Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12 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 = 0.7 mg/day (1.3 mg/day administered orally, but only 50 % of amount becomes bioavailable after oral intake).
Modified dose descriptor starting point:
other: lowest dose with pharmacological effect in humans for the inhalation route = 0.116666 mg/m³
Explanation for the modification of the dose descriptor starting point:

The leading health effect after repeated exposure to steroidal progestrins including progesterone 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 = 0.5 in the case of norethisterone

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:
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:
1 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 = 0.7 mg/day (1.3 mg/day administered orally, but only 50 % of the amount becomes bioavailable after oral intake).
Explanation for the modification of the dose descriptor starting point:

Norethisterone is a synthetic sex hormone and active ingredient of approved drugs since several decades. Norethisterone belongs to the category “steroidal progestins” and has progestogenic properties resembling those of the naturally occuring progesterone but is a more potent inhibitor of ovulation.

As known from an extensive data base animal experiments with steroidal hormones 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 norethisterone.
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:
active pharmaceutical ingredient of approved drugs
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