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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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:
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:

Due to lack of repeated dose toxicity data by the inhalation route, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA. The NOAEL (oral) has to be divided by a factor of 0.38 m3/kg body weight and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore:

NOAEC (corrected) = 50 mg/kg / 0.38 m3/kg x 0.5 x (6.7 m3/10m3) = 44.1 mg/m3

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is part of the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
5
Justification:
standard factor for worker
AF for the quality of the whole database:
1
Justification:
GLP and guideline compliant study
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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:
0.5 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):
100
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on dermal penetration are available. Following a worst case approach, dermal absorption of 100% is assumed. The NOAEL for DNEL derivation is therefore 50 mg/kg body weight.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
5
Justification:
standard factor for worker
AF for the quality of the whole database:
1
Justification:
GLP-compliant guideline study
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

No systemic effects were observed in rodent studies after short-term exposure to the test substance in doses up to 2000 mg/kg bw. Additionally, no inhalative peak exposures are expected as the substance has a low volatility. Thus, according to Chapter R8 of the ECHA guidance on information requirements and chemical safety assessment (2008) the systemic DNEL derived for long-term exposure is considered sufficient to ensure the safety of workers. The test article is not irritating to skin and eyes and has no skin sensitizing potential. In addition, the test article is not a mutagen in bacteria and mammalian cells and not clastogenic in mammalian cells as seen in the Bacterial Reverse Mutation Assay and In vitro Mammalian Chromosome Aberration Test, respectively. Test article-related adverse systemic effects upon subchronic oral exposure to rats consisted of increased liver weights accompanied by centrilobular hepatocellular hypertrophy and a dysregulation of the liver cell metabolism with a NOAEL of 50 mg/kg body weight. In a newly completed OECD 414 study, adverse effects were obtained with rats at a dose level of 500 mg/kg body weight with a NOAEL of 150 mg/kg body weight. In order to decide which NOAEL to choose as starting point for DNEL deviation, a worst case approach was followed. The most sensitive endpoint, resulting in the lowest DNELs, is the NOAEL observed in the subacute repeated dose toxicity study. Thus, the NOAEL of 50 mg/kg was used as starting point for DNEL calculation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 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:
50 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
21.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be modified into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA. Here, the NOAEL has to be divided by a factor of 1.15 m3/kg body weight. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point is therefore: NOAEC (corrected) = 50 mg/kg / 1.15 m3/kg x 0.5 = 21.7 mg/m3

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is part of the route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
10
Justification:
standard factor for the general population
AF for the quality of the whole database:
1
Justification:
GLP and guideline compliant study
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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):
200
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on dermal penetration are available. Following a worst case approach, dermal absorption of 100% is assumed. The NOAEL for DNEL derivation is therefore 50 mg/kg body weight.

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to humans
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
10
Justification:
standard factor for the general population
AF for the quality of the whole database:
1
Justification:
GLP-compliant guideline study
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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):
200
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
extrapolation from rat to human
AF for other interspecies differences:
2.5
Justification:
standard factor for remaining uncertainties
AF for intraspecies differences:
10
Justification:
standard factor for the general population
AF for the quality of the whole database:
1
Justification:
GLP-compliant guideline study
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
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

The considerations specified for workers also apply for the general population (see above).