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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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
Value:
262.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

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:
An extrapolation factor is needed since a subacute study is available.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.
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 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
Value:
1 200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 25 % of oral absorption. 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:
An extrapolation factor is needed since a subacute study is available.
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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General


DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.


 


Workers – Hazard via inhalation route


 


Long term systemic inhalation DNEL, worker


Calculation of dose descriptor


 


Step 1: Selection of the relevant dose descriptor (starting point):For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The oral NOAEL of 300 mg/kg bw/day, obtained from subacute toxicity testing (combined repeated dose toxicity study with the reproduction/developmental toxicity screening test) in rats, was considered as key value for the chemical safety assessment and therefore, most relevant starting point.


 


Step 2: Modification into a correct starting point:


In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For worker a NOEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.


 


NOEC (Worker)inhalation = 300 mg/kg bw/day * 1/4 *70 kg * 1/10 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 262.5 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.


Interspecies AF, remaining differences: 2.5


Intraspecies AF (worker): 5


AF for differences in duration: 6


 


In conclusion the long term systemic inhalation DNEL workers was calculated to be 3.5 mg/m³ bw/day.


 


Short term inhalation DNEL, worker


The test material is not classified and labelled for acute dermal and oral toxicity, according to Regulation (EC) No 1272/2008 (CLP). Furthermore, based on the physical parameters a peak exposure is not expected. The substance has a very low vapour pressure and a molecular weight of above 500 g/mol. Inhalation exposure is regarded as negligible.Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.


 


Local effects


The test item is classified for skin sensitisation cat. 1B according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Thus, a qualitative risk assessment is conducted.


 


Eye irritation: The test item is classified for eye irritation as cat. 2, based on the results of the eye irritation studies available. A qualitative risk assessment is conducted and the substance assigned to the low hazard band.


 


Workers – Hazard via dermal route


 


Long term systemic dermal DNEL, worker


Calculation of dose descriptor


 


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


For risk characterisation a dermal NOAEL was derived by route to route extrapolation.


The oral NOAEL of 300 mg/kg bw/day, obtained from combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was considered as key value for the chemical safety assessment and therefore, most relevant starting point.


 


Step 2: Modification into a correct starting point:


Based on the physical chemical properties of the substance (low to moderate water solubility, log Pow value =4.11, molecular weight above 500 g/mol) a low absorption rate of 25 % through skin was deduced.


In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat /ABS dermal human] = 300 mg/kg bw/day x (100/25) = 1200 mg/kg bw/d.


 


Step 3: Use of assessment factors: 300


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


Interspecies AF, remaining differences: 2.5


Intraspecies AF (worker): 5


Exposure duration AF (subacute exposure period): 6


 


In conclusion the long term systemic dermal DNEL workers were calculated to be 4 mg/kg bw/day.


 


Acute short term dermal DNEL, worker


The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.


 


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. November 2012.


- ECHA (2017). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017.


- 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:
0.75 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
Value:
112.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

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:
An extrapolation factor is needed since a subacute study is available.
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:
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 default value for the relatively homogenous group "worker" is used.
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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 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
Value:
1 200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 25 % of oral absorption. For details 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:
An extrapolation factor is needed since a subacute study is available.
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:
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:
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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral 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):
600
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation is required.

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:
An extrapolation factor is needed since a subacute study is available.
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:
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:
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
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 substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.


 


General population – Hazard via inhalation route


Long term systemic inhalation DNEL, general population


Calculation of dose descriptor


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


For risk characterisation an inhalation NOAEC was derived by route to route extrapolation. The oral NOAEL of 300 mg/kg bw/day, obtained from combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was considered as key value for the chemical safety assessment and therefore, most relevant starting point.


Step 2: Modification into a correct starting point:


In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For general population a NOEC long-term, inhalation was calculated assuming 60 kg per person, 24h light activity (20 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.


 NOEC (General population) inhalation = 300 mg/kg bw/day * 1/4 *60 kg * 1/20 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 112.5 mg/m³


Step 3: Use of assessment factors: 150


Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC


Interspecies AF, remaining differences: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6 (subacute study)


In conclusion, long term systemic inhalation DNEL, general population = 0.75 mg/m³.


 


Short term inhalation DNEL, general population


The test material is not classified and labelled for acute dermal and oral toxicity, according to Regulation (EC) No 1272/2008 (CLP). Furthermore, based on the physical parameters a peak exposure is not expected. The substance has a very low vapour pressure and a molecular weight of above 500 g/mol. Inhalation exposure is regarded as negligible.Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.


 


Local effects


The test item is classified for sensitisation cat. 1B according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, a qualitative assessment is conducted.  


 


Eye irritation: The test item is classified for eye irritation as cat. 2, based on the results of the eye irritation studies available. A qualitative risk assessment is conducted and the substance assigned to the low hazard band.


 


General population – Hazard via dermal route


 


Long term systemic dermal DNEL, general population


Calculation of dose descriptor


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


For risk characterisation a inhalation NOAEC was derived by route to route extrapolation.


The oral NOAEL of 300 mg/kg bw/day, obtained from combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in rats was considered as key value for the chemical safety assessment and therefore, most relevant starting point.


Step 2: Modification into a correct starting point:


Based on the physical chemical properties of the substance low to moderate water solubility, log Pow value =4.11, molecular weight above 500 g/mol) a dermal absorption rate of 25 % through skin was deduced.


In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 300 mg/kg bw/day x (100/25) = 1200 mg/kg bw/d.


Step 3: Use of assessment factors: 600


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


Interspecies AF, remaining differences: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6 (subacute study)


 


In conclusion, long term systemic dermal DNEL, general population = 2 mg/kg bw/day 


 


Acute short term dermal DNEL, general population


The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.


 


 


General population – Hazard via oral route


 


Long term systemic oral DNEL, general population


 


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


A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test


in rats is selected for DNEL derivation as it is the relevant repeated dose study performed. In this study, the oral NOAEL in rats is 300 mg/kg bw/day.


Step 2: Modification of the starting point:


Not required.


Step 3: Use of assessment factors: 600


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


Interspecies AF, remaining differences: 2.5


Intraspecies AF (general population): 10


Exposure duration AF: 6 (subacute study)


 


In conclusion, long term systemic oral DNEL, general population = 0.5 mg/kg bw/day


 


The test material is not classified and labelled for acute oral toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.


 


 


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. November 2012.


- ECHA (2017). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017.


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