Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA (2012) with substance-specific adaptations
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012): 0.38 m³/kg


Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (ECHA R.8, 2012): 6.7 m3/10 m3


Route-to-Route extrapolation factor/ Oral to inhalation extrapolation (ECHA R.8, 2012): 2. This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.39 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA (2012) with substance-specific adaptations
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral to dermal extrapolation (ECHA R.8, 2012): AF 1. This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well as indicated by physico-chemical parameters

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study period.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
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

 DNEL inhal worker long-term

















































































Description



Value/ factor



Remark



Step 1) Relevant dose-descriptor



NOAEL: 100 mg/kg bw/d



NOAEL for kidney findings at 300 mg/kg/d by oral gavage in OECD 422 protocol



Step 2) Modification of starting point



0.38 m³/kg


 


6.7 m3/10 m3



Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012)


-Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (10 m3/6.7 m3) is required (ECHA R.8, 2012)


 



Route-to-Route extrapolation



 



This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)



NAEC worker



88.2 mg/m3



 



Step 3) Assessment factors



 



 



Interspecies



1



No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)



Intraspecies



3



Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative.



Exposure duration



6



The NOAEL is based on a subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here (see additional considerations #2 below).



Dose response



1



The NOAEL is reliable. No adjustment is required.



Quality of database



1



The key study is of high quality, being rated K1. No adjustment is required.



Remaining uncertainties



1



The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below).



DNEL



 



Based upon a NOAEL of 100 mg/kg bw/d for rats, for approx. 54 d by the oral route.



4.9 mg/m3



Using a total factor (POD modifier and AF) of 20.4 (/ 0.38 x 10/6.7 m³ x 2 x 1 x 3 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, worker of 4,9 mg/m³ is derived.


    

 


DNEL dermal worker long-term






































































Description



Value/ factor



Remark



Step 1) Relevant dose-descriptor



NOAEL: 100 mg/kg bw/d



NOAEL for kidney findings at 300 mg/kg/d by oral gavage in OECD 422 protocol



Step 2) Modification of starting point



1



Oral to dermal extrapolation (ECHA R.8, 2012). This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well as indicated by physico-chemical parameters (see above)



NAEL worker



100 mg/kg bw/d



 



Step 3) Assessment factors



 



 



Interspecies



4



Allometric scaling rat to humans (ECHA R.8, 2012)



Intraspecies



3



Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 3 is sufficiently conservative.



Exposure duration



6



The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study (see also additional considerations #2 below).



Dose response



1



The NOAEL is reliable. No adjustment is required.



Quality of database



1



The key study is of high quality, being rated K1. No adjustment is required.



Remaining uncertainties



1



The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below).



DNEL



 



Based upon a NOAEL of 100 mg/kg bw/d for rats, for approx. 54 d by the oral route.



1.39 mg/kg bw/d



Using a total factor (POD modifier and AF) of 72 (1 x 4 x 3 x 6 x 1 x 1) a DNEL long-term, dermal, worker of 1.39 mg/kg bw/d is derived.



Further considerations: see "general population"


 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.45 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA (2012) with substance-specific adaptations
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012): 1.15 m³/kg


Route-to-Route extrapolation: Oral to inhalation extrapolation (ECHA R.8, 2012) AF: 2. This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)


 

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA (2012) with substance-specific adaptations
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral to dermal extrapolation (ECHA R.8, 2012) AF: 1. This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well as indicated by physico-chemical parameters

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study period.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
Most sensitive endpoint:
skin irritation/corrosion
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:
0.83 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA (2012) with substance-specific adaptations
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation required.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study period.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA R.8, 2012)
AF for other interspecies differences:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
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

DNEL inhal gen pop long-term (also Man via environment, inhalative)

















































































Description



Value/ factor



Remark



Step 1) Relevant dose-descriptor



NOAEL: 100 mg/kg bw/d



NOAEL for kidney findings at 300 mg/kg/d by oral gavage in OECD 422 protocol



Step 2) Modification of starting point



1.15 m³/kg



Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012)



Route-to-Route extrapolation



2



Oral to inhalation extrapolation (ECHA R.8, 2012). This is considered as conservative approach as physico-chemical parameters like molecular weight, water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)



NAEC general population



43.5 mg/m3



 



Step 3) Assessment factors



 



 



Interspecies



1



No allometric scaling rat to humans as intraspecies adjustment is accounted for in relative breathing volumes (ECHA R.8, 2012)



Intraspecies



5



Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.



Exposure duration



6



The NOAEL is based on a subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds the duration of a normal subacute study almost by a factor of two and long term data from metabolites indicate a lower exposure duration effect as used here (see also additional considerations #2 below).



Dose response



1



The NOAEL is reliable. No adjustment is required.



Quality of database



1



The key study is of high quality, being rated K1. No adjustment is required.



Remaining uncertainties



1



The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below).



DNEL



 



Based upon a NOAEL of 100 mg/kg bw/d for rats, for approx. 54 d by the oral route.



