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EC number: 208-289-7 | CAS number: 520-27-4
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1957
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- toxicokinetics
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Method described previously by Booth [Booth AN, Murray CW, Jones FT, DeEds F, 1956. J. Biol. Chem., 223: 251, see 'attached background material']: Breakdown products were identified after diosmin was ingested by rats, using ascending two-dimensional paper chromatograms of the ether extracts of acid urines which were developed with bottom phase of a mixture of chloroform, acetic acid, and water (2:1L1) in the first direction, followed by 20 per cent aqueous potassium chloride in the second direction.
- GLP compliance:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: obtained from Dr. R.M. Horowitz, Pasadena Laboratory, Agricultural Research Service. Obtained by isolation from lemon peel. Before use, these compounds were again crystallized, if necessary, until found to be chromatographically homogeneous in the two-dimensional TLC system used. - Radiolabelling:
- no
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Diet: purified diet consisting of starch, Cerelose, casein, Cellu flour, salts’ (including potassium acetate and magnesium oxide), oil, and vitamins. - Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
Administration by stomach tube of 400 mg of diosmin per rat on a purified diet. - Duration and frequency of treatment / exposure:
- Single dose administration.
- Dose / conc.:
- 400 other: mg/rat
- Remarks:
- approximately 1200 mg/kg bw (estimated).
- No. of animals per sex per dose / concentration:
- no data.
- Control animals:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (excretion)
- Tissues and body fluids sampled: urine.
- Time and frequency of sampling: urine samples were collected at 0 to 7, 7 to 21, 21 to 31, and 31 to 45 hour intervals.
- Analysis: use of ascending two-dimensional paper chromatograms of the ether extracts of acid urines which were developed with the bottom phase of a mixture of chloroform, acetic acid, and water (2: 1: 1) in the first direction, followed by 20 per cent aqueous potassium chloride in the second direction.
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine.
- Time and frequency of sampling: urine samples were collected at 0 to 7, 7 to 21, 21 to 31, and 31 to 45 hour intervals.
- Method type(s) for identification: TLC.
TREATMENT FOR CLEAVAGE OF CONJUGATES: systematic screening of the ether extracts of urine for conjugates of phenolic acids involved hydrolysis with 20 per cent HCl (usually for 2 hours under a reflux), followed by ether extraction of the hydrolysate and migration in the two-dimensional paper chromatographic system. After the air-dried chromatogram was first examined and all fluorescent and absorbing areas visibleunder ultraviolet light were marked, it was sprayed with diazotized sulfanilic acid to form dyes with the phenolic compounds. A direct comparison could then be made between the chromatograms before and after hydrolysis for the appearance of new areas and the disappearance of other areas. The hydrolysis procedure was also applied to specific areas cut out of unsprayed chromatograms of ether extracts of urine, in which case the phenolic acid or flavonoid released could be specifically associated with the suspected conjugate. - Type:
- metabolism
- Results:
- major metabolite: m-hydroxyphenylpropionic acid; traces of m-coumaric acid and diosmetin.
- Details on absorption:
- Diosmin can be absorbed in the gastrointestinal tract.
- Metabolites identified:
- yes
- Details on metabolites:
- The major metabolite was m-hydroxyphenylpropionic acid (m-HPPA), and only traces of m-coumaric acid and diosmetin were found on the chromatogram.
- Conclusions:
- Under test conditions, the test substance can be absorbed in the gastrointestinal tract, and the compounds excreted through urine as m-hydroxyphenylpropionic acid, along with traces of m-coumaric acid and diosmetin.
- Executive summary:
The metabolic fate of six flavonoids (hesperidin, hesperetin, diosmin, diosmetin, eriodictyol, and homoeriodictyol) has been studied after oral ingestion by rats, at a dose of 400 mg/rat (no guideline available, no GLP). Urine samples were collected at 0 to 7, 7 to 21, 21 to 31, and 31 to 45 hour intervals and examined by two-dimensional thin layer chromatography. Under test conditions, the test substance was absorbed in the gastrointestinal tract, and excreted through urine as m-hydroxyphenylpropionic acid, along with traces of m-coumaric acid and diosmetin.
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1993.
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Objective of study:
- toxicokinetics
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- Model of rat liver perfusion (Garattini et al. 1973).
