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EC number: 208-288-1 | CAS number: 520-26-3
- 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
Description of key information
A NOAEL of 750 mg/kg bw/d was seen in a feeding study on rats with 200 days of exposure time. No substance related effects were observed in this study. This correspond with the information that hesperidin, being present in citrus fruits at concentration up to 12%, is part of daily diet of mankind.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1939
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The test is not a guideline method nor GLP compliant, but fulfills basically scientific principles.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- As the study had been performed in 1939, prior to any guideline being available, no guideline could be followed. However, basic scientific principles were followed incl. negative control (no treatment) and two different concentrations of test substance application.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Albino
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- The rats averaging 50 grams body weight were used at the start of the feeding experiment.
- Route of administration:
- oral: feed
- Vehicle:
- not specified
- Details on oral exposure:
- Hesperidin was mixed with the stock diet in concentrations up to one percent by weight. The animals had free access to food and water at all times.
- Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 200 days
- Frequency of treatment:
- continuous
- Dose / conc.:
- 0.062 other: percent by body weight
- Dose / conc.:
- 1 other: percent by body weight
- No. of animals per sex per dose:
- six to eight rats per dose level, sex not specified
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Male albino rats averaging 50 grams body weight at the start of the feeding experiment were used, six to eight rats for each dosage level. The substance was mixed with the stock diet in concentrations up to one percent by weight.The animals had free access to food and water at all times.
- Positive control:
- no data
- Observations and examinations performed and frequency:
- Observations were made on growth curves, weights of important viscera, and macroscopic and microscopic examination of these tissues.
- Sacrifice and pathology:
- Histological examination of paraffin sections stained with hematoxylin-eosin
- Statistics:
- no data
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- During the last 50 days respiratory infection was observed throughout the laboratory colony, not related the test article affecting weight gain in this last period of experiment.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Growth curves of negative controls and dose groups fully parallel.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- only blood sugar values were monitored
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- During the last 50 days respiratory infection was observed throughout the laboratory colony, not related the test article.
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- The weights of the hearts, spleens, livers, adrenals, kidneys and testes were all within normal range and no macroscopical abnormalities were noted. Histopathological examinations showed no significant morphological changes.
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- At the end of 200 days all the rats were killed with ether and autopsied. The weights of the hearts, spleens, livers, adrenals. kidneys, and testes were all within the normal range. All organs appeared normal range. All organs appeared normal macroscopically except the lungs of rats having respiratory infection. Histological examination of paraffin sections stained with hematoxylin-eosin showed no significant morphological changes in the livers, hearts, kidneys, spleens, adrenals. and testes of rats receiving hesperidin.
- Dose descriptor:
- NOAEL
- Effect level:
- 1 other: percent by weight in food
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- No effects were observed; 1% in diet applied to rats were converted to ca. 750 mg/kg/day calculated for rats with a mean body weight of ca. 250 g and ca. 20 g/day of food consumption.
- Dose descriptor:
- NOAEL
- Effect level:
- 750 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Remarks:
- No effects were observed; 1% in diet applied to rats were converted to ca. 750 mg/kg/day calculated for rats with a mean body weight of ca. 250 g and ca. 20 g/day of food consumption.
- Critical effects observed:
- not specified
- Conclusions:
- There was no difference between control rats and those receiving hesperidin in the test, giving a negative result. Thus, the NOAEL can be set to 1% (ca. 750 mg) by weight per day in food in this study.
- Executive summary:
The continued feeding to healthy albino rats of hesperidin in a standard diet for a period of 200 days, in concentrations as high as one percent of the diet by weight, gave no evidences of cumulative injury as judged by growth curves, weights of important viscera, and macroscopic and microscopic examination of these tissues. There was no difference between control rats and those receiving hesperidin in the test, giving a negative result. Thus, the NOAEL can be set to 1% (ca. 750 mg) by weight per day in food in this study. This value is consistent with another NOAEL value on Neohesperidin dihydrochalcone (a surrogate to hesperidin) in the study of B.A.R. Lina, et al. (1990) and taking into account that rats of 50 g weight were used at the start of the experiment.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 750 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The study performed by Wilson et al. in 1939 investigated the effect of hesperidin at doses up to 1% by weight in food over a period of 200 days. Despite an lung inflammatory effect observed as of day 150, that occured within the entire laboratory colony and therefore is not treatment related, no adverse effects were noted. Therefore, 1% hesperidin in food by weight is considered as NOAEL which can be converted to 750 mg/kg bw/d (assuming an average weight of rats of ca. 250 g and ca. 20g food consumption per day). This result is consistent with the NOAEL value reported by B.A.R. Lina, et al. (1990) for neohesperidin dihydrochalcone from a subchronic oral feeding study. This finding is additionally supported by sub-chronic studies on Methyl hesperidin by Kawabe et al. Both studies do not show adverse effects at doses up to 1% by weight in diet. Only at 5% by weight in food slight effects were noted.
The suitability for methyl hesperidin and neohesperidin dihydrochalcone is discussed in the read across justification in section 13 and both substance are structurally very similar to hesperidin and do share common metabolistic pathways.
In 2002 Ohtsuki et al. reported an investigation to study the curing effects of hesperidin and glucosyl hesperidin (a solubilized form of hesperidin) on spontaneously hypersensitive rats. At a dose of 30 mg/kg bw/d, administered over a period of 25 weeks, effects on blood pressure reduction were noted to these hypersensitive rats, indicating a positive health effect - no other effects were described. However, for this study only an abstract was available for assessment and the reliability of this study could not be assessed (Klimisch 4).
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Although a very old study it was performed with high dose (1% in food over 200 days of exposure) and is well documented.
Justification for classification or non-classification
A 200 days feeding study on rats revealed no signs of systemic toxicity or negative effects in a dose relevant for classification. Hence, it can be concluded that the substance does not meet the criteria for classification and labeling for repeated dose toxicity (STOT), as set out in Regulation (EC) NO. 1272/2008 and in Directive 67/548/EEC respectively, as indicated by study results on hesperidin. Supporting studies on Methyl hesperidin and Neohesperidin dihydrochalcone (both structurally very similar sharing common metabolistic pathways) support this finding.
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