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EC number: 233-566-4 | CAS number: 10236-47-2
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 2012
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 006
- Report date:
- 2006
Materials and methods
- Objective of study:
- absorption
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- A single dose of 746.7 mg/kg test item was orally administered (by gavage) to 6 male Sprague Dawley rats, and the concentrations of the test item and its metabolites were determined in plasma at 0 (predose), 5, 15, 30, 45, 60, 120, 240, 360, 480, 720 and 1440 min after dosing by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
- GLP compliance:
- no
Test material
- Reference substance name:
- 7-(2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyloxy)-2,3-dihydro-4',5,7-trihydroxyflavone
- EC Number:
- 233-566-4
- EC Name:
- 7-(2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyloxy)-2,3-dihydro-4',5,7-trihydroxyflavone
- Cas Number:
- 10236-47-2
- Molecular formula:
- C27H32O14
- IUPAC Name:
- 7-(2-O-(6-deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyloxy)-2,3-dihydro-4',5,7-trihydroxyflavone
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- - Naringin (4',5',7-trihydroxy flavanone-7-rhamnonglucoside)
- Source: Sigma (St. Louis, MO)
- Purity: > 95% - Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: College of Military Medicine Animal Research Center (Guangzhou, China).
- Weight at study initiation: 250–300 g
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- 50% PEG400
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: the test item was dissolved into 127.9 mg/ml with 50% PEG400.
- Duration and frequency of treatment / exposure:
- single dose.
Doses / concentrations
- Dose / conc.:
- 746.7 mg/kg bw/day (nominal)
- No. of animals per sex per dose / concentration:
- 6 male rats.
- Control animals:
- yes
- Positive control reference chemical:
- Not applicable.
- Details on study design:
- SAMPLE PREPARATION
- A 0.1 ml aliquot sample plasma was transferred to a clean glass tube. Ten microliters of methanol with 1000 ng/ml internal standard was added and vortexed. Then 400 μl ethyl acetate (LC grade) was added to the tube and vortexed again for 2 min. After the sample was centrifuged at 6000×g for 10 min, the upper organic layer was transferred into a 5 ml
glass tube. 200 μl ethyl acetate was added to the deposition again and then the deposition was extracted as those mentioned above again. The organic layer was mixed together and
dried with nitrogen at room temperature. The dried residue was dissolved in 100 μl of the mobile phase. A 20 μl aliquot of the sample was injected into the LC/MS/MS.
ANALYTICAL METHOD
- Separation method: HPLC system (SHIMADZU HPLC system, SHIMADZU, Columbia, MD), consisting of an SCL-10A system controller, an LC-10AD HPLC pump, a DGU 12A-degasser, and a manual injector.
- Conditions: The HPLC column (100 mm × 2.0 mm) was a 5 μm BetaBasic-C18 ODS column (KEYSTONE Bellefonte, PA). Column temperature was maintained at room temperature.
The mobile phase consisted of methanol (70%) and water (30%), which was filtered through a 0.2 μm nylon filter before use. The flow rate was 0.4 ml/min and the total run time was
3.0 min for each injection.
- Detection method: MS (Applied Biosystems MDS Sciex API3000 Triple Quadrapole mass spectrometer (MS/MS) equipped with a heated nebulizer interface (500ºC)). The mass spectrometer chose the positive ionization mode as the detection mode with the collision gas off. At the same time the mass spectrometer temperature was set at 370ºC. Under these conditions, the analytes yielded protonated molecules at m/z 581.3 for naringin, m/z 273.4 for naringenin and m/z 611.5 for hesperidin.
- Internal or external calibration: internal (standard: hesperidin, source: National Institute for the control of pharmaceutical and biological products, HPLC grade).
- Limits of detection and quantification: LOQ = 0.5 ng/ml.
- Extraction recovery (indicate if results are corrected or not for recoveries): The mean recovery values for the entire procedure were found to be 90.58, 91.64, 94.15% for naringin.
- Validation: The assay was validated in rat plasma. The retention time was 0.5, 0.5, and 1.07 min for naringin, hesperidin and naringenin, respectively. The absence of a signal at the
retention time of naringin, naringenin and hesperidin in the blank plasma established the specificity of the assay. For naringin, the accuracy values of the assay varied from 93.02 to 96.37%, the within-day precision values ranged from 3.9 to 5.3%, the between-day precision values ranged from 1.7 to 4.9%; the assay was linear from 5 to 1000 ng/ml, using 0.1 ml rat plasma, with a regression coefficient (r2) >0.9996. - Details on dosing and sampling:
- TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: plasma.
