Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
882 mg/m³
Explanation for the modification of the dose descriptor starting point:

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and inhalation absorption (default assumptions), breathing rate and exposure time to give a modified (inhalation) NOAEC of 882 mg/m3.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Extrapolation from studies of up to sub-chronic in duration, to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required: already taken into account in modification of the starting point.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value: no significant remaining uncertainty
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:
10 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and dermal absorption (default assumptions) to give a modified (dermal) NOAEL of 1000 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Extrapolation from studies of up to sub-chronic in duration, to chronic exposure.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point derived from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value: no significant 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Workers

No toxicological adverse effects of treatment were seen in a screening study, one-generation study or a prenatal developmental toxicity study at a dose level of 1000 mg/kg bw/d. The NOAEL of 1000 mg/kg bw/d is therefore used as the starting point for the derivation of long-term systemic DNEL values for workers. Short-term systemic DNELs are not derived in the absence of any identified hazard. Local DNELs are not derived in the absence of any identified hazard.

Long-term systemic inhalation DNEL

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and inhalation absorption (default assumptions), breathing rate and exposure time to give a modified (inhalation) NOAEC of 882 mg/m3. The corrected starting point is adjusted through the application of individual assessment factors of 1 (for dose-response relationship), 2 (for the duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties). Combining the individual assessment factors results in an overall assessment factor of 25. Applying the overall assessment factor to the corrected starting point results in a DNEL of 35 mg/m3.

Long-term systemic dermal DNEL

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and dermal absorption (default assumptions) to give a modified (dermal) NOAEL of 1000 mg/kg bw/d. The corrected starting point is adjusted through the application of individual assessment factors of 1 (for dose-response relationship), 2 (for the duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties). Combining the individual assessment factors results in an overall assessment factor of 100. Applying the overall assessment factor to the corrected starting point results in a DNEL of 10 mg/kg bw/d.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
435 mg/m³
Explanation for the modification of the dose descriptor starting point:

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and inhalation absorption (default assumptions) and breathing rate to give a modified (inhalation) NOAEC of 435 mg/m3.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Default value: studies of up to sub-chonic duration extrapolated to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
Not required: already accounted for in correction of the starting point
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value: no significant remaining uncertainty
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:
5 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and dermal absorption (default assumptions) to give a modified (dermal) NOAEL of 1000 mg/kg bw/d.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Extrapolation from studies of up to sub-chronic duation to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point is from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value: no significant remaining uncertainty
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:
5 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point of 1000 mg/kg bw/d is from an oral study and does not therefore require correction.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
2
Justification:
Default value: extrapolation from studies of up to sub-chronic duration to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value: starting point is from a rat study
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value: general population
AF for the quality of the whole database:
1
Justification:
Default value
AF for remaining uncertainties:
1
Justification:
Default value: no significant 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

General Population

No toxicological adverse effects of treatment were seen in a screening study, one-generation study or a prenatal developmental toxicity study at a dose level of 1000 mg/kg bw/d. The NOAEL of 1000 mg/kg bw/d is therefore used as the starting point for the derivation of long-term systemic DNEL values for the general population. Short-term systemic DNELs are not derived in the absence of any identified hazard. Local DNELs are not derived in the absence of any identified hazard.

Long-term systemic inhalation DNEL

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and inhalation absorption (default assumptions) and breathing rate to give a modified (inhalation) NOAEC of 435 mg/m3. The corrected starting point is adjusted through the application of individual assessment factors of 1 (for dose-response relationship), 2 (for the duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 10 for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties). Combining the individual assessment factors results in an overall assessment factor of 50. Applying the overall assessment factor to the corrected starting point results in a DNEL of 9 mg/m3.

Long-term systemic dermal DNEL

The starting point of 1000 mg/kg bw/d is corrected for the relative extent of oral and dermal absorption (default assumptions) to give a modified (dermal) NOAEL of 1000 mg/kg bw/d. The corrected starting point is adjusted through the application of individual assessment factors of 1 (for dose-response relationship), 2 (for the duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties). Combining the individual assessment factors results in an overall assessment factor of 200. Applying the overall assessment factor to the corrected starting point results in a DNEL of 5 mg/kg bw/d.

Long-term systemic oral DNEL

The starting point of 1000 mg/kg bw/d is from an oral study and does not therefore require correction. The starting point is adjusted through the application of individual assessment factors of 1 (for dose-response relationship), 2 (for the duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties). Combining the individual assessment factors results in an overall assessment factor of 200. Applying the overall assessment factor to the corrected starting point results in a DNEL of 5 mg/kg bw/d.