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Diss Factsheets

Administrative data

Description of key information

Weight of evidence: In a subacute oral toxicity study in GFI rats, no toxic effects were observed at 200 mg/kg bw/d, in a subchronic oral toxicity study in mice no toxic effects were observed at 620 mg/kg bw/d, and in a subchronic oral toxicity study in minipigs, no toxic effects were observed at 250 mg/kg bw. Based on the available information, the NOAEL of the test item is greater than 200 mg/kg bw/d (worst case), since no treatment related adverse effects were observed at the highest dose tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1976.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
only one dose tested, analytical verification of doses not reported.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: GIF
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Initial weight: 200-280g
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
50 days
Frequency of treatment:
daily
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 animals (m/f).
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: weekly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): weekly controls.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified

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: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (blood counts)
- Time schedule for collection of blood: at 0, 25 and 50 days of treatment.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 10.

CLINICAL CHEMISTRY: Yes
- How many animals: 10.
- Parameters examined: haemoglobin, urea , GPT and GOT

URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- Macroscopical and microscopical examinations of spleen, kidney, heart, liver, lung and bladder were performed on all animals.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Treatment of white rats with diosmin in a dosage of 200 mg/kg daily in diet for 50 days led to no toxic manifestations.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Conclusions:
Under test conditions the test item was found to be non toxic, with a NOAEL ≥ 200 mg/kg bw.
Executive summary:

A study on the subacute oral toxicity of the test item in rats was performed with a procedure similar to OECD 407 (no GLP). White GIF-strain rats received the test item at a dose of 200 mg/kg bw test item in their diet per day for 50 days, and the following parameters were examined: weight development, blood count, macroscopic and histologic assessment of organs, and biochemistry (GOT, GPT, urea). Under test conditions, the test substance showed no toxic effects. Therefore, the NOAEL of the test item in rats is ≥ 200 mg/kg bw.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1976.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
only 2 doses tested
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
ICR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Initial weight: 28-33g
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
196 days
Frequency of treatment:
daily
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
620 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Positive control:
No data.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: weekly.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): weekly controls.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg
body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain dat
a: Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted aver
ages from the consumption and body weight gain data: Not specified

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (blood counts)
- Time schedule for collection of blood: at 0, 25 and 50 days of treatment.
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 10.

CLINICAL CHEMISTRY: Yes
- How many animals: 10.
- Parameters examined: haemoglobin, urea , GPT and GOT

URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Not specified
IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
- Macroscopical and microscopical examinations of spleen, kidney, heart, liver, lung and bladder were performed on all animals.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Treatment of mice with diosmin in a dosage of 60 and 620 mg/kg daily in diet for 196 days led to no toxic manifestations.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 620 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed.
Key result
Critical effects observed:
no
Conclusions:
Under test conditions diosmin was found to be non toxic.
Executive summary:

A study on the subchronic oral toxicity of the test item in mice was performed with a procedure similar to OECD 408 (no GLP). 11 white ICR mice of either sex per dose group received the test item doses of 60 or 620 mg/kg bw test item per day in their diets for 196 days, and the following parameters were examined: weight development, blood count, macroscopic and histologic assessment of organs, and biochemistry (GOT, GPT, urea). Under test conditions, the test substance showed no toxic effects. Therefore, the NOAEL of the test item in mice is ≥ 620 mg/kg bw.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1976.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)
Deviations:
yes
Remarks:
only 2 doses tested, treatment for 180 days.
GLP compliance:
no
Limit test:
no
Species:
miniature swine
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Pharmaceutical Institute of the University of Siena, courtesy of Prof. G. Segre.
Route of administration:
oral: feed
Vehicle:
other: milk
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: a suspension in milk of the test item was administered to the animals.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
180 days
Frequency of treatment:
daily
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
No. of animals per sex per dose:
No data.
Control animals:
yes, concurrent no treatment
Positive control:
No data.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Not specified
DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Not specified
FOOD EFFICIENCY: Not specified
OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: blood count after 0, 45, 90 and 180 days of treatment.

CLINICAL CHEMISTRY: Yes
- Parameters examined: haemoglobin, glucose, urea , uric acid, GOT, GPT, serum lability after Kunkel and Mac Lagan and alkaline phosphatase.

