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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.45 mg/m³
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):
18
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
44.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Considering no effects were observed at the highest dose tested in the semi-chronic inhalation toxicity study in rats, and no indication is present at what dose level systemic effects can be expected, the oral NOAEL is more relevant to use as starting point.

Starting point: NOAEL of 50 mg/kg bw/day in a 28-day repeated dose toxicity study in rat.

Conversion of an oral NOAEL into a corrected NOAEC:

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

= 50 mg/kg bw/day * 1/0.38 m3/kg/8h * ABSoral-rat /ABSinhal-human * 6.7 m3(8h)/10 m3(8h)

= 50 mg/kg bw/day * 1/0.38 m3/kg/8h * 0.5 * 6.7 m3 (8h)/10 m3(8h)

= 50 mg/kg bw/day /0.38 * 0.5 * (6.7/10) = 44.1 mg/m3.

With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume; ABSoral-rat /ABSinhal-human= 50/100= 0.5, assuming no differences in inhalation absorption between rats and humans.

AF for dose response relationship:
1
Justification:
Value is NOAEL
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:
DNEL (Derived No Effect Level)
Value:
32.8 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
3
Dose descriptor starting point:
NOAEC
Value:
58.3 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
98.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point: NOAEC of 58.3 mg/m3 in an acute inhalation toxicity study in rats (4 hour exposure).

For the acute exposure duration, timescaling seems to be appropriate (Table R.8-20). Habers law: Cn * t = k 58.33 * 4 = 7.93x105, so C = 37.93 x105/0.25 (15 min) = 147 mg/m3.

Corrected inhalatory NAEC based on the inhalation starting point =

147 mg/m3* 6.7/10 a = 98.5 mg/m3

 

a: 8 hour respiration rate human/respiratory volume light activity worker

AF for dose response relationship:
1
Justification:
Value is NOAEC
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

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.5 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
9
Dose descriptor starting point:
LOAEC
Value:
58.3 mg/m³
AF for dose response relationship:
3
Justification:
Extrapolation of LOAEC to NAEC as there was a clear dose response and lowest tested dose level causes respiratory damage/irritation without macroscopic abnormalities while these effects were noted at the next higher dose level
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 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):
72
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Either the oral or inhalation study could be used as starting point to derive a dermal DNEL. As in the inhalation studies local effects were leading, resulting in a NOAEC of greater or equal than value for systemic effects, the oral study seems to be more reliable as starting point.

Starting point: NOAEL of 50 mg/kg bw/day in a sub-acute oral toxicity study in rats.Oral absorption is considered to be 50% and dermal absorption is considered to be 100%:

50 mg/kg bw/d * 50/100 = 25 mg/kg bw/d

AF for dose response relationship:
1
Justification:
Value is NOAEL
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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

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:
0.72 mg/m³
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):
30
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
21.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Considering no effects were observed at the highest dose tested in the semi-chronic inhalation toxicity study in rats, and no indication is present at what dose level systemic effects can be expected, the oral NOAEL is more relevant to use as starting point.

Oral absorption is considered to be 50% and inhalation absorption is considered to be 100%:

Corrected inhalatory NAEC based on the oral starting point=

50 mg/kg bw/d * 1/1.15a * 50/100b = 21.7 mg/m3

 

a: 24 hour ventilation rate rat

b: oral/inhalation absorption 

AF for dose response relationship:
1
Justification:
Value is NOAEC
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:
DNEL (Derived No Effect Level)
Value:
29.4 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
5
Dose descriptor starting point:
NOAEC
Value:
58.3 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
147 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point: NOAEC of 58.3 mg/m3in an acute inhalation toxicity study in rats 4 hour exposure).

For the acute exposure duration, time-scaling seems to be appropriate (Table R.8-20). Habers law: Cn * t = k 58.3WE3 * 4 = 7.93x10E5, so C = 37.93 x10E5 /0.25 (15 min) = 147 mg/m3.

AF for dose response relationship:
1
Justification:
Value is NOAEC
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

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.9 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
other: ECETOC guidance (Technical Report No. 110, October 2010)
Overall assessment factor (AF):
15
Dose descriptor starting point:
LOAEC
Value:
58.3 mg/m³
AF for dose response relationship:
3
Justification:
Extrapolation of LOAEC to NOAEC as there was a clear dose response and lowest tested dose level causes respiratory damage/irritation without macroscopic abnormalities while these effects were noted at the next higher dose level.
AF for interspecies differences (allometric scaling):
1
Justification:
No correction for caloric demand for inhalation
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.21 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):
120
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Starting point: NOAEL of 50 mg/kg bw/day in a sub-acute oral toxicity study in rats. Oral absorption is considered to be 50% and dermal absorption is considered to be 100%: 50 mg/kg bw/d * 50/100 = 25 mg/kg bw/d

AF for dose response relationship:
1
Justification:
Value is NOAEL
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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.42 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):
120
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Value is NOAEL
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:
high hazard (no threshold derived)

Additional information - General Population

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