Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
126.63 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
6 300 mg/m³
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation needed. Experimental rat inhalatory NOAEC was converted into human inhalatory NOAEC considering: the duration of animals and workers exposure ratio (6h/24h).

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEC Duration of exposure:
AF for differences in duration of exposure:
2
Justification:
Duration is extrapolated from sub-chronic (90-day) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allomatric scaling is not applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
Default factor mentioned in ECHA Guidance R8
AF for intraspecies differences:
10
Justification:
"it is usually assumed that a default assessment factor of 10 is sufficient to protect the larger part of the population, including e.g. children and the elderly".
AF for the quality of the whole database:
1
Justification:
The read accross study has been performed according to OECD guidelines (Klimisch code 2)
AF for remaining uncertainties:
1
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.97 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
1 197 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation is needed. Experimental rat inhalatory NOAEC was converted into human dermal NOAEL considering: the "8h exposure rat standard Respiratory Volume" (0.38 m3/kg); the "rat inhalatory absorption"/"human dermal absorption" ratio (50/100).

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEC (as mentioned in ECHA Guidance R8 v2.1
AF for differences in duration of exposure:
2
Justification:
Duration is extrapolated from sub-chronic (90 days) to chronic (as mentioned in ECHA Guidance R8 v2.1
AF for interspecies differences (allometric scaling):
4
Justification:
An AS factor of 4 for rat as compared to humans is presented in ECHA Guidance R8 v2.1
AF for other interspecies differences:
2.5
Justification:
Default factor mentioned in ECHA Guidance R8 v2.1
AF for intraspecies differences:
5
Justification:
As mentioned in ECHA Guidance R8 v2.1: "For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill".
AF for the quality of the whole database:
1
Justification:
The read accross study has been performed according to OECD guidelines (Klimisch code 2)
AF for remaining uncertainties:
1
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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
31.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
1 575 mg/m³
Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation needed. Experimental rat inhalatory NOAEC was converted into human inhalatory NOAEC considering: the duration of animals and workers exposure ratio (6h/24h).

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEC Duration of exposure:
AF for differences in duration of exposure:
2
Justification:
Duration is extrapolated from sub-chronic (90-day) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allomatric scaling is not applicable when setting an inhalation DNEL based on an inhalation animal study
AF for other interspecies differences:
2.5
Justification:
Default factor mentioned in ECHA Guidance R8
AF for intraspecies differences:
10
Justification:
"it is usually assumed that a default assessment factor of 10 is sufficient to protect the larger part of the population, including e.g. children and the elderly".
AF for the quality of the whole database:
1
Justification:
The read accross study has been performed according to OECD guidelines (Klimisch code 2)
AF for remaining uncertainties:
1
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:
18.11 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
3 622.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation is needed. Experimental rat inhalatory NOAEC was converted into human dermal NOAEL considering: the "24h exposure rat standard Respiratory Volume" (1.15 m3/kg); the worst-case "rat inhalatory absorption"/"human dermal absorption" ratio (50/100).

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEC (as mentioned in ECHA Guidance R8 v2.1
AF for differences in duration of exposure:
2
Justification:
Duration is extrapolated from sub-chronic (90 days) to chronic (as mentioned in ECHA Guidance R8 v2.1
AF for interspecies differences (allometric scaling):
4
Justification:
An AS factor of 4 for rat as compared to humans is presented in ECHA Guidance R8 v2.1
AF for other interspecies differences:
2.5
Justification:
Default factor mentioned in ECHA Guidance R8 v2.1
AF for intraspecies differences:
10
Justification:
As mentioned in ECHA Guidance R8 v2.1: "it is usually assumed that a default assessment factor of 10 is sufficient to protect the larger part of the population, including e.g. children and the elderly".
AF for the quality of the whole database:
1
Justification:
The read accross study has been performed according to OECD guidelines (Klimisch code 2)
AF for remaining uncertainties:
1
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:
36.225 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
7 245 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation is needed. Experimental rat inhalatory NOAEC was converted into human oral NOAEL considering: the "24h exposure rat standard Respiratory Volume" (1.15 m3/kg); the "rat inhalatory absorption"/"human oral absorption" ratio (100/100) because a two times higher oral compared to inhalation absorption appears on empirical grounds not justified.

AF for dose response relationship:
1
Justification:
Starting point for the DNEL calculation is a NOAEC
AF for differences in duration of exposure:
2
Justification:
Duration is extrapolated from sub-chronic (90 days) to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
An AS factor of 4 for rat as compared to humans is presented in ECHA Guidance R8 v2.1.
AF for other interspecies differences:
2.5
Justification:
Default factor mentioned in ECHA Guidance R8
AF for intraspecies differences:
10
Justification:
As mentioned in ECHA Guidance R8 : "it is usually assumed that a default assessment factor of 10 is sufficient to protect the larger part of the population, including e.g. children and the elderly".
AF for the quality of the whole database:
1
Justification:
The read accross study has been performed according to OECD guidelines (Klimisch code 2)
AF for remaining uncertainties:
1
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

Starting point of DNEL derivation is NOAEC = 6300 mg/m³ from a sub-chronic (90-day inhalation repeated dose with Methylal)