Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.05 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
Modified dose descriptor starting point:
NOAEC
Value:
176.31 mg/m³
Explanation for the modification of the dose descriptor starting point:
NAEC worker (8h) = (100mg/kg bw/0.38 m³/kg bw) * 6.7 m³/ 10 m³ [where: NAEC is the modified starting point; 100 mg/kg bw is the NOEL for oral repeated dose toxicity; 0.83 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity)]
AF for dose response relationship:
1
Justification:
Data well supported
AF for differences in duration of exposure:
2
Justification:
Sub-Chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Scaling issues just evaluated in modified starting point
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
5
Justification:
Worker population
AF for the quality of the whole database:
1
Justification:
Good quality and reliability
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
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 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
Modified dose descriptor starting point:
other: NOEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.
AF for dose response relationship:
1
Justification:
Data well supported
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric Scaling
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
5
Justification:
Worker population
AF for the quality of the whole database:
1
Justification:
Good quality and reliability
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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

In order to derive DNELs for worker population, the No Observed Effect Level recorded for the oral repeated dose toxicity has been chosen.

The Repeated dose toxicity study (90 days) was reported in the NTP Technical Report and was conducted as a range finding for a two years study.

Inhalation Systemic effects - Long-term

NAEC worker (8h) = (100 mg/kg bw / 0.38 m³/kg bw) * 6.7 m³/ 10 m³

[where: NAEC is the modified starting point; 100 mg/kg bw is the NOEL for oral repeated dose toxicity; 0.83 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure; for workers a further correction is needed for the difference between respiratory rates under standard conditions and under conditions of light activity. This correction factor derives from the inhalation volumes in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity)]

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: difference in duration of exposure subchronic-chronic (2), remaining differences (2.5), intraspecies differences for worker (5).

This results in an overall assessment factor of 25. The DNEL for long-term inhalation exposure, systemic effects is therefore 7.05 mg/m³.

Dermal Systemic effects - Long-term

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: difference in duration of exposure subchronic-chronic (2), interspecies difference (4), remaining differences (2.5), intraspecies differences for worker (5).

This results in an overall assessment factor of 100. The DNEL for long-term dermal exposure, systemic effects is therefore 1 mg/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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
Modified dose descriptor starting point:
NOAEC
Value:
86.96 mg/m³
Explanation for the modification of the dose descriptor starting point:
NAEC worker (8h) = (100 mg/kg bw/1.15 m³/kg bw) [where: NAEC is the modified starting point; 100 mg/kg bw is the NOEL for oral repeated dose toxicity; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]
AF for dose response relationship:
1
Justification:
Data well supported
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Scaling issues just evaluated in modified starting point
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Good quality and reliability
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
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):
200
Modified dose descriptor starting point:
other: NOEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.
AF for dose response relationship:
1
Justification:
Data well supported
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
From rat to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Good quality and reliability
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
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):
200
Modified dose descriptor starting point:
other: NOEL
Value:
100
Explanation for the modification of the dose descriptor starting point:
No default factor should be introduced when performing on the same route; 100 mg/kg bw/day is the NOEL for oral repeated dose toxicity.
AF for dose response relationship:
1
Justification:
Data well supported
AF for differences in duration of exposure:
2
Justification:
From sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
From rats to humans
AF for other interspecies differences:
2.5
Justification:
Remaining differences
AF for intraspecies differences:
10
Justification:
General population
AF for the quality of the whole database:
1
Justification:
Good quality and reliability
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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

In order to derive DNELs for general population, the No Observed Effect Level recorded for the oral repeated dose toxicity has been chosen.

The Repeated dose toxicity study (90 days) was reported in the NTP Technical Report and was conducted as a range finding for a two years study.

 

Inhalation Systemic effects - Long-term

NAEC worker (8h) = (100 mg/kg bw/1.15 m³/kg bw)

[where: NAEC is the modified starting point; 100 mg/kg bw is the NOEL for oral repeated dose toxicity; 1.15 m³/kg bw is the default respiratory volume for the rat corresponding to the daily duration of human exposure]

 

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: difference in duration of exposure subchronic-chronic (2), remaining differences (2.5), intraspecies differences for general population (10).

This results in an overall assessment factor of 50. The DNEL for long-term inhalation exposure, systemic effects is therefore 1.74 mg/m³.

 

Dermal Systemic effects - Long-term

On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: difference in duration of exposure subchronic-chronic (2), interspecies difference (4), remaining differences (2.5), intraspecies differences for general population (10).

This results in an overall assessment factor of 200. The DNEL for long-term dermal exposure, systemic effects is therefore 05 mg/m³.

 

Oral Systemic effects - Long-term

No default factor should be introduced when performing on the same route; 100 mg/kg bw/day is the NOEL for oral repeated dose toxicity.

Subsequently other assessment factors are listed, which have to be taken into account for the final DNEL calculation: difference in duration of exposure subchronic-chronic (2), interspecies difference (4), remaining differences (2.5), intraspecies differences for general population (10).

This results in an overall assessment factor of 200. The DNEL for long-term oral exposure, systemic effects is therefore 05 mg/m³.