- Time and frequency of sampling: Approximately 0.5 ml blood was withdrawn from each rat according to a schedule of 0 (predose), 5, 15, 30, 45, 60, 120, 240, 360, 480, 720 and 1440 min after dosing. - Statistics:
- Data was collected and processed using Sciex Analyst 1.1. Plasma concentration–time profiles were analyzed by WinNonlin computer software, Version 4.0 (Pharsight Corporation, Mountain View, CA), using a noncompartmental method.
Results and discussion
- Preliminary studies:
- Naringenin’s conjugates in the homogenates of different tissues were confirmed to be completely hydrolyzed within 2 h in the preliminary test. Meanwhile, no obvious loss of naringin was observed during this process.
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- the test item was quickly absorbed into the body (Tmax 45min), and declined rapidly within 2h.
- Type:
- excretion
- Results:
- After 24h, the test item was no longer detectable.
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- The test item was quickly absorbed into the body and could be detected 5 min after oral administration. The concentration of naringin in plasma reached nearly 2300 ng/ml in 45 min (Tmax) and declined rapidly, within 2 h. The Cmax was 3782.50 ± 986.82 ng/ml, and the AUC(0–24) was 6026.32 ± 1562.63 ng/ml h.
- Details on excretion:
- The test item could not be detected after 24h.
Toxicokinetic parametersopen allclose all
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 3782.50 ± 986.82 ng/ml
- Remarks:
- in plasma.
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 0.75 ± 0.25 h
- Remarks:
- in plasma.
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 6026.32 ± 1562.63 ng/ml h
- Remarks:
- in plasma (0-24).
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- The concentration of naringenin and naringenin glucuronide in plasma increased more slowly after oral administration of naringin. The Tmax of naringenin and naringenin glucuronide occurred at 9 and 7.5 h. For naringenin, the Cmax was 227.05±88.41 ng/ml, and the AUC0–24 was 1252.24±461.66 ng/ml h, whereas for naringenin glucuronide, the Cmax was 43575.00±8409.00 ng/ml, and the AUC(0–24) was 238269.00±53253.10 ng/ml h. The AUC0–24 of naringenin glucuronide was higher than naringin and naringenin, indicating that naringenin glucuronide is the main existent form in rat plasma after oral administration.
Any other information on results incl. tables
Table 1. Relevant pharmacokinetic parameters.
Parameter |
Average ± S.D. (n = 6) |
Naringin |
|
Tmax (h) |
0.75±0.25 |
Cmax (ng/ml) |
3782.50±986.82 |
AUC [0-24] (ng/ml h) |
6026.32±1562.63 |
MRT (h) |
6.47±1.18 |
CL (ml/h) |
0.028±0.008 |
HL-λz (h) |
5.34±1.07 |
Naringenin |
|
Tmax (h) |
9.00±1.50 |
Cmax (ng/ml) |
227.05±88.41 |
AUC [0-24] (ng/ml h) |
1252.24±461.66 |
MRT (h) |
8.16±1.59 |
CL (ml/h) |
0.30±0.070 |
HL-λz (h) |
2.98±0.65 |
Naringenin glucuronide |
|
Tmax (h) |
7.50±1.00 |
Cmax (ng/ml) |
43575.00±8409.00 |
AUC [0-24] (ng/ml h) |
238269.00±53253.10 |
MRT (h) |
6.37±0.60 |
CL (ml/h) |
0.0004±0.00019 |
HL-λz (h) |
1.84±0.16 |
Applicant's summary and conclusion
- Conclusions:
- The test item was quickly absorbed into the body, and could be detected 5 min after oral administration. The concentration of naringin in plasma reached nearly 2300 ng/ml in 45 min (Tmax) and declined rapidly, within 2 h. Based on these results, the test item shows no bioaccumulation potential.
- Executive summary:
A study on the absorption of the test item in rats was performed. A single dose of 746.7 mg/kg test item was orally administered (by gavage) to 6 male Sprague Dawley rats, and the concentrations of the test item and its metabolites were determined in plasma at 0 (predose), 5, 15, 30, 45, 60, 120, 240, 360, 480, 720 and 1440 min after dosing by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The test item was quickly absorbed into the body and could be detected 5 min after oral administration. The Tmax was 45 min. The plasma concentration also declined quickly, within 2 h. Its metabolites, naringenin and naringenin glucuronide, were produced slowly after oral administration and Tmax for them were 9 and 7.5 h, respectively. After 24 h, no test item could be detected. Based on these results, the test item shows no bioaccumulation potential.
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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