Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.24 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):
25
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
881.05 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose toxicity study conducted via the inhalation route of exposure the use of a PoD using the oral route of exposure has been employed. The NOAEL is taken from repeat dose oral toxicity studies in rats. It is assumed that oral absorption of the substance is half that of inhalation absorption.

Inhalatory N(L)OAEC = oral N(L)OAEL*(1/0.38 m3/kg/d)*0.67*(ABSoral/ABSinh.)

= 1000 * 2.63 * 0.67 * 0.5

= 881.05 mg/m3

 

DNEL = PoD/AF

= 881.05/25

= 35.24 mg/m3

AF for dose response relationship:
1
Justification:
As the dose descriptor is the NOAEL, the default assessment factor is 1.
AF for differences in duration of exposure:
2
Justification:
To account for using PoD taken from a subchronic study to calculate a chronic DNEL.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is usually not applied in the derivation of the inhalation DNEL.
AF for other interspecies differences:
2.5
Justification:
Default factor.
AF for intraspecies differences:
5
Justification:
To account for intraspecies differences in an occupational setting.
AF for the quality of the whole database:
1
Justification:
The database is of good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties identified therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.24 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):
25
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.35 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
This factor is applied because the dose-descriptor starting point is a LOAEC. At this dose level, the adverse effects were of minimal severity.
AF for differences in duration of exposure:
1
Justification:
Local effects on the respiratory tract are related to the deposited dose per unit of surface area. Below a certain concentration the clearance capacity of the lungs is not overwhelmed and the lungs retain the ability to clear the deposited substance. Therefore, the lung effects are not suspected to worsen with increasing exposure duration.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
1
Justification:
No additional assessment factor is added for interspecies extrapolation from rodent to human, since the respiratory rate of rats (0.29 m3/kg-day according to Pauluhn (2010)) leads to a greater lung tract burden as compared to humans (0.14 m3/kg-day), thus the effects observed in rats are exaggerated and provide a “built in” safety margin.
AF for intraspecies differences:
5
Justification:
A factor of 5 is applied for worker DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 1.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.35 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

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:
DNEL (Derived No Effect Level)
Value:
8.69 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):
50
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

In the absence of a repeated dose toxicity study conducted via the inhalation route of exposure the use of a PoD using the oral route of exposure has been employed. The NOAEL is taken from repeat dose oral toxicity studies in rats.It is assumed that oral absorption of the substance is half that of inhalation absorption.

 

Inhalatory N(L)OAEC = oral N(L)OAEL*(1/1.15 m3/kg bw/d)*(ABSoral/ABSinh.)

= 1000 * 0.869 * 0.5

= 434.5 mg/m3

 

DNEL = PoD/AF

= 434.5/50

= 8.69 mg/m3

AF for dose response relationship:
1
Justification:
As the dose descriptor is the NOAEL, the default assessment factor is 1.
AF for differences in duration of exposure:
2
Justification:
To account for using PoD taken from a subchronic study to calculate a chronic DNEL.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is usually not applied in the derivation of the inhalation DNEL.
AF for other interspecies differences:
2.5
Justification:
Default factor.
AF for intraspecies differences:
10
Justification:
To account for intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The database has good quality studies, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties identified therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.69 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):
50
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
This factor is applied because the dose-descriptor starting point is a LOAEC. At this dose level, the adverse effects were of minimal severity.
AF for differences in duration of exposure:
1
Justification:
Local effects on the respiratory tract are related to the deposited dose per unit of surface area. Below a certain concentration the clearance capacity of the lungs is not overwhelmed and the lungs retain the ability to clear the deposited substance. Therefore, the lung effects are not suspected to worsen with increasing exposure duration.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation.
AF for other interspecies differences:
1
Justification:
No additional assessment factor is added for interspecies extrapolation from rodent to human, since the respiratory rate of rats (0.29 m3/kg-day according to Pauluhn (2010)) leads to a greater lung tract burden as compared to humans (0.14 m3/kg-day); thus the effects observed in rats are exaggerated and provide a “built in” safety margin.
AF for intraspecies differences:
10
Justification:
A factor of 10 is applied for the general population DNELs.
AF for the quality of the whole database:
1
Justification:
The key study is considered as a reliable study with a klimisch score of 1.
AF for remaining uncertainties:
1
Justification:
No other assessment factor is applied.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

DNEL = PoD/AF

= 1000/200

= 5 mg/kg bw/day

 

AF for dose response relationship:
1
Justification:
As the dose descriptor is the NOAEL, the default assessment factor is 1.
AF for differences in duration of exposure:
2
Justification:
To account for using PoD taken from a subchronic study to calculate a chronic DNEL.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling to account for differences in allometry in using the rat as a test model.
AF for other interspecies differences:
2.5
Justification:
Default factor.
AF for intraspecies differences:
10
Justification:
To account for intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The database has good quality studies, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties identified therefore the default factor of 1 applies.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
200
DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population