Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
625
Modified dose descriptor starting point:
NOAEC
Value:
62.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
The repeat dose oral NOAEL was divided by 2 to account for potential increase in absorption between oral to inhalation exposure (ECHA Guidance Document r.8 pg 28).
AF for dose response relationship:
1
Justification:
NOAEL to NOAEL
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Already taken into account during conversion of the oral NOAEL to an inhalation NOAEC
AF for other interspecies differences:
2.5
Justification:
Uncertainty between lab animal and human
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
Data of sufficiently reliable quality
AF for remaining uncertainties:
25
Justification:
Losartan free acid is the precursor to an Active Pharmaceutical Ingredient with an intended effect to decrease blood pressure. A conservative uncertainty factor has been added in line with the established manufacturing facility exposure limit. Given the already conservative nature of the route to route extrapolation, the addition of further uncertainty factor of 25 ensures that the long-term, inhalation DNEL for systemic effects is conservative and protective, most likely overestimating the inhalation hazard of the substance.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
100% equivalent dermal ad oral exposure are assumed. Oral exposure typically leads to greater absorption than dermal exposure, therefore, data from oral toxicity test are sufficient for extrapolation to dermal effects, and are indeed conservative or worst case.
AF for dose response relationship:
1
Justification:
NOAEL to NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not relevant for dermal
AF for other interspecies differences:
2.5
Justification:
Uncertainty between lab animal and human population
AF for intraspecies differences:
5
Justification:
Workers (rather than general population)
AF for the quality of the whole database:
1
Justification:
Data of sufficiently reliable quality
AF for remaining uncertainties:
1
Justification:
Application of a more conservative uncertainty factor is not reasonable for dermal exposure as absorption via ingestion or inhalation would be greater than absorption via dermal exposure. Given the already conservative nature of the route-to-route extrapolation, the it is not necessary to add further uncertainty factor (as applied in the derivation of inhalation DNEL).
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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