1.45 mg/m3



Using a total factor (POD modifier and AF) of 69 (/ 1.15 m³ x 2 x 1 x 5 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, gen. pop. of 1,45 mg/m³ is derived.


 


    

 


 


 


DNEL dermal general population long-term (also Man via environment, dermal)












































































Description



Value/ factor



Remark



Step 1) Relevant dose-descriptor



NOAEL: 100 mg/kg bw/d



NOAEL for kidney findings at 300 mg/kg/d by oral gavage in OECD 422 protocol



Step 2) Modification of starting point



1



Oral to dermal extrapolation (ECHA R.8, 2012). This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well as indicated by physico-chemical parameters (see above)



NAEL general population



100 mg/kg bw/d



 



Step 3) Assessment factors



 



 



Interspecies



4



Allometric scaling rat to humans (ECHA R.8, 2012)



Intraspecies



5



Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.



Exposure duration



6



The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study period (see also additional considerations #2 below).



Dose response



1



The NOAEL is reliable. No adjustment is required.



Quality of database



1



The key study is of high quality, being rated K1. No adjustment is required.



Remaining uncertainties



1



The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below).



DNEL



 



Based upon a NOAEL of 100 mg/kg bw/d for rats, for approx. 54 d by the oral route.



0.83 mg/kg bw/d



Using a total factor (POD modifier and AF) of 120 (1 x 4 x 5 x 6 x 1 x 1) a DNELlong-term, dermal, gen.pop. of 0.83 mg/kg bw/d is derived.


    

 


DNEL oral general population long-term (also Man via environment, oral)












































































Description



Value/ factor



Remark



Step 1) Relevant dose-descriptor



NOAEL: 100 mg/kg bw/d



NOAEL for kidney findings at 300 mg/kg/d by oral gavage in OECD 422 protocol



Step 2) Modification of starting point



1



No route-to-route extrapolation required.



NAEL general population



100 mg/kg bw/d



 



Step 3) Assessment factors



 



 



Interspecies



4



Allometric scaling rat to humans (ECHA R.8, 2012)



Intraspecies



5



Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 is sufficiently conservative.



Exposure duration



6



The NOAEL is based on an subacute study of approx. 54 d for the relevant sex (males). AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal subacute study period (see also additional considerations #2 below).



Dose response



1



The NOAEL is reliable. No adjustment is required.



Quality of database



1



The key study is of high quality, being rated K1. No adjustment is required.



Remaining uncertainties



1



The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below).



DNEL



 



Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 d by the oral route.



0.83 mg/kg bw/d



Using a total factor (POD modifier and AF) of 120 (1 x 4 x 5 x 6 x 1 x 1) a DNELlong-term, oral, gen.pop. of 0.83 mg/kg bw/d is derived.


    

 


Further considerations



  1. AF for remaining differences based on analysis of the toxicological relevant metabolites of HEMA.


 


There is clear evidence that HEMA is rapidly metabolized to the metabolites MAA and the corresponding alcohol (here: EG), as shown by Dow (2013, 2017). In these studies, comparable fast metabolism rates of 1-5 min in the rat liver were shown for HEMA.


The underlaying approach for the following consideration is the comparison of a representative DNEL value of the parent ester HEMA against the analogous values of the metabolites on molar basis. For this approach, the oral route was considered due to the suitable data availability of the relevant substances: For HEMA and EG oral data are available while for MAA no oral data are available but reliable data from the donor substance MMA (Methyl Methacrylate;  see below table).


While the DNELs cannot be directly compared on explicit number level due to their different starting points (subacute vs. chronic studies), a rough comparison identifies the HEMA DNEL as sufficiently low to cover the repeated dose hazard of the metabolites when using an AF of 1 for “remaining uncertainties”. As consequence, an AF of 1 for “remaining uncertainties” (plus all other used AFs) is considered as sufficiently conservative and does not have to be adopted further.


Table: Summary of NOAELs regarding repeated dose toxicity considering the toxicological relevant metabolite
















































NOAEL


Repeated dose toxicity, oral


 



HEMA


(MW 130)



 



MMAa


(MW 100)



EGb


(MW 62)



NOAEL (mg/kg bw/d)



100



 



124-164



150



NOAEL (mM/kg bw/d)



0.76



 



1.24-1.64



2.4



Study type/ species



OECD 422, rat



 



2-yr, pre-guideline, rat



OECD 452, rat



Sum of AFs



120 (see above)



 



20 (see REACH dossier MMA)



20 (own assessmentc)



DNEL (mM/kg bw/d)



0.006



 



0.062-0.082



0.12



a donor substance for the methacrylic metabolite MAA (no oral studies available for MAA itself)


b specific alcohol metabolite of HEMA


c no oral DNEL calculated in the current REACH dossier


 



  1. AF for exposure duration


The starting point is the NOAEL of the screening study with an exposure period of approx. 54 d for the relevant sex (males). The chosen AF of 6 for the extrapolation from sub-acute to chronic exposure (ECHA 2012) represents a conservative approach as this study period exceeds a standard subacute study (28 d) almost by a factor of 2.