Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 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):
75
Modified dose descriptor starting point:
NOAEC
DNEL value:
44.1 mg/m³
Explanation for the modification of the dose descriptor starting point:
The substance is not susceptible to transformation in stomach acid. The target organ liver will be reached independently from the original route.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor according to ECHA guidance document Chapter R8 for subacute exposure duration (starting point) is used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
There is no evidence for other interspecies differences
AF for intraspecies differences:
5
Justification:
The default factor for WORKER according to ECHA guidance document Chapter R8 is used
AF for the quality of the whole database:
1
Justification:
The NOAEL was derived from a recent high quality GLP-compliant guideline study
AF for remaining uncertainties:
2.5
Justification:
Standard factor for remaining uncertainties according to ECHA guidance document Chapter R8
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:
0.08 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):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The substance is not susceptible to transformation in stomach acid. The target organ liver will be reached independently from the original route. Uptake of this highly insoluble substance after ingestion is facilitated by emulgation with bile acids. This is not possible for the dermal route.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor according to ECHA guidance document Chapter R8 for subacute exposure duration (starting point) is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used
AF for other interspecies differences:
1
Justification:
There is no evidence for other interspecies differences
AF for intraspecies differences:
5
Justification:
The default factor for WORKER according to ECHA guidance document Chapter R8 is used
AF for the quality of the whole database:
1
Justification:
The NOAEL was derived from a recent high quality GLP-compliant guideline study
AF for remaining uncertainties:
2.5
Justification:
Standard factor for remaining uncertainties according to ECHA guidance document Chapter R8
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

Identification of relevant dose descriptor

For the derivation of the DNELs, the combined oral repeated dose toxicity study and reproduction/developmental toxicity screening test in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 25 mg/kg/day.

Calculation of DNELs

Systemic, long-term, inhalative

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, May 2008. 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). The corrected starting point is therefore:

NOAEC (corrected) = 25 mg/kg / 0.38 m3/kg x (6.7 m3/10m3) = 44.1 mg/m3

The DNEL is calculated as follows: NOAEL (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Exposure duration: 6

Remaining uncertainties: 2.5

The overall assessment factor employed for the inhalation route is therefore 75.

DNEL = 44.1 mg/m3/ 75 = 0.59 mg/m3

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Allometric scaling (rat to human): 4

Exposure duration: 6

Remaining uncertainties: 2.5

Overall, an assessment factor of 300 was employed for the dermal route.

DNEL= 25 mg/kg body weight / 300 = 0.08 mg/kg body weight.

Systemic, short-term, dermal and by inhalation

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.

Local, long-term and short-term, dermal and by inhalation

Based on the available key toxicological information, the test item is not subject to classification for irritation and sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
21.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
The substance is not susceptible to transformation in stomach acid. The target organ liver will be reached independently from the original route.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor according to ECHA guidance document Chapter R8 for subacute exposure duration (starting point) is used.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
There is no evidence for other interspecies differences
AF for intraspecies differences:
10
Justification:
The default factor for the GENERAL POPULATION according to ECHA guidance document Chapter R8 is used
AF for the quality of the whole database:
1
Justification:
The NOAEL was derived from a recent high quality GLP-compliant guideline study
AF for remaining uncertainties:
2.5
Justification:
Standard factor for remaining uncertainties according to ECHA guidance document Chapter R8
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:
0.04 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The substance is not susceptible to transformation in stomach acid. The target organ liver will be reached independently from the original route. Uptake via the skin of this highly insoluble substance is not facilitated by emulgation in bile acids, as is the case for ingestion.
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor according to ECHA guidance document Chapter R8 for subacute exposure duration (starting point) is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used
AF for other interspecies differences:
1
Justification:
There is no evidence for other interspecies differences
AF for intraspecies differences:
10
Justification:
The default factor for the GENERAL POPULATION according to ECHA guidance document Chapter R8 is used
AF for the quality of the whole database:
1
Justification:
The NOAEL was derived from a recent high quality GLP-compliant guideline study
AF for remaining uncertainties:
2.5
Justification:
Standard factor for remaining uncertainties according to ECHA guidance document Chapter R8
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:
0.04 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
25 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable
AF for differences in duration of exposure:
6
Justification:
The default extrapolation factor according to ECHA guidance document Chapter R8 for subacute exposure duration (starting point) is used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for differences between rats and humans is used
AF for other interspecies differences:
1
Justification:
There is no evidence for other interspecies differences
AF for intraspecies differences:
10
Justification:
The default factor for the GENERAL POPULATION according to ECHA guidance document Chapter R8 is used
AF for the quality of the whole database:
1
Justification:
The NOAEL was derived from a recent high quality GLP-compliant guideline study
AF for remaining uncertainties:
2.5
Justification:
Standard factor for remaining uncertainties according to ECHA guidance document Chapter R8
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

Identification of relevant dose descriptor

For the derivation of the DNELs, the combined oral repeated dose toxicity study and reproduction/developmental toxicity screening test in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 25 mg/kg/day.

Calculation of DNELs

Systemic, long-term, inhalative

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, May 2008. Here, the NOAEL has to be divided by a factor of 1.15 m3/kg body weight. The corrected starting point is therefore:

NOAEC (corrected) = 25 mg/kg / 1.15 m3/kg = 21.7 mg/m3

The DNEL is calculated as follows: NOAEC (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Exposure duration: 6

Remaining uncertainties: 2.5

The overall assessment factor employed for the inhalation route is therefore 150.

DNEL = 21.7 mg/m3/ 150 = 0.14 mg/m3

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. Since no data on skin penetration is available a worst case approach was chosen and an absorption of 100% is assumed. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 10

Allometric scaling (rat to human): 4

Exposure duration: 6

Remaining uncertainties: 2.5

Overall, an assessment factor of 600 was employed for the dermal route.

DNEL= 25 mg/kg body weight / 600 = 0.04 mg/kg body weight.

Systemic, long-term, oral:

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 10

Allometric scaling (rat to human): 4

Exposure duration: 6

Remaining uncertainties: 2.5

The overall assessment factor employed for the oral route is therefore 240.

DNEL= 25 mg/kg body weight / 600 = 0.04 mg/kg body weight.

Systemic, short-term, dermal, oral and by inhalation

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.

Local, long-term and short-term, dermal and by inhalation

Based on the available key toxicological information, the test item is not subject to classification for irritation and sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).