Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.47 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
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
370.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL has been corrected for the following points:

  1. differences in the inhalatory volume between rat and human. In particular, NOEAL has been multiplied for 2.63 in accordance with the ECHA guidance default;
  2. differences in the bioavailability between oral and inhalation exposure. In particular, NOAEL has been multiplied for 0.5 in accordance with the ECHA guidance default;
  3. differences in the inhalatory volume for light activity at work. In particular, NOAEL has been multiplied for 0.67 in accordance with the ECHA guidance default;
  4. differences between human and experimental exposure conditions (EXPCOND). In particular, NOEAL has been multiplied for 1.4 (7 days per week(exposure in experimental oral toxicity study)/5 days per week(exposure expected for human population of workers)) in accordance with ECHA guidance.
AF for dose response relationship:
1
Justification:
Application of AF for dose-response relationship is not required as a NOAEL can be clearly identified.
AF for differences in duration of exposure:
6
Justification:
Application of an AF of 6 is deemed to be appropriate for the extrapolation from subacute to chronic exposure, in accordance with ECHA guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor has to be applied as differences in allometric scaling has already been considered by correcting the NOAEL for the differences in the inhalatory volume between rat and human.
AF for other interspecies differences:
2.5
Justification:
Since toxicokinetics in human and animal are unknown, the application of an additional AF of 2.5 is deemed to be appropriate for the extrapolation from rat to human, in accordance with ECHA guidance.
AF for intraspecies differences:
5
Justification:
Application of an AF of 5 is deemed to be appropriate to consider the intraspecific variability among workers, in accordance with ECHA guidance.
AF for the quality of the whole database:
2
Justification:
Application of an AF of 2 is deemed to be appropriate to consider the restrictions in the reliability of read-across data for the repeated dose study, though the read-across is suitably justified.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are found.
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:
0.7 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
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL has been corrected for differences between human and experimental exposure conditions (EXPCOND). In particular, NOEAL has been multiplied for 1.4 (7 days per week(exposure in experimental oral toxicity study)/5 days per week(exposure expected for human population of workers)).

AF for dose response relationship:
1
Justification:
Application of AF for dose-response relationship is not required as a NOAEL can be clearly identified.
AF for differences in duration of exposure:
6
Justification:
Application of an AF of 6 is deemed to be appropriate for the extrapolation from subacute to chronic exposure, in accordance with ECHA guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Application of an AF of 4 is deemed to be appropriate for the extrapolation from rat to human (allometric scaling), in accordance with ECHA guidance.
AF for other interspecies differences:
2.5
Justification:
Since toxicokinetics in human and animal are unknown, the application of an additional AF of 2.5 is deemed to be appropriate for the extrapolation from rat to human, in accordance with ECHA guidance.
AF for intraspecies differences:
5
Justification:
Application of an AF of 5 is deemed to be appropriate to consider the intraspecific variability among workers, in accordance with ECHA guidance.
AF for the quality of the whole database:
2
Justification:
Application of an AF of 2 is deemed to be appropriate to consider the restrictions in the reliability of read-across data for the repeated dose study, though the read-across is suitably justified.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are found.
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

NOAEL obtained from the repeated dose toxicity test (i.e. 300 mg/kg bw/day) is the same of the NOAEL obtained for the reproductive/developmental toxicity (i.e. 300 mg/kg bw/day). Therefore, DNELs provided above are deemed to be suitable in order to cover both toxicological endpoints.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.435 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):
300
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
130.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAEL has been corrected for the following points:

  1. differences in the inhalatory volume between rat and human. In particular, NOEAL has been multiplied for 0.87 in accordance with the ECHA guidance default;
  2. differences in the bioavailability between oral and inhalation exposure. In particular, NOAEL has been multiplied for 0.5 in accordance with the ECHA guidance default;
  3. differences in the inhalatory volume for light activity at work. In particular, NOAEL has been multiplied for 0.67 in accordance with the ECHA guidance default.
AF for dose response relationship:
1
Justification:
Application of AF for dose-response relationship is not required as a NOAEL can be clearly identified.
AF for differences in duration of exposure:
6
Justification:
Application of an AF of 6 is deemed to be appropriate for the extrapolation from subacute to chronic exposure, in accordance with ECHA guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
No assessment factor has to be applied as differences in allometric scaling has already been considered by correcting the NOAEL for the differences in the inhalatory volume between rat and human.
AF for other interspecies differences:
2.5
Justification:
Since toxicokinetics in human and animal are unknown, the application of an additional AF of 2.5 is deemed to be appropriate for the extrapolation from rat to human, in accordance with ECHA guidance.
AF for intraspecies differences:
10
Justification:
Application of an AF of 10 is deemed to be appropriate to consider the intraspecific variability in the general population, in accordance with ECHA guidance.
AF for the quality of the whole database:
2
Justification:
Application of an AF of 2 is deemed to be appropriate to consider the restrictions in the reliability of read-across data for the repeated dose study, though the read-across is suitably justified.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are found.
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:
0.25 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):
1 200
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL was not corrected to obtain the starting point.

AF for dose response relationship:
1
Justification:
Application of AF for dose-response relationship is not required as a NOAEL can be clearly identified.
AF for differences in duration of exposure:
6
Justification:
Application of an AF of 6 is deemed to be appropriate for the extrapolation from subacute to chronic exposure, in accordance with ECHA guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Application of an AF of 4 is deemed to be appropriate for the extrapolation from rat to human (allometric scaling), in accordance with ECHA guidance.
AF for other interspecies differences:
2.5
Justification:
Since toxicokinetics in human and animal are unknown, the application of an additional AF of 2.5 is deemed to be appropriate for the extrapolation from rat to human, in accordance with ECHA guidance.
AF for intraspecies differences:
10
Justification:
Application of an AF of 10 is deemed to be appropriate to consider the intraspecific variability in the general population, in accordance with ECHA guidance.
AF for the quality of the whole database:
2
Justification:
Application of an AF of 2 is deemed to be appropriate to consider the restrictions in the reliability of read-across data for the repeated dose study, though the read-across is suitably justified.
AF for remaining uncertainties:
0
Justification:
No remaining uncertainties are found.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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):
1 200
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

NOAEL was not corrected to obtain the starting point.

AF for dose response relationship:
1
Justification:
Application of AF for dose-response relationship is not required as a NOAEL can be clearly identified.
AF for differences in duration of exposure:
6
Justification:
Application of an AF of 6 is deemed to be appropriate for the extrapolation from subacute to chronic exposure, in accordance with ECHA guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Application of an AF of 4 is deemed to be appropriate for the extrapolation from rat to human (allometric scaling), in accordance with ECHA guidance.
AF for other interspecies differences:
2.5
Justification:
Since toxicokinetics in human and animal are unknown, the application of an additional AF of 2.5 is deemed to be appropriate for the extrapolation from rat to human, in accordance with ECHA guidance.
AF for intraspecies differences:
10
Justification:
Application of an AF of 10 is deemed to be appropriate to consider the intraspecific variability in the general population, in accordance with ECHA guidance.
AF for the quality of the whole database:
2
Justification:
Application of an AF of 2 is deemed to be appropriate to consider the restrictions in the reliability of read-across data for the repeated dose study, though the read-across is suitably justified.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are found.
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

NOAEL obtained from the repeated dose toxicity test (i.e. 300 mg/kg bw/day) is the same of the NOAEL obtained for the reproductive/developmental toxicity (i.e. 300 mg/kg bw/day). Therefore, DNELs provided above are deemed to be suitable in order to cover both toxicological endpoints.