Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.7 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):
75
Dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
278.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

The dose descriptor starting point for 8 hours of exposure was calculated according to Ref Figure R.8-3:

Corrected inhalatory NOEC =oral NOEL * (1 / sRV, rat) * (ABSoral, rat / ABSinh-human) * (sRVhuman / wRV)

Where

- sRV, rat = standard Respiratory Volume, rat =m3/kg for 8 hours

- ABS = absorption

- ABSoral, rat / ABSinh-human = 1 / 2 (default factor for extrapolation from oral to inhalation)

- sRVhuman = standard Respiratory Volume, human = 6.7 m3/person for 8 hours

- wRV = standard Respiratory Volume, worker = 10 m3/person for 8 hours

Therefore the dose descriptor starting point is:

316 mg/kg bw * (1 /m3/kg bw) * 1/2 * (6.7 m3 / 10 m3) = 278.6 mg/m3

AF for dose response relationship:
1
Justification:
Assessment factor for dose response (starting point is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
Assessment factors for exposure duration (sub-acute to chronic study)
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human) since this is already accounted for when obtaining the corrected NOEC
AF for other interspecies differences:
2.5
Justification:
Assessment factors for remaining non-metabolic differences
AF for intraspecies differences:
5
Justification:
Assessment factors for workers
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional factors are required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.5 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
125
Dose descriptor starting point:
other: LD50
DNEL value:
5 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
8 816 mg/m³
Explanation for the modification of the dose descriptor starting point:

No acute inhalation study is available. Therefore the data of the acute oral toxicity study are used: LD50 oral, rat >5000 mg/kg bw.

The dose descriptor starting point for 4 hours of exposure was calculated according to Ref Figure R.8-3:

Corrected inhalatory NOEC =

= oral NOEL * (1 / sRV, rat) * (ABSoral, rat / ABSinh-human) * (sRVhuman / wRV)

Where

- sRV, rat = standard Respiratory Volume, rat =m3/kg bw for 4 hours

- ABS = absorption

- ABSoral, rat / ABSinh-human = 1 / 2 (default factor for extrapolation from oral to inhalation)

- sRVhuman = standard Respiratory Volume, human =m3/person for 4 hours

- wRV = standard Respiratory Volume, worker = 5 m3/person for 4 hours

Therefore the dose descriptor starting point is:

5000 mg/kg bw * (1 / 0,19 m3/kg bw) * 1/2 * (3.35 m3 / 5 m3) = 8816 mg/m3

AF for dose response relationship:
10
Justification:
As some transient signs of toxicity were noted at that dose, a factor of 10 is therefore applied to cover the ratio of LD50/NOAEC
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human) since this is already accounted for when obtaining the corrected NOEC
AF for other interspecies differences:
2.5
Justification:
Assessment factors for remaining non-metabolic differences
AF for intraspecies differences:
5
Justification:
Assessment factors for workers
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional factors are required

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 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):
300
Dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal absorption is considered to be generally lower than the oral absorption. As a worst case it is therefore assumed that the NOAELdermal = NOAELoral.

AF for dose response relationship:
1
Justification:
Assessment factor for dose-response (starting point is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
Assessment factors for exposure duration (sub-acute to chronic study)
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factors for remaining non-metabolic differences
AF for intraspecies differences:
5
Justification:
Assessment factors for workers
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Justification:
No additional factors are required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not required; as acute dermal study was available.

