Diosmin

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Weight of evidence. Based on the available information from the analogue salt of diosmin, the substance is deemed to be not teratogenic.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

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 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

only one dose tested, no information on analytical verification of concentration.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Source: diosmin, sodium salt.

Species:

mouse

Strain:

ICR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Average initial weight: 29 g.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The sodium salt of diosmin was dissolved in water and given by esophageal tube in a daily dose of 50 mg/kg from the 4th to the 12th post-coital days.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

8 days.

Frequency of treatment:

Daily

Duration of test:

Up to 20 days after conception (group 2).

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose:

4 groups (2 controls and 2 dosed) of 11 females each.

Control animals:

yes, concurrent no treatment

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 19 (group 1)
- Sacrifice (group 2): On the 0, 6, 13 or 20th day after birth the mother animals and offspring were sacrificed.
- Organs examined: in the offspring the following organs were macroscopically and histologically examined: heart, liver, spleen and kidneys. In the mother animals the right and left uterine horns were examined with respect to sites of implantation and absorption.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes. Sex, weight and length were determined.
- Soft tissue examinations: The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail.
- Skeletal examinations: Yes. The skeletons were examined, in particular with respect to vertebral block or cleft formation, number, length, possible fusions and ossifications, form and number of bones.
- Head examinations: No data

- In another group, delivery was by spontaneous birth. The foetuses were macroscopically examined with respect to palatal clefts and malformations of extremities and the tail. Sex, weight and lenght of the foetuses were determined. The development of the animals was followed (openning of the eyes, growth of hair, etc.).

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

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:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

no effects observed

Details on maternal toxic effects:

No maternal toxic effects were observed.

Key result

Dose descriptor:

NOAEL

Effect level:

> 50 mg/kg bw (total dose)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): The average weight was of 1.4 g in controls and 1.25 g in treated animals .

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Description (incidence and severity):

The mean number of animals per litter was 12.3 in the control group and 11.5 in the treated group.

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Description (incidence and severity):

Neither in the control nor in the diosmin group did the inspection of 126 skeletal preparations each show any pathological findings.

Visceral malformations:

no effects observed

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

Assessment of the foetuses did not reveal any difference between the two experimental groups and the control.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 50 mg/kg bw (total dose)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: teratogenicity

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

- After laparotomy, the mean number of animals per litter was 12.3 in the control group and 11.5 in the diosmin treated group. The average weight was of 1.4 g. in controls and 1.25g. in diosmin treated animals. Neither in the control nor in the diosmin group did the inspection of 126 skeletal preparations each show any pathological findings.

- After spontaneous delivery, the average number of animals per litter was 11.35 and 11.4 (respectively in the control and diosmin group). Postnatal mortality (20-day period) was of 19 and 26%, respectively. Weight gain, length, development, gross behavior, growth of hair and opening of the eyes were identical in the two groups. Organ weights, macroscopical and histological findings did not differ significantly in the diosmin treated animals from the control ones.

Table 1. Experimental results on mice.

11 mother animals each	Sites of implantation	Number of fetuses		Absorptions	Malformations	Underdeveloped
Controls	152	Live	125	17	0	26
		Dead	10
Diosmin	143	Live	126	17	0	1
		Dead	0

 

Conclusions:

Under test conditions, the test item has no teratogenic effects. The NOAEL for developmental toxicity in mice is ≥ 50mg/kg bw/d.

Executive summary:

A study was conducted to assess the teratogenicity potential of the sodium salt of diosmin, by a method similar to OECD 414 (no GLP). Two groups of 11 female ICR mice each were orally administered 50 mg/kg bw/d of test item from the 4th to the 12th post-coital days. Two further control groups were run in parallel. In one of the groups, the foetuses were delivered by laparotomy on the 19th day after conception and the sites of implantation and absorption in both horns of the uterus were determined. The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail; the sex weight and length were determined; then, they were killed and their skeletons stained and examined. In the other treated group, delivery was by spontaneous birth and the development of the animals was followed. There was no reduction in number of foetuses, no increase in absorption sites, no significant alteration of rate of malformations, postnatal morbility, weight gain and development or histology of several organs. Thus, it was concluded that the test item does not have any teratogenic effects. The NOAEL for developmental toxicity of the test item in mice is greater than 50 mg/kg bw/d.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

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 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

only one concentration, no information of analytical verification of concentrations.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: SIV

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Average initial weight: 245g.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The sodium salt of diosmin was dissolved in water and given by esophageal tube in a daily dose of 100 mg/kg from the 4th to the 14th post-coital days.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy.

Duration of treatment / exposure:

10 days.

Frequency of treatment:

daily

Duration of test:

up to the 20th day after birth.

Dose / conc.:

100 mg/kg bw/day (nominal)

No. of animals per sex per dose:

4 groups (2 controls and 2 dosed) of 11 females each.

Control animals:

yes, concurrent no treatment

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21 (group 1)
- Sacrifice (group 2): On the 0, 6, 13 or 20th day after birth the mother animals and offspring were sacrificed.
- Organs examined: in the offspring the following organs were macroscopically and histologically examined: heart, liver, spleen and kidneys. In the mother animals the right and left uterine horns were examined with respect to sites of implantation and absorption.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes. Sex, weight and length were determined.
- Soft tissue examinations: The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail.
- Skeletal examinations: Yes. The skeletons were examined, in particular with respect to vertebral block or cleft formation, number, length, possible fusions and ossifications, form and number of bones.
- Head examinations: No data

- In another group, delivery occurred spontaneously. The foetuses were macroscopically examined with respect to palatal clefts and malformations of extremities and the tail. Sex, weight and lenght of the foetuses were determined. The development of the animals was followed (opening of the eyes, growth of hair, etc.).

