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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.65 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
54
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
35.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

Starting point: LOAEL of 100 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.

Conversion of an oral LOAEL into a corrected LOAEC:

For workers (8h exposure/day), the corrected inhalatory LOAEC = oral LOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human * sRVhuman/wRV

           = 100 * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3(8h)/10 m3(8h)

           = 100 * 1/0.38 m3/kg/8h * 10%/50% * 6.7 m3 (8h)/10 m3(8h)

= 100 /0.38 * 10%/50% * (6.7/10) = 35.3 mg/m3.

 

With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume;

ABSoral-rat /ABSinhal-human= 100/100= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
3
Justification:
Value is LOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; is included in dose descriptor starting point
AF for other interspecies differences:
1
Justification:
No remaining differences.
AF for intraspecies differences:
3
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Reliable studies used
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.46 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
216
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite.Correction dermal LOAEL: 100 x 10/10a= 100 mg/kg bw/day (a% oral/dermal absorption)

AF for dose response relationship:
3
Justification:
Value is LOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
1
Justification:
No remaining differences
AF for intraspecies differences:
3
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Reliable studies used
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:
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:
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:
0.19 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
90
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
Value:
17.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and inhalation intake in the absence of evidence of the opposite.

For the general population (24h exposure/day), the corrected inhalatory LOAEC = oral LOAEL * 1/sRVrat * ABSoral-rat /ABSinhal-human

 

           = 100 * 1/1.15 m3/kg * ABSoral-rat /ABSinhal-human

 

           = 100 * 1/1.15 m3/kg * 10/50 = 17.4 mg/m3

 

With ABS: Absorption, sRV: Standard Respiratory Volume;

ABSoral-rat /ABSinhal-human= 10/50= 1, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
3
Justification:
Value is LOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure general population
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation; is included in dose descriptor starting point
AF for other interspecies differences:
1
Justification:
No remaining differences
AF for intraspecies differences:
5
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
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:
0.28 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
360
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Kinetics (metabolism, distribution and excretion) are considered to be similar for oral and dermal intake in the absence of evidence of the opposite.Correction dermal LOAEL: 100 x 10/10a= 100 mg/kg bw/day (a% oral/dermal absorption).

AF for dose response relationship:
3
Justification:
Value is LOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure worker
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
1
Justification:
No remaining differences
AF for intraspecies differences:
5
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
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:
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:
0.28 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
360
Dose descriptor starting point:
LOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

As the starting point is an oral repeated dose study, no modification is needed.

 

AF for dose response relationship:
3
Justification:
Value is LOAEL
AF for differences in duration of exposure:
6
Justification:
Extrapolation from subacute study to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Correction for caloric demand from rat to human
AF for other interspecies differences:
1
Justification:
No remaining differences
AF for intraspecies differences:
5
Justification:
Difference in sensitivity among general population
AF for the quality of the whole database:
1
Justification:
Reliable studies used
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