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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.46 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 234.21 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated inhalative exposure. Using a conservative approach, an oral absorption rate of 50 % compared to the respiratory absorption rate is expected. (Absorption rate oral / Absorption rate inhalation = 0.5). For further details, please refer to the field ‘additional information – worker’.

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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.6 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
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. As a worst-case-approach but also considering physico-chemical properties of the substance, the same absorption via the dermal route (end route) as compared to the oral route (starting route) is assumed. For details, please refer to the discussion.


 


 

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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
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
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
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:
low hazard (no threshold derived)

Additional information - workers

General


DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). 


Acute/short-term, systemic effects


Short-term DNELs are not required as the acute toxicity of the test item is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP).


Acute/long-term, local effects


Skin irritation/corrosion: Based on the available acute skin irritation study the test item is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.  


Eye irritation/corrosion: The test item was found to be irritating to the eyes and is classified as H319 according to Regulation (EC) No 1272/2008. A qualitative assessment will be conducted. 


Respiratory irritation/corrosion:


The test item is classified for eye irritation Cat 2 according to Regulation (EC) No 1272/2008 (CLP). Therefore, a hazard for local effects on the mucous membranes of the respiratory tract cannot completely ruled out when inhaled. Thus, a qualitative risk assessment will be conducted.


Long term, systemic effects


Occupational exposure to the test item occurs mainly by dermal route, and may also occur by inhalation route. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.  


 


Exposure by inhalation


Step 1: Selection of the relevant dose descriptor (starting point): The NOAEL of 1000 mg/kg bw/day is identified as the relevant dose descriptor and starting point. This value was assessed in a weight-of-evidence approach including read across data with the hydrolysis products of the substance itself as well as read-across repeated dose toxicity-results recorded in the reproduction/developmental toxicity screening studies (OECD 414) with structural analogues (10 days dosing).


Step 2: Modification into a correct starting point: Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).  


Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day


Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/day


Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5 (50%/ 100%)


Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³


Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³  


Frequency of exposure used in study: 7 days/week


Frequency of exposure of the worker: 5 days/week


Corrected inhalatory NOAEC for workers = 1000 mg/kg bw/day × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³) x (7/5) = 1234,21 mg/m³  


Step 3: Use of assessment factors: 75


Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.


Other interspecies differences AF: 2.5


Intraspecies AF (worker): 5


Exposure duration AF: 6


 


In conclusion, long term systemic inhalation DNEL, workers = 16.46 mg/m3  


   


 


Dermal exposure


Step 1: Selection of the relevant dose descriptor (starting point):


The NOAEL of 1000 mg/kg bw/day, assessed for the oral repeated dose toxicity endpoint was selected as starting point.


Step 2: Modification of the starting point: Assuming that dermal absorption is the same as oral absorption, a worker DNEL (long-term dermal exposure) is derived.  


Frequency of exposure used in study: 7 days/week


Frequency of exposure of the worker: 5 days/week


ABS (oral rat): 100%


ABS (dermal human):100%


 


Corrected dermal NOAEL for workers:


= 1000mg/kg bw/d x 100%/100% x 7/5 = 1400 mg/kg bw/d


 


Step 3: Use of assessment factors: 300


Interspecies AF, allometric scaling (rat to human): 4


Other interspecies differences AF: 2.5


Intraspecies AF (worker): 5


Exposure duration AF: 6 


 


In conclusion, long term systemic dermal DNEL, workers = 4.6 mg/kg bw/day  


 


 


References


(not included as endpoint study record)  


- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. ECHA-2010-G-19-EN.


 


- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. ECHA-14-G-06-N.


 


- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.


 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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):
150
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated inhalative exposure. Using a conservative approach, an oral absorption rate of 50 % compared to the respiratory absorption rate is expected. (Absorption rate oral / Absorption rate inhalation = 0.5). For further details, please refer to the field ‘additional information – general population’.

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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.67 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:
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:

There are no relevant experimental data on repeated dermal exposure. As a worst-case-approach but also considering physico-chemical properties of the substance, the same absorption via the dermal route (end route) as compared to the oral route (starting route) is assumed. For details, please refer to the field ‘additional information – general population’.

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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
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:
1.67 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:
1 000 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:
6
Justification:
The default extrapolation factor for exposure duration is used: subacute (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is applied.
AF for other interspecies differences:
2.5
Justification:
The recommended AF for other interspecies differences is applied.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
DNEL Derivation is considered conservative, reflecting reasonable worst case assumptions. Therefore, no further AF for remaining uncertainties is applied.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

General


DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). 


Acute/short-term, systemic effects


Short-term DNELs are not required as the acute toxicity of the test item is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP).


Acute/long-term, local effects


Skin irritation/corrosion: Based on the available acute skin irritation study the test item is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.  


Eye irritation/corrosion: The test item was found to be irritating to the eyes and is classified as H319 according to Regulation (EC) No 1272/2008. A qualitative assessment will be conducted. 


Respiratory irritation/corrosion:


The test item is classified for eye irritation Cat 2 according to Regulation (EC) No 1272/2008 (CLP). Therefore, a hazard for local effects on the mucous membranes of the respiratory tract cannot completely ruled out when inhaled. Thus, a qualitative risk assessment will be conducted.


Long term, systemic effects


Long-term DNELs for inhalation, dermal and oral exposure were calculated for the general population. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.  


 


Exposure by inhalation


Step 1: Selection of the relevant dose descriptor (starting point): The NOAEL of 1000 mg/kg bw/day is identified as the relevant dose descriptor and starting point. This value was assessed in a weight-of-evidence approach including read across data with the hydrolysis products of the substance itself as well as read-across repeated dose toxicity-results recorded in the reproduction/developmental toxicity screening studies (OECD 414) with structural analogues (10 days dosing).


Step 2: Modification into a correct starting point: Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived. This DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).  


Relevant dose descriptor (NOAEL): 1000 mg/kg bw/day


Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw


Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5 (50%/ 100%)


Corrected inhalatory NOAEC for general population = 1000 mg/kg bw/day × 0.5 × (1 / 1.15 m³/kg bw/d)  = 434.78 mg/m³  


Step 3: Use of assessment factors: 150


Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.


Other interspecies differences AF: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6


In conclusion, long term systemic inhalation DNEL, general population = 2.9 mg/m3  


   


 


Dermal exposure


Step 1: Selection of the relevant dose descriptor (starting point):


The NOAEL of 1000 mg/kg bw/day, assessed for the oral repeated dose toxicity endpoint was selected as starting point.


Step 2: Modification of the starting point: Assuming that dermal absorption is the same as oral absorption, a general population DNEL (long-term dermal exposure) is derived.  


ABS (oral rat): 100%


ABS (dermal human):100%


Corrected dermal NOAEL for general population:


= 1000 mg/kg bw/d x 100%/100% = 1000 mg/kg bw/d


Step 3: Use of assessment factors: 600


Interspecies AF, allometric scaling (rat to human): 4


Other interspecies differences AF: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6 


In conclusion, long term systemic dermal DNEL, general population= 1.67 mg/kg bw/day  


 


Oral exposure


Step 1: Selection of the relevant dose descriptor (starting point):


The NOAEL of 1000 mg/kg bw/day, assessed for the oral repeated dose toxicity endpoint was selected as starting point.


Step 2: Use of assessment factors: 600


Interspecies AF, allometric scaling (rat to human): 4


Other interspecies differences AF: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6


 


In conclusion, long term systemic oral DNEL, general population = 1.67 mg/kg bw/day  


 


References


(not included as endpoint study record)  


- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. ECHA-2010-G-19-EN.


- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. ECHA-14-G-06-N.


- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.