Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 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):
54
Dose descriptor starting point:
LOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
44.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

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 to the opposite.

Starting point: LOAEL of 50 mg/kg bw/day in a short-term 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

= 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 * 50/100 * 6.7 m3(8h)/10 m3(8h)

= 50 mg/kg bw/day/0.38 * 1/2 * (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:
3
Justification:
Value is LOAEL; a NOAEL of 30 mg/kg bw/day based on the same adverse effects was observed in the reproduction/developmental screening study. An assessment factor of 3 is therefore considered reliable.
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure worker from short-term toxicity study
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 other interspecies differences that need to be considered.
AF for intraspecies differences:
3
Justification:
Difference in sensitivity among workers
AF for the quality of the whole database:
1
Justification:
Results based on reliable study with the substance
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium 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:
0.23 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):
216
Dose descriptor starting point:
LOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
LOAEL
DNEL value:
25 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: 50 mg/kg bw/day x 50/100a= 25 mg/kg bw/day (a% oral/dermal absorption)

AF for dose response relationship:
3
Justification:
Value is LOAEL; a NOAEL of 30 mg/kg bw/day based on the same adverse effects was observed in the reproduction/developmental screening study. An assessment factor of 3 is therefore considered reliable.
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure general population from short-term toxicity data.
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:
Results based on reliable study with the substance
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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium 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:
0.24 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):
90
Dose descriptor starting point:
LOAEL
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
LOAEC
DNEL value:
21.7 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 LOAEC * 1/sRVrat * ABSoral-rat /ABSinhal-human

           = 50 mg/kg bw/day * 1/1.15 m3/kg * ABSoral-rat /ABSinhal-human

            = 50 mg/kg bw/day * 1/1.15 m3/kg * 1/2 = 21.7 mg/m3

With ABS: Absorption, sRV: Standard 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:
3
Justification:
Value is LOAEL; a NOAEL of 30 mg/kg bw/day based on the same adverse effects was observed in the reproduction/developmental screening study. An assessment factor of 3 is therefore considered reliable.
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure general population from short-term toxicity study
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 other interspecies differences
AF for intraspecies differences:
5
Justification:
Difference in sensitivity within general population
AF for the quality of the whole database:
1
Justification:
Results based on reliable study with the substance
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.24 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 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
DNEL value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 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: 50 mg/kg bw/day x 50/100a= 25 mg/kg bw/day (a% oral/dermal absorption).

AF for dose response relationship:
3
Justification:
Value is LOAEL; a NOAEL of 30 mg/kg bw/day based on the same adverse effects was observed in the reproduction/developmental screening study. An assessment factor of 3 is therefore considered reliable.
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure general population from short-term toxicity data
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:
Results based on reliable study with the substance
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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 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
DNEL value:
50 mg/kg bw/day
AF for dose response relationship:
3
Justification:
Value is LOAEL; a NOAEL of 30 mg/kg bw/day based on the same adverse effects was observed in the reproduction/developmental screening study. An assessment factor of 3 is therefore considered reliable.
AF for differences in duration of exposure:
6
Justification:
Extrapolation to chronic exposure from short-term study.
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:
Results based on reliable study on the substance
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population