Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.3 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
358.3 mg/m³
Explanation for the modification of the dose descriptor starting point:
No experimental data available for the inhalation route.
AF for dose response relationship:
1
Justification:
Experimental data show reliable dose-response relationship
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Rat to human correction undertaken during route-to route extrapolation of starting dose
AF for other interspecies differences:
2.5
Justification:
Standard default value in ECHA guidance.
AF for intraspecies differences:
5
Justification:
Standard default value in ECHA guidance.
AF for the quality of the whole database:
1
Justification:
Data base is good
AF for remaining uncertainties:
1
Justification:
No other uncertainties apparent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.1 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):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
406.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No experimental data available for the repeated dose dermal route.
AF for dose response relationship:
1
Justification:
Experimental data show reliable dose-response relationship.
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
Standard default value in ECHA guidance.
AF for intraspecies differences:
5
Justification:
Standard default value in ECHA guidance.
AF for the quality of the whole database:
1
Justification:
Data base is good
AF for remaining uncertainties:
1
Justification:
No other uncertainties apparent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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

The DNEL for long-term inhalation exposure was derived from a NOAEL of 406.4 mg/kg bw/day for a sub-chronic dietary toxicity study in rats (Pharmakon Europe, 1993) . The corrected starting dose was calculated using the formula 406.4 mg/kg bw/day x 1/0.38 (rat standard breathing volume) x 0.5 (absorption differences) x  6.7/10 0 (light worker activity) = 358.3. mg/m3. An overall assessment factor of 25 was calculated, based on the ECHA guidance in R8, Figure R-6, May 2008, giving a DNEL of 14.3 mg/m3.

The DNEL for long-term dermal exposure was derived from a NOAEL of 406.4 mg/kg bw/day for a sub-chronic oral toxicity study in rats (Pharmakon Europe, 1993). The corrected starting dose was calculated using the formula 406.4 mg/kg bw/day x 1 (absorption difference) = 406.5 mg/kg bw/day. An allometric scaling factor of 4 was used (rat to human) and an overall assessment factor of 100 was calculated, based on the ECHA guidance in R8, Figure R-6, May 2008, giving a DNEL of 4.1 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
176.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
No experimental data available for the inhalation route.
AF for dose response relationship:
1
Justification:
Experimental data show reliable dose-response relationship
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Rat to human correction undertaken during route-to route extrapolation of starting dose
AF for other interspecies differences:
2.5
Justification:
Standard default value in ECHA guidance.
AF for intraspecies differences:
10
Justification:
Standard default value in ECHA guidance.
AF for the quality of the whole database:
1
Justification:
Data base is good
AF for remaining uncertainties:
1
Justification:
No other uncertainties apparent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
406.4 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No experimental data available for the dermal route.
AF for dose response relationship:
1
Justification:
Experimental data show reliable dose-response relationship
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human extrapolation.
AF for other interspecies differences:
2.5
Justification:
Standard default value in ECHA guidance.
AF for intraspecies differences:
10
Justification:
Standard default value in ECHA guidance.
AF for the quality of the whole database:
1
Justification:
Data base is good
AF for remaining uncertainties:
1
Justification:
No other uncertainties apparent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
2 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):
200
Modified dose descriptor starting point:
NOAEL
DNEL value:
406.4 ng/kg bw/day
AF for dose response relationship:
1
Justification:
Experimental data show reliable dose-response relationship
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Rat to human extrapolation
AF for other interspecies differences:
2.5
Justification:
Standard default value in ECHA guidance.
AF for intraspecies differences:
10
Justification:
Standard default value in ECHA guidance.
AF for the quality of the whole database:
1
Justification:
Data base is good
AF for remaining uncertainties:
1
Justification:
No other uncertainties apparent
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

The DNEL for long-term inhalation exposure was derived from a NOAEL of 406.5 mg/kg bw/day from a sub-chronic dietary toxicity study in rats (Pharmakon Europe, 1993). The corrected starting dose was calculated using the formula 406.4 mg/kg bw/day x 1/1.15 (rat standard breathing volume) x 0.5 (absorption differences) = 176.7 mg/m3. An overall assessment factor of 50 was calculated, based on the ECHA guidance given in R8, Figure R-6, May 2008, giving a DNEL of 3.5 mg/m3.

The DNEL for long-term dermal exposure was derived from a NOAEL of 406.5 mg/kg bw/day from a sub-chronic oral toxicity study in rats (Pharmakon Europe, 1993). The corrected starting dose was calculated using the formula 406.4 mg/kg bw/day x 1 (absorption difference) = 406.5 mg/kg bw/day. An allometric scaling factor of 4 was used (rat to human) and an overall assessment factor of 200 was calculated, based on the ECHA guidance given in R8, Figure R-6, May 2008, giving a DNEL of 2.0 mg/kg bw/day.

 

The DNEL for long-term oral exposure was derived from a NOAEL of 406.4 mg/kg bw/day from a sub-chronic dietary toxicity study in rats (Pharmakon Europe, 1993). Using an allometirc scaling factor of 4 (rat to human) and overall assessment factor of 200 was calculated, based on the ECHA guidance given in R8, Figure R-6, May 2008, giving a DNEL of 2.0 mg/kg bw/day.