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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.118 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
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
8.82 mg/m³
Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period). Thus, the corrected dose descriptor for inhalation is [10mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [2/1] X [6.7 m3/10m3]. Thus, the corrected dose descriptor for inhalation is 8.82 mg/m3 for workers.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No 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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.033 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
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
The DNEL is based on a subacute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
The experimental animal was a rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default AF according to ECHA REACH guidance. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is not considered to be acutely toxic with reported dermal LD50 = > 2,000 mg/kg bw in rats. Therefore not meeting the criteria for classification under GHS or Regulation (EC) No 1272/2008 (CLP).

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL values are derived using the approach recommended by ECHA and default assessment factors. NOAEL of 10 mg/kg bw/day from an OECD 407 oral repeated dose toxicity study in rats selected over the NOAEL of 4 mg/kg bw/day from an OECD 421 study. This is because the dose selection for the OECD 421 study was based on the observation in the OECD 407 although the NOAEL dose was not used in the reproductive screening study.  No mortality was observed at up to 40 mg/kg bw/day and all observations at the median dose of 10 mg/kg bw/day were within historical control data and as such considered non-adverse in nature. Furthermore, the common target organ toxicity observed in both studies were noted in dosage 20 mg/kg bw/day.

Therefore, for the long-term inhalation systemic DNEL, the value was derived from the systemic NOAEL of 10 mg/kg bw/day from an OECD 407 oral repeated dose toxicity study in rats and a corrected (inhalation) starting point of 8.82 mg/m3.  In the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).  A short-term inhalation systemic DNEL is not derived in the absence of any acute hazard. Inhalation local dermal DNEL values are not derived in the absence of any indication of a hazard or relevant data. Furthermore, the substance is a liquid with a low volatility (<50 Pa; defined in ECHA, 2014) of 4.9 Pa at 20°C, which indicates a negligible potential to inhale vapours of the substance under ambient handling conditions.

A long-term dermal systemic DNEL value was derived from the systemic NOAEL of 10 mg/kg bw/d from a 28-day rat oral toxicity study based on the assumption that, in general, dermal absorption will not be higher than oral absorption. Therefore, no default factor (i.e. factor 1) was introduced when performing oral-to-dermal extrapolation. A short-term dermal systemic DNEL as well as local dermal DNELs were not derived in the absence of any hazard following acute and local dermal exposures.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.03 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
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4.35 mg/m³
Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012). To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h). Thus, the corrected dose descriptor for inhalation is [10 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [2/1]. Thus, the corrected dose descriptor for inhalation is 4.35 mg/m3 for the general population

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No 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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.02 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
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is not considered to be acutely toxic with reported dermal LD50 = > 2,000 mg/kg bw in rats. Therefore not meeting the criteria for classification under GHS or Regulation (EC) No 1272/2008 (CLP).

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.02 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
Value:
10 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
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:
no hazard identified

Additional information - General Population

DNEL values are derived using the approach recommended by ECHA and default assessment factors. NOAEL of 10 mg/kg bw/day from an OECD 407 oral repeated dose toxicity study in rats selected over the NOAEL of 4 mg/kg bw/day from an OECD 421 study. This is because the dose selection for the OECD 421 study was based on the observation in the OECD 407 although the NOAEL dose was not used in the reproductive screening study.  No mortality was observed at up to 40 mg/kg bw/day and all observations at the median dose of 10 mg/kg bw/day were within historical control data and as such considered non-adverse in nature. Furthermore, the common target organ toxicity observed in both studies were noted in dosage 20 mg/kg bw/day.

Therefore, for the long-term inhalation systemic DNEL, the value was derived from the systemic NOAEL of 10 mg/kg bw/day from an OECD 407 oral repeated dose toxicity study in rats and a corrected (inhalation) starting point of 8.82 mg/m3.  In the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).  A short-term inhalation systemic DNEL is not derived in the absence of any acute hazard. Inhalation local dermal DNEL values are not derived in the absence of any indication of a hazard or relevant data.

A long-term dermal systemic DNEL value was derived from the systemic NOAEL of 10 mg/kg bw/d from a 28-day rat oral toxicity study based on the assumption that, in general, dermal absorption will not be higher than oral absorption. Therefore, no default factor (i.e. factor 1) was introduced when performing oral-to-dermal extrapolation. A short-term dermal systemic DNEL as well as local dermal DNELs were not derived in the absence of any hazard following acute and local dermal exposures.

A long-term oral systemic DNEL value was derived from the systemic NOAEL of 10 mg/kg bw/d from a 28-day rat oral toxicity study based on the assumption of 100% oral absorption. The substance was classified as Harmful if ingested (Acute Tox. 4, H302). However, the available data was insufficient to derive a DNEL (oral) for acute systemic exposure. Since the DNELs for long-term systemic exposure are adequate to protection.

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