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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.4 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:
1 230 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation oral to inhalation:

Starting point: NOAEL (rat) of 1000 mg/kg bw/day from sub-acute toxicity study

 

For the derivation of a NOAEC for worker the following corrections have to be applied to the oral NOAEL (rat).

The oral NOAEL (rat) is multiplied with 1/0.38 m³/kg bw/8h (default respiratory volume in rat, table R.8.2 of CSR guidance) to give the corresponding rat inhalation 8h-NOAEC (no-observed adverse effect concentration).

To obtain the starting point for workers, a factor of 0.67 is applied to the NOAEC to account for the differences in inhalation rates between animals at rest and humans involved in light activity.

Further to account for differences in exposure conditions between worker (5 days/week) and experimental exposure (7days/week) a correction factor of 1.4 is applied.

 

Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human).

 

For workers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC

 

= 1000 x 1/0.38 x 50/100 x 6.7/10 x 1.4

 

The corrected inhalation NOAECworker(8h) is therefore:

= 1230 mg/m³(8h-TWA)

 

The applied total assessment factor is 75. The relevant dose descriptor, NOAEC of 1230 mg/m³ (8h-TWA) was calculated by route-to-route extrapolation from the derived NOAEL of 1000 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
6
Justification:
Default AF for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account for differences in metabolic rates.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study is conducted according to modern regulatory standards and is adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF is deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
49.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

The DNEL for acute inhalation toxicity was set for a reference period of 15 minutes at 3 times the value (default 3) of the long-term DNEL. This approach is appropriate because similar mechanisms of actions are probably involved in the responses to single and repeated exposure (TGD R8). 

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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.67 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):
300
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Long term dermal toxicity studies are not available. It is assumed that dermal absorption will not be higher than oral absorption.

 

To account for differences in exposure conditions between worker (5 days/week) and experimental exposure (7days/week) a correction factor of 1.4 is applied.

No additional factor for oral-to-dermal extrapolation is deemed necessary.

 

The corrected dermal NOAELworker(5d) is therefore:

= 1000 mg/kg bw/d x 1.4 = 1400 mg/kg bw/d

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
6
Justification:
Default AF for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
5
Justification:
The default factor of 5 for workers is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study is conducted according to modern regulatory standards and is adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF is deemed necessary
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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
Value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:

To assess consumer inhalation exposure, the oral NOAEL (rat) is multiplied with 1/1.15 m³/kg bw (Table R.8.2 of CSR guidance) to give the corresponding 24h-NOAEC (no-observed adverse effect concentration). Due to the absence of route specific information a default factor of 2 is included by assuming 50 % for oral absorption (ABS oral-rat) and 100 % absorption after inhalation (ABS inh-human).

For consumers the corrected inhalation NOAEC is calculated according to the following equation:

corrected inhalation NOAEC       = oral NOAEL x 1/sRV rat x ABS oral-rat/ ABS inh-rat x ABS oral-human/ ABS inh-human

= 1000 x 1/1.15 x50/100

The corrected inhalation NOAEC consumer (24h) is therefore = 435 mg/m³(24-h)

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
6
Justification:
Default AF for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
It is not necessary to apply an allometric scaling factor because the starting point has been corrected for differences in respiratory volume and this takes account for differences in metabolic rates.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study is conducted according to modern regulatory standards and is adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF is deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

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:

Long term dermal toxicity studies are not available. The dermal NOAEL is determined to be equal to the oral NOAEL. Based on the assumption, that dermal absorption will not be higher than oral absorption, no additional assessment factor deemed necessary for oral-to-dermal extrapolation.

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
6
Justification:
Default AF for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study is conducted according to modern regulatory standards and is adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF is deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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)

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:

No modification necessary NOAEL from oral study

AF for dose response relationship:
1
Justification:
The starting point for the DNEL calculation is a NOAEL, therefore the default assessment factor of 1 for a standard procedure is considered appropriate.
AF for differences in duration of exposure:
6
Justification:
Default AF for extrapolation from sub-acute to chronic.
AF for interspecies differences (allometric scaling):
4
Justification:
The starting point is an oral dose descriptor from a rat study. It is therefore necessary to include an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
Due to the absence of toxicokinetic data an additional factor of 2.5 for other interspecies differences is applied according to TGD 8.
AF for intraspecies differences:
10
Justification:
The default factor of 10 for general population is used to take account of intraspecies variability.
AF for the quality of the whole database:
1
Justification:
The key study is conducted according to modern regulatory standards and is adequately reported.
AF for remaining uncertainties:
1
Justification:
No additional AF is deemed necessary.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

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