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

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:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified

Changes in number of pregnant:

not specified

Other effects:

no effects observed

Details on maternal toxic effects:

No maternal toxic effects were observed.

Key result

Dose descriptor:

NOAEL

Effect level:

> 100 mg/kg bw (total dose)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): The average weight was of 3.56 and 3.17 g, respectively.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

After laparotomy, the mean number of animals per litter was of 13.9, both in the control and in the diosmin treated group.

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Description (incidence and severity):

The inspection of 234 and of 277 skeletal preparations, respectively, did not reveal any pathological features.

Visceral malformations:

no effects observed

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

Assessment of the foetuses did not reveal any difference between the two experimental groups.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 100 mg/kg bw (total dose)

Based on:

act. ingr.

Basis for effect level:

other: teratogenicity

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

- After laparotomy, the mean number of animals per litter was 13.9, both in the control group and in the diosmin treated group. The average weight was of 3.56g. in controls and 3.17g. in diosmin treated animals. The inspection of 234 and 277 skeletal preparations, respectively, did not reveal any pathological features. Assessment of the foetuses led to the same conclusion.

- After spontaneous delivery, the average number of animals per litter was 12.9 and 11.6 (respectively in the control and diosmin group). Postnatal mortality (20-day period) was, of 11 and 20%, respectively. Weight gain, length, development, gross behavior, growth of hair and opening of the eyes were identical in the two groups. Organ weights, macroscopical and histological findings did not differ significantly in the diosmin treated animals from the control ones.

Table 1. Experimental results on rats.

11 mother animals each	Sites of implantation	Number of fetuses		Absorptions	Malformations	Underdeveloped
Controls	294	Live	277	17	0	72
		Dead	0
Diosmin	291	Live	234	13	0	120
		Dead	44*

 * 3 whole litters died on the 17th and 18th day after conception.

 

Conclusions:

Under test conditions, diosmin has no teratogenic effects. The NOAEL for rats is ≥ 100mg/kg.

Executive summary:

A study was conducted to assess the teratogenicity potential of the sodium salt of diosmin, by a method similar to OECD 414 (no GLP). Two groups of female SIV rats each were orally administered 100 mg/kg bw/d of test item from the 4th to the 14th post-coital days. Two further control groups were run in parallel. In one of the groups, the foetuses were delivered by laparotomy on the 21st day after conception and the sites of implantation and absorption in both horns of the uterus were determined. The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail; the sex weight and length were determined; then, they were killed and their skeletons stained and examined. In the other treated group, delivery was by spontaneous birth and the development of the animals was followed. There was no reduction in number of foetuses, no increase in absorption sites, no significant alteration of rate of malformations, postnatal morbility, weight gain and development or histology of several organs. Thus, it was concluded that the test item does not have any teratogenic effects. The NOAEL for developmental toxicity in rat is greater than 100 mg/kg bw/d.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Both studies have a Klimisch score of 2.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Weight of evidence: Read-across from analogue substance. Heusser and Oswald (1977) performed teratogenic toxicity studies for the analogue substance diosmin, sodium salt, which was administered by gavage to SIV rats and ICR mice, at doses of 100 and 50 mg/kg bw, respectively.

- In a study conducted to assess the teratogenicity potential of the sodium salt of diosmin, by a method similar to OECD 414 (no GLP), two groups of female SIV rats each were orally administered 100 mg/kg bw/d of test item from the 4th to the 14th post-coital days. Two further control groups were run in parallel. In one of the groups, the foetuses were delivered by laparotomy on the 21st day after conception and the sites of implantation and absorption in both horns of the uterus were determined. The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail; the sex weight and length were determined; then, they were killed and their skeletons stained and examined. In the other treated group, delivery was by spontaneous birth and the development of the animals was followed. There was no reduction in number of foetuses, no increase in absorption sites, no significant alteration of rate of malformations, postnatal morbility, weight gain and development or histology of several organs. Thus, it was concluded that the test item does not have any teratogenic effects. The NOAEL for developmental toxicity in rat is greater than 100 mg/kg bw/d.

- In a study conducted to assess the teratogenicity potential of the sodium salt of diosmin, by a method similar to OECD 414 (no GLP), two groups of 11 female ICR mice each were orally administered 50 mg/kg bw/d of test item from the 4th to the 12th post-coital days. Two further control groups were run in parallel. In one of the groups, the foetuses were delivered by laparotomy on the 19th day after conception and the sites of implantation and absorption in both horns of the uterus were determined. The foetuses were examined with respect to palatal clefts and malformations of the extremities and tail; the sex weight and length were determined; then, they were killed and their skeletons stained and examined. In the other treated group, delivery was by spontaneous birth and the development of the animals was followed. There was no reduction in number of foetuses, no increase in absorption sites, no significant alteration of rate of malformations, postnatal morbility, weight gain and development or histology of several organs. Thus, it was concluded that the test item does not have any teratogenic effects. The NOAEL for developmental toxicity of the test item in mice is greater than 50 mg/kg bw/d.

Based on the available information for the read-across approach, the target substance is deemed to be non teratogenic.

Justification for classification or non-classification

Based on the available information, the substance is not classified for toxicity to reproduction in accordance with CLP Regulation (EC) No. 1272/2008.