AF for dose response relationship:
1
Justification:
As no toxic signs were noted at the LD50, dermal, the dermal LD50 is considered to be also the NOAEL, dermal. A factor of 1 is therefore applied to cover the ratio of LD50/NOAEL.
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factor for any remaining non-metabolic differences
AF for intraspecies differences:
5
Justification:
Assessment factor for workers
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional assessment factors are required

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
skin irritation/corrosion

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:
0.92 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):
150
Dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
137.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting point:

The dose descriptor starting point for 24 hours of exposure was calculated according to Ref Figure R.8-3:

Corrected inhalatory NOEC= oral NOEL * (1 / sRV, rat) * (ABSoral, rat / ABSinh-human)

Where

- sRV, rat = standard Respiratory Volume, rat =m3/kg for 24 hours)

- ABS = absorption

- ABSoral, rat / ABSinh-human = 1 / 2 (default factor for extrapolation from oral to inhalation)

Therefore the starting dose descriptor is:

316 mg/kg bw * (1 /m3/kg bw) * 1/2 = 137.4 mg/m3

AF for dose response relationship:
1
Justification:
Assessment factor for dose response (starting point is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
Assessment factors for exposure duration (sub-acute to chronic study)
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human) since this is already accounted for when obtaining the corrected NOEC
AF for other interspecies differences:
2.5
Justification:
Assessment factor for any remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional assessment factors are required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.1 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
250
Dose descriptor starting point:
other: LD50
DNEL value:
5 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
5 263 mg/m³
Explanation for the modification of the dose descriptor starting point:

Dose descriptor starting point:

No acute inhalation study is available. Therefore the data of the acute oral toxicity study are used: LD50 oral, rat >5000 mg/kg bw.

The dose descriptor starting point for 4 hours of exposure was calculated according to Ref Figure R.8-3:

Corrected inhalatory NOEC= oral NOEL * (1 / sRV, rat) * (ABSoral, rat / ABSinh-human)

Where

- sRV, rat = standard Respiratory Volume, rat =m3/kg bw for 4 hours

- ABS = absorption

- ABSoral, rat / ABSinh-human = 1 / 2 (default factor for extrapolation from oral to inhalation)

Therefore the starting dose descriptor is:

5000 mg/kg bw * (1 /m3/kg bw) * 1/2 = 5263 mg/m3

AF for dose response relationship:
10
Justification:
As some transient signs of toxicity were noted at that dose, a factor of 10 is therefore applied to cover the ratio of LD50/NOAEC
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human) since this is already accounted for when obtaining the corrected NOEC)
AF for other interspecies differences:
2.5
Justification:
Assessment factors for remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factors for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional factors are required

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
600
Dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal absorption is considered to be generally lower than the oral absorption. As a worst case it is therefore assumed that the NOAELdermal = NOAELoral.

AF for dose response relationship:
1
Justification:
Assessment factor fior dose-response (starting point is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
Assessment factors for exposure duration (sub-acute to chronic study)
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factors for remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factors for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional factors are required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not required; as an acute dermal study was available

AF for dose response relationship:
1
Justification:
As no toxic signs were noted at the LD50, dermal, the dermal LD50 is considered to be also the NOAEL, dermal. A factor of 1 is therefore applied to cover the ratio of LD50/NOAEL.
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factor for any remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional assessment factors are required

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
acute toxicity

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
600
Dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
316 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Not required; as an repeated dose oral toxicity study was available

AF for dose response relationship:
1
Justification:
Assessment factor for dose-response (starting point is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
Assessment factors for exposure duration (sub-acute to chronic study)
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factor for any remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional assessment factors are required
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1 000
Dose descriptor starting point:
other: LD50
DNEL value:
5 000 mg/kg bw/day
Modified dose descriptor starting point:
other: LD50
DNEL value:
5 000 mg/kg bw/day
AF for dose response relationship:
10
Justification:
As some transient signs of toxicity were noted at that dose, a factor of 10 is therefore applied to cover the ratio of LD50/NOAEC
AF for interspecies differences (allometric scaling):
4
Justification:
Assessment factor applied for interspecies difference - allometric (metabolic rate) scaling (rat-to-human)
AF for other interspecies differences:
2.5
Justification:
Assessment factor for any remaining non-metabolic differences
AF for intraspecies differences:
10
Justification:
Assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Good quality study
AF for remaining uncertainties:
1
Justification:
No additional assessment factors are required

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population