlimb grip strength was lower than control for males receiving 500 or 1000 mg/kg/day and higher than the control for females receiving 1000 mg/kg/day. But these contradicting differences suggest an unlikely relationship to treatment. In the remaining tests from the functional observation battery or in the assesment of locomotor activity, clinical signs or histopathology of neurological or musculoskeletal tissues no treatment related effects were noted.
ORGAN WEIGHTS
The group mean, absolute kidney weight was higher than control for males and females treated 1000 mg/kg/day. These findings were considered to be of unlikely relationship to treatment.
GROSS PATHOLOGY
Most tissues were macroscopically unremarkable and the findings seen were generally consistent with the usual patterns og findings in animals of this strain and age. There were no macroscopic findings due to effects of the test article.
HISTOPATHOLOGY: NON-NEOPLASTIC
There was a dose-related increase in very minor corticomedullary mineralisation in the kidney of treated females. Corticomedullary mineralisation was characterised by small deposits of basophilic, granular material in the region of the outer stripe of the renal medulla.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No data
HISTORICAL CONTROL DATA (if applicable)
No data
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: original NCD unit is mg/kg/day.
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The repeated oral dose toxicity of L-TEE was tested in a repeated oral gavage study in rats for 28 days. The study was performed in compliance with the regulatory guidelines OECD (407) and EC (Method B7). No adverse findings were noted in this study and the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 1000 mg/kg/day.
- Executive summary:
L-TEE was tested in a repeated oral gavage study in rats. L-TEE was administered at doses 250, 500 or 1000 mg/kg/day to rats for 28 days. The study was performed in compliance with the regulatory guidelines OECD (407) and EC (Method B7).
The No-Observed-Effect-Level (NOEL) could not be established in this study because of the minimal/slight corticomedullary mineralisation in the kidneys and increased lymphocyte counts in females treated at 250, 500 or 1000 mg/kg/day. However, no adverse findings were noted in this study and the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 1000 mg/kg/day.
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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