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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
48.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance R.8 2012 and ECETOC 2010
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEC
Value:
872.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available; route-to-route extrapolation from an oral study

according to OECD 422 with a NOAEL of 1000 mg/kg bw/d

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. 50 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 substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
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. (ECETOC, 2010)
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:
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:
13.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance R.8 2012 and ECETOC 2010
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available; route-to-route extrapolation from an oral study according to

OECD 422 with a NOAEL of 1000 mg/kg bw/d

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. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.
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 substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
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. (ECETOC, 2010)
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:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified

Additional information - workers

Sytemic effects, long term

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with TREGDMA in rats

 

DNEL inhal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:1000 mg/kg bw/d

NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage

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

2

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

NAEC worker

872.4 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. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on a subacute study of approx. 50 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.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

No remaining differences

DNEL

 

Based upon a NOAEL of 1000 mg/kg bw/d for male rats, for 50 d by the oral route.

48.5 mg/m3

Using a total factor (POD modifier and AF) of 20.6 (/ 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, workerof 48.5 mg/m³ is derived.

 

 

DNEL dermal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:1000 mg/kg bw/d

NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage

Step 2) Modification of starting point

1

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

NAEL worker

1000 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. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on a subacute study of approx. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

No remaining uncertainties

DNEL

 

Based upon a NOAEL of 1000 mg/kg bw/d for male rats, for 50 d by the oral route.

13.9 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 DNELlong-term, dermal, workerof 13.9 mg/kg bw/d is derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance R.8 2012 and ECETOC 2010
Overall assessment factor (AF):
69
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEC
Value:
333 mg/m³
Explanation for the modification of the dose descriptor starting point:
no repeated dose toxicity study via inhalation route is available; route-to-route extrapolation from an oral study according to OECD 422 with a NOAEL of 1000 mg/kg bw/d
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. 50 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 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 substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
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. (ECETOC, 2010)
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:
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance R.8 2012 and ECETOC 2010
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available; route-to-route extrapolation from an oral study according to

OECD 422 with a NOAEL of 1000 mg/kg bw/d

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. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.
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 substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
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. (ECETOC, 2010)
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:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
8.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance R.8 2012 and ECETOC 2010
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEL
Value:
1 000 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. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.
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 substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
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. (ECETOC, 2010)
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:
No remaining uncertainties.
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

Sytemic effects, long term

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with TREGDMA in rats

DNEL inhal gen pop long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:1000 mg/kg bw/d

NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage

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 water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)

NAEC general population

333 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. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.

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

No remaining uncertainties

DNEL

 

Based upon a NOAEL of 1000 mg/kg bw/d for male rats, for 50 d by the oral route.

14.5 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 11.11 mg/m³ is derived.

 

 

 

DNEL dermal general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:1000 mg/kg bw/d

NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage

Step 2) Modification of starting point

1

Oral to dermal extrapolation (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012) and oral absorption is indicated to be significantly higher (see above)

NAEL general population

1000 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. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.

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

No remaining uncertainties

DNEL

 

Based upon a NOAEL of 1000 mg/kg bw/d for male rats, for 50 d by the oral route.

8.33 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 8.33 mg/kg bw/d is derived.

 

 

 

DNEL oral general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:1000 mg/kg bw/d

NOAEL determined by the highest dose tested in an OECD 422 study in rats by oral gavage

Step 2) Modification of starting point

1

No route-to-route extrapolation required.

NAEL general population

1000 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. (ECETOC, 2010)

Exposure duration

6

The NOAEL is based on an subacute study of approx. 50 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 and long term data from metabolites indicate a lower exposure duration effect as used here.

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 uncertainty derived from the use of data from the structurally similar chemical (HPMA = C3 monoester isomers instead of C3 diester isomers, which are at the same time the primary metabolites after proposed rapid hydrolysis, with same metabolic pathways) is compensated for the oral route by differences in kinetics (the target substance has a higher molecular weight which is unfavourable for oral absorption). In addition, even without an additional uncertainty factor the assessment is considered to be very conservative, because in the known uses the substance is used as a monomer - infrequently with very short reaction times and resulting real exposure periods in the order of minutes - more than two orders of magnitude below the 24/7 exposure assumed in consumer scenarios.

DNEL

 

Based upon a NOAEL of 1000 mg/kg bw/d for male rats, for 50 d by the oral route.

8.33 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 8.33 mg/kg bw/d is derived.