URINALYSIS: Yes
- Parameters examined: density, pH, glucose, haemoglobin, protein, bilirubin, ketones and sediment.

NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organs examined: Stomach, liver, intestine, lung, heart , kidney, spleen, thyroid gland, adrenal glands, ovaries and testes, brain, duodenum, small intestine, lymph nodes, epididymus, uterus and peripheral nerves.

HISTOPATHOLOGY: Yes
- Organs examined: Stomach, liver, intestine, lung, heart , kidney, spleen, thyroid gland, adrenal glands, ovaries and testes.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
Treatment of male and female minipigs with diosmin in a dosage of 50 and 250 mg./kg daily in diet for 180 days led to no toxic manifestations. No systematic deviations of clinical, biochemical or hematological values pointing to a toxicological effect of the substance were found.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no
Conclusions:
Under test conditions diosmin was found to be non toxic, with a NOAEL > 250 mg/kg bw.
Executive summary:

A study on the subacute oral toxicity of the test item in minipigs was performed with a procedure similar to OECD 409 (no GLP). Male and female minipigs received the test item at doses of 50 or 250 mg/kg bw test item per day for 180 days, and the following parameters were observed: weight, blood count at 0, 45, 90, of treatment, blood chemistry (hemoglobin, glucose, uric acid, GOT, GPT, serum lability after Kunkel and Mac Lagan and alkaline phosphatase; urianaysis: density, pH, glucose, hemoglobin, protein, bilirubin, ketones and sediment. After dissection, the following organs were examined macroscopically and histologically: stomach, liver, intestine, lung, heart, kidney, spleen, thyroid gland, adrenal glands, ovaries and testes, whereas the other organs were only examined macroscopically: brain, duodenum, small intestine, lymph nodes, epididymus, uterus and peripheral nerves. No systemic deviations of clinical, biochemical or hematological values pointing to a toxicological effect of the substance were found. Therefore, the NOAEL of the test item in minipigs is ≥ 250 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
All studies have a Klimisch score of 2.

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

Weight of evidence:

- A study on the subacute oral toxicity of the test item in rats was performed with a procedure similar to OECD 407 (no GLP). White GIF-strain rats received the test item at a dose of 200 mg/kg bw test item in their diet per day for 50 days, and the test substance showed no toxic effects. Therefore, the NOAEL of the test item in rats is ≥ 200 mg/kg bw.

- A study on the subchronic oral toxicity of the test item in mice was performed with a procedure similar to OECD 408 (no GLP). 11 white ICR mice of either sex per dose group received the test item doses of 60 or 620 mg/kg bw test item per day in their diets for 196 days, and the following parameters were examined: weight development, blood count, macroscopic and histologic assessment of organs, and biochemistry (GOT, GPT, urea). Under test conditions, the test substance showed no toxic effects. Therefore, the NOAEL of the test item in mice is ≥ 620 mg/kg bw.

- A study on the subacute oral toxicity of the test item in minipigs was performed with a procedure similar to OECD 409 (no GLP). Male and female minipigs received the test item at doses of 50 or 250 mg/kg bw test item per day for 180 days, and the following parameters were observed: weight, blood count at 0, 45, 90, of treatment, blood chemistry (hemoglobin, glucose, uric acid, GOT, GPT, serum lability after Kunkel and Mac Lagan and alkaline phosphatase; urianalysis: density, pH, glucose, hemoglobin, protein, bilirubin, ketones and sediment. After dissection, the following organs were examined macroscopically and histologically: stomach, liver, intestine, lung, heart, kidney, spleen, thyroid gland, adrenal glands, ovaries and testes, whereas the other organs were only examined macroscopically: brain, duodenum, small intestine, lymph nodes, epididymus, uterus and peripheral nerves. No systemic deviations of clinical, biochemical or hematological values pointing to a toxicological effect of the substance were found. Therefore, the NOAEL of the test item in minipigs is ≥ 250 mg/kg bw.

Based on the available information, the NOAEL of the test item is greater than 200 mg/kg bw, since no treatment related adverse effects were observed at the highest dose tested.

Justification for classification or non-classification

Based on the available data, the substance is not classified as STOT RE according to CLP Regulation (EC) No. 1272/2008.