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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.8 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
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
881.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation from an oral dose to an inhalation dose the starting point needs to be modified to correct for the breathing volume of the rat and respiratory volume under standard conditions (6.7 m3/person) versus under conditions of light activity for workers (10 m3/person). Based on ECHA’s recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans. Therefore, the inhalation starting dose = oral BMDL10 x 1/(0.38 m3/kg/day) x 6.7m3/10m3.  In addition, ECHA recommends in the absence of route-specific information on the starting route, to include a default factor of 2 (i. e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation.

Therefore, the inhalation starting route for the worker population = (1000/0.38)*(6.7/10)*0.5= 881.6 mg/m3

AF for dose response relationship:
1
Justification:
A default assessment factor of 1 was applied when the NOAEL from the oral reproductive screening toxicity study (OECD 422) was used
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 was applied for duration of exposure (subacute study: 28-day study in males to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor was applied when the oral NOAEL from the a reproductiv screening study (OECD 422) study was used for the derivation of inhalation long-term DNEL.
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 was applied for workers
AF for the quality of the whole database:
1
Justification:
A default assessment factor of 1 was used.
AF for remaining uncertainties:
1
Justification:
No additional uncertainties were considered
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:
3.33 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
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered for both the dermal and oral routes. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for an exposure route. In addition, it will be assumed that dermal absorption will not be higher than oral absorption. Therefore, the starting dose for calculation of the dermal DNEL is 1000 mg/kg/day.

AF for dose response relationship:
1
Justification:
A default assessment factor of 1 was applied when the NOAEL from the oral reproductive screening toxicity study (OECD 422) was used.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 was applied for duration of exposure (subacute study: 28-day study in males to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the reproductive screening toxicity study (OECD 422), which was used to derive the dermal long-term DNEL.
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 was applied for workers.
AF for the quality of the whole database:
1
Justification:
A default assessment factor of 1 was used.
AF for remaining uncertainties:
1
Justification:
No additional uncertainties were considered
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation from an oral dose to an inhalation dose, the starting point needs to be modified to correct for the breathing volume of the rat.  Based on ECHA’s recommendations, it is assumed that respiratory absorption is equivalent between the animals and humans. Therefore, the inhalation starting dose =oral NOAELx 1/(1.15 m3/kg/day). In addition, ECHA recommends in the absence of route-specific information on the starting route, to include a default factor of 2 (i. e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation.

Therefore, the inhalation starting dose for the general population = 1000 mg/kg/day x 1/(1.15 m3/kg/day) x 0.5 = 434.78 mg/m3

AF for dose response relationship:
1
Justification:
A default assessment factor of 1 was applied when the NOAEL from the oral reproductive screening toxicity study (OECD 422) was used.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 was applied for duration of exposure (subacute study: 28-day study in males to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor was applied when the oral NOAEL from the reproductive screening study (OECD 422) was used for the derivation of inhalation long-term DNEL
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
A default assessment factor of 1 was used
AF for remaining uncertainties:
1
Justification:
No additional uncertainties were considered
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:
1.67 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
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For route-to-route extrapolation for the dermal route, the absorption differences between the animal and human need to be considered for both the dermal and oral routes. The default situation, in the absence of information, is to assume the same bioavailability for experimental animals and humans for an exposure route. In addition, it will be assumed that dermal absorption will not be higher than oral absorption. Therefore, the starting dose for calculation of the dermal DNEL is 1000 mg/kg/day.

AF for dose response relationship:
1
Justification:
A default assessment factor of 1 was applied when the NOAEL from the oral reproductive screening toxicity study (OECD 422) was used.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 was applied for duration of exposure (subacute study: 28-day study in males to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the reproductive screening toxicity study (OECD 422), which was used to derive the dermal long-term DNEL
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
A default assessment factor of 1 was used
AF for remaining uncertainties:
1
Justification:
No additional uncertainties were considered
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
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:
1.67 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
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The oral NOAEL of 1000 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAELrat= oral NOAELhuman= 1000 mg/kg bw.

AF for dose response relationship:
1
Justification:
A default assessment factor of 1 was applied when the NOAEL from the oral reproductive screening toxicity study (OECD 422) was used.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 was applied for duration of exposure (subacute study: 28-day study in males to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
Default for rats
AF for other interspecies differences:
2.5
Justification:
An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
1
Justification:
A default assessment factor of 1 was used
AF for remaining uncertainties:
1
Justification:
No additional uncertainties were considered
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population