- GLP compliance:
- no
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: supplied by Geymonat S.p.A. (Italy).
- Purity: analytical grade - Radiolabelling:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Male Crl:CD (SD) BR rats
- Weight at study initiation: 250 ± 4 g
- Diet: 'open formula' standard diet (Altromin MT, Rieper, Italy) ad libitum
- Water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.5
- Humidity (%): 55
- Photoperiod (hrs dark / hrs light): 12/12 cycle - Route of administration:
- other:
- Details on exposure:
- The flavonoids, dissolved in 0.5 N NaOH, were added to the perfusion medium (0.25%v/v) at the concentration which showed a protective effect in cultured rat hepatocytes (25p)
- Duration and frequency of treatment / exposure:
- Single dose, 90min exposure.
- Dose / conc.:
- 1 other: µM
- Remarks:
- 1-10µM
- Dose / conc.:
- 10 other: µM
- Remarks:
- 1-10 µM
- No. of animals per sex per dose / concentration:
- Not specified.
- Control animals:
- yes
- Details on study design:
- - Liver perfusion: Livers were isolated by a previously-descrlbed surgical technique (Bartosek et al. 1972) under pentobarbital sodium anesthesia (50mg/kg body weight, i.p.), and the biliary duct and portal vein were cannulated. T h e perfusion medium consisted of Krebs-Ringer bicarbonate buffer p H 7.4 containing 0.1% (w/v) glucose, 4%) (w/v) BSA and washed human red blood cells as the oxygen carrier at a concentration which gives a haematocrit of 13-1 5%. A constant medium/liver tissue ratio (9 ml/g) and constant flow (1 ml/g liverlmin) were used. The livers were perfused for 90min.
- Details on dosing and sampling:
- TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: liver, bile
- Time and frequency of sampling: 90-min perfusion period
- The following parameters were studied during the 90-min perfusion period: the concentrations of diosmin and diosmetin, the activity of lactate dehydrogenase (LDH) and urea levels by standard kits. Bile flow and excretion of the flavonoids were determined as previously described (Cova et al. 1992). At the end of perfusion period the liver was weighed and one lobe was used to measure ATP levels. Part of the remaining tissue was homogenized with 0.25M sucrose-phosphate buffer p H 7.4 and deproteinated with 50% (w/v) trichloroacetic acid to determine glutathione (CSH) as non-protein sulphydryl groups in the supernatant fraction. Biochemical parameters: Urea, LDH, GSH and ATP.
- Method type(s) for identification: HPLC. Diosmin and diosmetin were extracted by adding 100µL DMSO to 100µL perfusion medium, shaking for 30min and then centrifuged at 1600g for 10min, and 50uL of the resultant supernatant were injected into the HPLC apparatus. Bile (25µL) was analysed by HPLC without any treatment.
- Conditions: Jasco PU-980 HPLC apparatus in isocratic conditions. A Lichrospher 100RP 18 column (5µm; 4 x 125mm) was used with a mobile phase of methanol/acetic acid/water (40/7/53) and a flow rate of 1ml/min. The eluate was monitored for absorbance at 345nm, and the retention times were 2.6 and 11min for diosmin and diosmetin, respectively.
- Limits of detection and quantification: Recoveries of the flavonoids were 100 and 90% in perfusion and bile, respectively. - Statistics:
- The Easyfit computer program (Sacchi Landriani et al. 1983) was used to evaluate individual pharmacokinetic parameters from the perfusion data. T h e medium concentration-time curves fitted a two-compartment model. The biexponential equation was chosen according to the statistical method MAICE (minimum Akaike’s Information Criterion estimation) (Yamaoka et al. 1978). Kinetic and biochemical parameters were compared using one-way analysis of variance. Statistical differences were accepted at the p < 0.05 confidence level.
- Type:
- excretion
- Results:
- The disappearance curves of diosmin and diosmetin from the perfusion medium followed a two-compartment model. Both substances rapidly disappeared from the perfusion medium and were no longer detectable after 45 min.
- Details on excretion:
- Liver: Diosmin is actively metabolized by the liver in a short time. The test substance rapidly disappeared from the perfusion medium and was no longer detectable after 45 min. The clearance was higher than that of diosmetin, suggesting that this flavonoid is extensively metabolized by the liver.
