Estradiol

Endpoint summary

Description of key information

LD50 oral (rat):> 2000 mg/kg bw [report, Ishida 2001]

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

according to Japanese Guidelines for Toxicity Studies of Drugs, Notification 1-24, 1989

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CLEA JAPAN INC.
- Age at study initiation: 4-5 weeks
- Weight at study initiation: 70-120 g
- Fasting period before study: 16-20 h
- Housing: individually
- Diet (e.g. ad libitum): Solid food CE-2, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 11 days
- Method of randomisation in assigning animals to test and control groups: Stratified sequenced randomization

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 55 ± 10%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

Formulation in 0.5% CMC-Na + 0.04% Tween-80

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50 mg/mL
- Amount of vehicle (if gavage): 4.0, 1.0, 1.9, 4.0 mL/100 g
- Purity: 0.5% CMC-Na + 0.04% Tween-80

MAXIMUM DOSE VOLUME APPLIED: 4.0 mL/100 g


CLASS METHOD
- Rationale for the selection of the starting dose:
Doses were chosen based on the results of previous combination study in rats with E2 + gestodene.

Doses:

0, 500, 950, 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Remarks:

no positive control one vehicle control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Survival: daily; Body weight: Day 0, 1, 2, 3, 6, 10, 14; Clinical signs: on day 0 (after 30 min, 1h, 3h, 5h, the next day two times and afterwards once a day.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

no mortality occurred

Clinical signs:

other: no clinical signs were reported

Gross pathology:

No findings within gross necropsy

Conclusions:

Inj the present study which was conducted equivalent to OECD test guideline 423, female Sprague-Dawley rats (5/group) were orally administered a single dose Estradiol and were observed for the following 14 days. The doses applied were. 0, 500, 950, 2000 mg/kg bw. No mortality occurred in any of the groups, no clinical signs were observed, no gross abnormalties were observed at necrospy. However, there was a slight reduction in body weight and food consumption in the treated animals as compared to the control animals. Based on these results the LD50 value for acute oral toxicity is considered > 2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study similar to OECD test guideline 423, groups of fasted, 4-5 weeks old female Sprague Dawley rats (5/group) were given a single oral dose of E§stradiol in 0.5% CMC-Na + 0.04% Tween-80 at doses of 0, 500, 950, 2000 mg/kg bw and observed for 14 days.

 

Oral LD50 Females > 2000 mg/kg bw

No mortality occurred during the test

 

Estradiol is of low Toxicity based on the LD50 in female Sprague Dawley rats.

There were no treatment related clinical signs or necropsy findings. However, body weight was slightly decreased in the treatment groups as compared to the control group animals.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In an acute oral toxicity study similar to OECD test guideline 423, groups of fasted, 4-5 weeks old female Sprague Dawley rats (5/group) were given a single oral dose of 0.5% CMC-Na + 0.04% Tween-80 at doses of 0, 500, 950, 2000 mg/kg bw and observed for 14 days.

 

Oral LD50 Females > 2000 mg/kg bw

No mortality occurred during the test

 

Estradiol is of low Toxicity based on the LD50 in female Sprague Dawley rats.

There were no treatment related clinical signs or necropsy findings. However, body weight was slightly decreased in the treatment groups as compared to the control group animals.

 

Additional human data from clinical studies are available. In one study estradiol was administered orally at a dose of 4584 mg to 24 healthy voluteers (postmenopausal women). Blood samples were taken up to 48h after administration. The subjects were asked about their health and especially about following symptoms at all test points: headache, nausea, sensation of heat, anxiety and oppression, mammary tension und metrorrhagia. The only side effect reported was headache. The subjective tolerance of the substance was good.

From the CCDS (Company Core Data Sheet) of estradiol containing hormonal replacement therapy undesirable effect were reported from clinical studies. Very common (≥ 1/10) side effects were: application site irritation, which is considered to rather result from the transdermal delivery system than from estradiol, and breast pain. Common effects (≥ 1/100, < 1/10) are considered: abdominal pain, bloating, nausea, changes in body weight, headache, dizziness and breast tenderness or changes in uterine bleeding pattern. Uncommon (≥ 1/1000, < 1/100) effects were reported, e.g. muscle cramps, migraine or breast enlargement.

Justification for classification or non-classification

Due to the results of the key study no classification is required according to Regulation (EC) 1272/2008/EC (CLP).