Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26.9 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
DNEL value:
763 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
672.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

There is no repeated dose inhalation data. Therefore the repeated dose oral data has been used. NOAEL value of 763 mg/kg bw/d from oral 90 day repeated dose study is chosen as starting point. The NOAEC value is calculated as follows = 763 x (1/0.38) x (1/2) x (6.7/10) = 672.6 mg/m3. The absorption rate for inhalation is assumed to be 100%.

AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Not typically applied in the derivation of an inhalation DNEL
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
136.25 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):
100
Dose descriptor starting point:
NOAEL
DNEL value:
763 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
13 625 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The database of available repeat dose dermal studies includes two sub-chronic 90 day studies as well as two chronic/carcinogenicity studies, conducted in both rats and mice. These studies were limited in design such that not all important endpoints were investigated. These studies found only local effects based on epidermal hyperplasia and no systemic toxicity. So for the purpose of calculating a DNEL value for systemic effects, the oral NOAEL has been used. NOAEL value of 763 mg/kg bw/d from oral 90 day repeated dose study is chosen as starting point. The dermal NOAEL is based on the oral NOAEL of 763 mg/kg/day but also takes account of relative oral and dermal absorption of 50% and 2.8% respectively. It is calculated as follows: NOAEL = 763 x (50/2.8) = 13625 mg/kg/day.

AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.096 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
DNEL value:
4 800 mg/m³
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Default value for local effects
AF for other interspecies differences:
1
Justification:
Default value for effects via simple destruction of membranes
AF for intraspecies differences:
5
Justification:
Workers
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Although a good quality dermal toxicity study is available, for the derivation of systemic DNELs the study with oral exposure will be used. In the dermal studies only local effects have been observed. The derivation of the inhalation DNELs is also based on the oral study.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.6 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
DNEL value:
763 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
331.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

No inhalation studies available. Therefore the repeated dose oral data has been used. NOAEL value of 763 mg/kg bw/d from oral 90 day repeated dose study is chosen as starting point. The NOAEC value is calculated as follows = 763 x (1/1.15) x (1/2) = 331.7 mg/m3. The absorption rate for inhalation is assumed to be 100%.

AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Not typically applied in the derivation of an inhalation DNEL
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
68.1 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
763 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
13 625 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The database of available repeat dose dermal studies includes two sub-chronic 90 day studies as well as two chronic/carcinogenicity studies, conducted in both rats and mice. These studies were limited in design such that not all important endpoints were investigated. These studies found only local effects based on epidermal hyperplasia and no systemic toxicity. So for the purpose of calculating a DNEL value for systemic effects, the oral NOAEL has been used. NOAEL value of 763 mg/kg bw/d from oral 90 day repeated dose study is chosen as starting point. The dermal NOAEL is based on the oral NOAEL of 763 mg/kg/day but also takes account of relative oral and dermal absorption of 50% and 2.8% respectively. It is calculated as follows: NOAEL = 763 x (50/2.8) = 13625 mg/kg/day.

AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.048 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
DNEL value:
4 800 mg/m³
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
1
Justification:
Chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Default value for local effects
AF for other interspecies differences:
1
Justification:
Default value for effects via simple destruction of membranes
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.8 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
DNEL value:
763 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL
AF for differences in duration of exposure:
2
Justification:
Sub-chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
The database has a 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:
No remaining uncertainties identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Although a good quality dermal toxicity study is available, for the derivation of systemic DNELs studies with oral exposure will be used. In the dermal studies only local effects have been observed. The derivation of the inhalation DNELs is also based on the oral study.