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 7.01 ± 0.99 min
- Remarks:
- half-life of the λz phase.
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 165 ± 19
- Key result
- Test no.:
- #1
- Toxicokinetic parameters:
- other: CL = 11.45 ± 1.59 ml/min
- Remarks:
- hepatic clearance.
- Test no.:
- #1
- Toxicokinetic parameters:
- other: λz = 0.107 ± 0.014 min-1
- Remarks:
- slope of the last linear phase of the log blood concentration vs. time plot.
- Metabolites identified:
- yes
- Details on metabolites:
- A broad peak appeared in bile and a small part of the initial amount of the substance was excreted in its original form and as the glucuronide.
- Conclusions:
- Diosmin is actively metabolized by the liver in a short time, with a broad peak appearing in bile, and a small part of the initial amount of the substance was excreted in its original form and as the glucuronide.
- Executive summary:
The metabolism of the test item was studied in vitro, on a model of rat liver perfusion, following basic scientific principles (no GLP). Under test conditions, diosmin is actively metabolized by the liver in a short time, with a broad peak appearing in bile, and a small part of the initial amount of the substance was excreted in its original form and as the glucuronide. The substance was rapidly eliminated, with a clearance rate was 11.4 ml/min, and it was no longer detectable after 45 min. The main toxicokinetic parameters in liver were t(1/2) = 7.01 ± 0.99 min and AUC = 165 ± 19 nmol/ml·min. Based on the available information, no bioaccumulation potential is expected.
Referenceopen allclose all
Biochemical parameters: Urea in the perfusion medium increased at a zero-order rate (108 ± 8mg/100ml min) and LDH release at a first-order rate (21.5 ± 2.2min-1). The liver contents of GSH and ATP after perfusion were 1.77 ± 0.06 mg/g and 1.95 ± 0.08pmol/g, respectively. These parameters were not significantly affected by either diosmin or diosmetin.
Table 1. Bilary excretion of diosmin.
Perfusion intervals (min) |
Concentration (µmol/ml) |
Total content (µmol) |
0-30 |
0.550 ± 0.040 |
0.109 ± 0.004 |
31-60 |
0.251 ± 0.037 |
0.057 ± 0.008 |
61-90 |
0.122 ± 0.020 |
0.026 ± 0.003 |
0-90 |
|
0.191 ± 0.013 |
Description of key information
Weight of evidence: An in vivo metabolism study in rats by Booth (1958) reports the absorption of the test item in the gastrointestinal tract after oral administration, and excretion as m-hydroxyphenylpropionic acid, and traces of m-coumaric acid and diosmetin. An in vitro tat liver perfusion model study by Perego (1993) reports rapid metabolization of the test item in the liver and excretion through bile as a glucuronide. An in vivo pharmacokinetics study in rats by Ma (2007) reports slow absorption of the test item in the gastrointestinal tract, probably due to the low solubility of the test item. Based on the information available, no concerns for the bioaccumulation of the substance were found.
Key value for chemical safety assessment
- Bioaccumulation potential:
- no bioaccumulation potential
Additional information
Weight of evidence
- On a study by Booth et al. (1956), the metabolic fate of diosmin and other flavonoids was studied after oral ingestion by rats, at a dose of 400 mg/kg bw. The study meets generally accepted scientific principles. Based on the results, it can be concluded that the test substance can be absorbed in the gastrointestinal tract, and excreted through urine as m-hydroxyphenylpropionic acid, along with traces of m-coumaric acid and its aglycone diosmetin.
- On a study by Perego et al (1993), the metabolism of diosmin was studied in a model of rat liver perfusion, following basic scientific principles. Under test conditions, diosmin was actively metabolized by the liver in a short time, with a broad peak appearing in bile, and a small part of the initial amount of the substance was excreted in its original form and as the glucuronide.
- On a study by Ma (2007), the pharmacokinetic parameters of diosmin were determined after oral administration of three doses at levels of 225, 325, 425 mg/kg bw, by HPLC-UV method. The mean plasma concentration curves were found to fit a one compartment mode. The absorption was found to be slow, probably due to the low water solubility of the compound.
Based on the information available, no concerns for the bioaccumulation of the substance were found.
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