Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.71 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:
LOAEC
DNEL value:
406.56 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 on page 19 of Guidance Document, Chapter R.8 (2010). 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). The corrected dose descriptor for inhalation is [500 mg/kg bw/day] / [0.38 m3/kg bw/day] X [6.7 m3/10m3] /2. Then, a correction factor based on the ratio between the molecular mass of the registered substance (190.28 g/mol) and and the supporting substance (206.3 g/mol) was applied to extrapolate the corrected starting point for the registered substance. Thus, the corrected dose descriptor for inhalation is 406.56 mg/m3 for workers
AF for dose response relationship:
6
Justification:
Taking into account the uncertainties in the dose descriptor, an assessment factor was applied on the LOAEL to extrapolate a NOAEL. In the ECETOC TR No. 86 (2003), a review of published studies in which the ratios of LOAELs to NOAELs were compared for a range of different chemicals and different study duration indicates than LOAEL rarely exceed the NOAEL by more than arbour 5-6 fold and is typically closer to 3. As a worst-case, and since it is difficult to conclude on the severity of the effect observed, this factor of 6 was applied on the LOAEL.
AF for differences in duration of exposure:
2
Justification:
Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.77 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:
LOAEL
DNEL value:
461.17 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. A correction factor based on the ratio between the molecular mass of the registered substance (190.28 g/mol) and and the supporting substance (206.3 g/mol) was applied to extrapolate the corrected starting point for the registered substance. Thus, the corrected dose descriptor for inhalation is 461.17 mg/kg bw for workers
AF for dose response relationship:
6
Justification:
Taking into account the uncertainties in the dose descriptor, an assessment factor was applied on the LOAEL to extrapolate a NOAEL. In the ECETOC TR No. 86 (2003), a review of published studies in which the ratios of LOAELs to NOAELs were compared for a range of different chemicals and different study duration indicates than LOAEL rarely exceed the NOAEL by more than arbour 5-6 fold and is typically closer to 3. As a worst-case, and since it is difficult to conclude on the severity of the effect observed, this factor of 6 was applied on the LOAEL.
AF for differences in duration of exposure:
2
Justification:
Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.67 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
Modified dose descriptor starting point:
LOAEC
DNEL value:
200.51 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 on page 19 of Guidance Document, Chapter R.8 (2010). 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). The corrected dose descriptor for inhalation is [500 mg/kg bw/day] / [1.15 m3/kg bw/day] /2. Then, a correction factor based on the ratio between the molecular mass of the registered substance (190.28 g/mol) and and the supporting substance (206.3 g/mol) was applied to extrapolate the corrected starting point for the registered substance. Thus, the corrected dose descriptor for inhalation is 200.51 mg/m3 for consumers
AF for dose response relationship:
6
Justification:
Taking into account the uncertainties in the dose descriptor, an assessment factor was applied on the LOAEL to extrapolate a NOAEL. In the ECETOC TR No. 86 (2003), a review of published studies in which the ratios of LOAELs to NOAELs were compared for a range of different chemicals and different study duration indicates than LOAEL rarely exceed the NOAEL by more than arbour 5-6 fold and is typically closer to 3. As a worst-case, and since it is difficult to conclude on the severity of the effect observed, this factor of 6 was applied on the LOAEL.
AF for differences in duration of exposure:
2
Justification:
Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.38 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
Modified dose descriptor starting point:
LOAEL
DNEL value:
461.17 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. A correction factor based on the ratio between the molecular mass of the registered substance (190.28 g/mol) and and the supporting substance (206.3 g/mol) was applied to extrapolate the corrected starting point for the registered substance. Thus, the corrected dose descriptor for inhalation is 461.17 mg/kg bw/day for consumers.
AF for dose response relationship:
6
Justification:
Taking into account the uncertainties in the dose descriptor, an assessment factor was applied on the LOAEL to extrapolate a NOAEL. In the ECETOC TR No. 86 (2003), a review of published studies in which the ratios of LOAELs to NOAELs were compared for a range of different chemicals and different study duration indicates than LOAEL rarely exceed the NOAEL by more than arbour 5-6 fold and is typically closer to 3. As a worst-case, and since it is difficult to conclude on the severity of the effect observed, this factor of 6 was applied on the LOAEL.
AF for differences in duration of exposure:
2
Justification:
Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-4 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
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:
0.38 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
Modified dose descriptor starting point:
LOAEL
DNEL value:
461.17 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A correction factor based on the ratio between the molecular mass of the registered substance (190.28 g/mol) and and the supporting substance (206.3 g/mol) was applied to extrapolate the corrected starting point for the registered substance. Thus, the corrected dose descriptor for inhalation is 461.17 mg/kg bw/day for consumers.
AF for dose response relationship:
6
Justification:
Taking into account the uncertainties in the dose descriptor, an assessment factor was applied on the LOAEL to extrapolate a NOAEL. In the ECETOC TR No. 86 (2003), a review of published studies in which the ratios of LOAELs to NOAELs were compared for a range of different chemicals and different study duration indicates than LOAEL rarely exceed the NOAEL by more than arbour 5-6 fold and is typically closer to 3. As a worst-case, and since it is difficult to conclude on the severity of the effect observed, this factor of 6 was applied on the LOAEL.
AF for differences in duration of exposure:
2
Justification:
Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
4
Justification:
Table R.8-5 ECHA REACH Guidance
AF for other interspecies differences:
2.5
Justification:
Table R.8-5 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Table R.8-5 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
studies available for all key systemic endpoints
AF for remaining uncertainties:
1
Justification:
studies available for all key systemic endpoints
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