Registration Dossier
Registration Dossier
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EC number: 200-164-5 | CAS number: 53-16-7
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 µg/m³
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: Internal Operating Procedure: Procedure for setting occupational guidance values (SARW) for active pharmaceutical incredients (API).
- Overall assessment factor (AF):
- 10
- Dose descriptor starting point:
- other: lowest oral daily dose with pharmacological effect (SSTDmin.) in humans = 0.05 mg/day (1 mg/day administered orally, but only 5 % of amount becomes bioavailable after oral intake).
- Modified dose descriptor starting point:
- other: lowest dose with pharmacological effect in humans for the inhalation route = 0.02083 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The leading health effect after repeated exposure to steroidal estrogens including estradiol-17ß and estrone among others is based on the interference with the body's hormonal balance. The toxic effects of steroidal estrogens are an exaggeration of the normal pharmacological effects and result in an increase of female characteristics.
For such a systemic effect extrapolation from oral to inhalation is possible.SSTmin (dose desriptor starting point) diveded by: (0.2* + 0.8** x f) x V = Modified dose descriptor starting point
* proportion of the dose, which is absorbed via lung
** proportion of the dose, which is absorbed in the gastrointestinal tract
f bioavailability after oral administration = 0.05 in the case of estradiol
V Volume of air inhaled during an 8 -hours workshift = 10 m³
- AF for dose response relationship:
- 2
- Justification:
- starting point is a LOEL
- AF for differences in duration of exposure:
- 1
- Justification:
- typically covered by clinical data
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not applicable (clinical data are used)
- AF for other interspecies differences:
- 1
- Justification:
- not applicable (clinical data are used)
- AF for intraspecies differences:
- 5
- Justification:
- While the pharmacological effect of an active compound is considered therapeutically desirable in patients treated for a particular medical condition, workers have to be protected from pharmacological effects of an active pharmaceutical ingredient (API)
- AF for the quality of the whole database:
- 1
- Justification:
- endogeneous substance and approved drug
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.07 µg/kg bw/day
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other:
- Overall assessment factor (AF):
- 10
- Dose descriptor starting point:
- other: lowest oral daily dose with pharmacological effect (SSTDmin.) in humans = 0.05 mg/day (1 mg/day administered orally, but only 5 % of the amount becomes bioavailable after oral intake).
- Explanation for the modification of the dose descriptor starting point:
Estradiol and its metabolite estrone are essential endogeneous steroidal estrogens. Exogenous estradiol and estrone are widely used for oral contraception and in post-menopausal hormonal therapy. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. Adverse effects in animals and humans are driven by the pharmacological activity because adversity is an exaggeration of the normal pharmacological effects. For such a systemic effect extrapolation from oral to dermal route is justified.
As known from an extensive data base animal experiments with estrogens are only of limited predictive value for qualitative and even more for quanatitative extrapolation tu humans because of a large diversity in factors responsible for endocrine regulation between experimental animals and man.
The absorption after oral exposure is assumed to be identical to the absorption after dermal exposure (worst case) = 1 Therefore the most sensitive endpoint to consider is the lowest oral daily dose with pharmacological effects in humans (SSTmin) of estradiol is used as surrogate for estrone.- AF for dose response relationship:
- 2
- Justification:
- starting point is a LOEL
- AF for differences in duration of exposure:
- 1
- Justification:
- typically covered by clinical data
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- not applicable (clinical data are used)
- AF for other interspecies differences:
- 1
- Justification:
- not applicable (clinical data are used)
- AF for intraspecies differences:
- 5
- Justification:
- While the pharmacological effect of an active compound is considered therapeutically desirable in patients treated for a particular medical condition, workers have to be protected from pharmacological effects of an active pharmaceutical ingredient (API)
- AF for the quality of the whole database:
- 1
- Justification:
- endogeneous substance and approved drug
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - workers
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- no hazard identified
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- no hazard identified
Additional information - General Population
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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