Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.45 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance (2012) & ECETOC (2010)
Overall assessment factor (AF):
36
Modified dose descriptor starting point:
NOAEC
Value:
88.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

The substance is predicted to be readily absorbed by both routes. Hence, the oral no-effect-levels is regarded as relevant for the assessment.

However, for chemical safety assessment an oral absorption rate of 50% and and inhalative absorption rate of 100% is assumed, leading to a route-to-route extrapolation factor of 2 as a worst case default value (ECHA R.8 guidance, 2012).

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). The default 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:
No other factor required, standard metabolic pathways, equally present in rodents and humans.
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 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
2
Justification:
The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite, same metabolic pathways).
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:
1.3 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 (2012) & ECETOC (2010)
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite, same metabolic pathways); on the other hand the predicted skin permeation rate of HEMA is 25 times higher than that of EGDMA. It is expected that this difference compensates any remaining uncertainties.

For chemical safety assessment absorption rates of 50% are assumed for both oral and dermal route, leading to a route-to-route extrapolation factor of 1 as a worst case default value (ECHA R.8 guidance, 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 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. 50 d for the relevant sex (males). The default 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:
No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The uncertainty derived from the use of data from the structurally similar chemical (HEMA=ethyleneglycol mono instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with the same subsequent metabolic
pathways) is compensated for the dermal route by differences in kinetics (the target substance has a higher molecular weight which results in a significantly slower dermal absorption than HEMA).
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

The NOAEL for EGDMA of 100 mg/kg is based on a subacute OECD 422 study with HEMA, the metabolite after the cleavage of the first ester bond of EGDMA. For EGDMA this is a conservative value for several reasons: First of all the NOAEL derived in the HEMA study is based on very slight effects in the kidney and BUN in the absence of histopathology, which is of questionable biological significance and the duration of the study was almost 50 days compare with the 28 d in a typical subacute study. In addition, compared to EGDMA, HEMA is a much smaller molecule for which faster absorption and distribution is predicted. A NOAEL derived for EGDMA from this study is likely to be conservative. The majority of these arguments are also adressed in the tables below.

DNEL inhal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:100 mg/kg bw/d

NOAEL for slight effects on kidneys in male rats given HEMA 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

2

Oral to inhalation extrapolation (ECHA R.8, 2012)[KK1] 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. (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

2

The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with same metabolic pathways)[KK2] 

DNEL

 

Based upon a NOAEL of 100 mg/kg bw/d for male rats, for 50 d by the oral route.

2,45 mg/m3

Using a total factor (POD modifier and AF) of 40.8 (/ 0.38 x 10/6.7 m³ x 2 x 1 x 3 x 6 x 1 x 1 x 2) a DNELlong-term, inhal, workerof 2.45 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 slight effects on kidneys in male rats given HEMA 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 very conservative approach as the relative dermal absorption is calculated to be low Heylings 2012)[KK3] and oral absorption is indicated to be significantly higher 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. (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 studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The uncertainty derived from the use of data from the structurally similar chemical (HEMA=ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with the same subsequent metabolic pathways) is compensated for the dermal route by differences in kinetics (the target substance has a higher molecular weight which results in a significantly slower dermal absorption than HEMA)

DNEL

 

Based upon a NOAEL of 100 mg/kg bw/d for male rats, for 50 d by the oral route.

1.3 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 1.3 mg/kg bw/d is derived.

 

Further considerations

1. Alternative starting point

A repeated dose/ reproduction toxicity screening study with the primary metabolite served as starting point for the calculation of the long term systemic DNELs above. The available developmental toxicity study with the substance itself (thus reducing metabolism related uncertainties) was considered but neglected as alternative starting point for following reasons: a) the exposure period of the developmental study is approx. only half of a standard subacute study and a suitable AF addressing such short period and accepted by health authorities is not known; b) in the developmental study only female rats were studied; this sex was slightly less sensitive than males in the screening study with the primary metabolite; c) the additional influence of pregnancy is unknown; d) the metabolism of EGDMA is well investigated – the substance hydrolyses to the primary metabolite HEMA in the order of minutes and also the subsequent metabolism is well understood so that the used AFs for remaining differences are considered as additional conservative aspect in current DNEL evaluation.

2. AF for exposure duration

The starting point is the NOAEL of the screening study with an exposure period of approx. 50 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. Moreover, comparison of long term data from the well investigated secondary metabolites MAA/MMA and EG indicate a comparable relation curve between effect levels and exposure periods as expressed in default AFs for exposure duration: when comparing subchronic vs. chronic oral studies, the spacing factors for systemic NOAEL levels of MAA/MMA and EG are 1 (inhalation, rat, BASF 2008 vs. Lomax 1997) and ca. 2 (oral, mouse; both NTP 1993) , respectively, while

the default AF for subchronic to chronic extrapolation is 2.

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 REACH Guidance (2012) & ECETOC (2010)
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

The substance is predicted to be readily absorbed by both routes. Hence, the oral no-effect-levels is regarded as relevant for the assessment.

However, for chemical safety assessment an oral absorption rate of 50% and and inhalative absorption rate of 100% is assumed, leading to a route-to-route extrapolation factor of 2 as a worst case defaultvalue (ECHA R.8 guidance, 2012).

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). The default 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:
Extrapolation rat oral to human inhalation, no allometric scaling factor necessary
AF for other interspecies differences:
1
Justification:
No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with same metabolic pathways). As a default, an uncertainty factor would be used in this case. On the other hand, 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 default consumer scenarios.
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:
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 REACH Guidance (2012) & ECETOC (2010)
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite, same metabolic pathways); on the other hand the predicted skin permeation rate of HEMA is 25 times higher than that of EGDMA. It is expected that this difference compensates any remaining uncertainties.

For chemical safety assessment absorption rates of 50% are assumed for both oral and dermal route, leading to a route-to-route extrapolation factor of 1 as a worst case default value (ECHA R.8 guidance, 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 as indicated by physico-chemical parameters.

AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment 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). The default AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal 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:
No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment required.
AF for remaining uncertainties:
1
Justification:
The uncertainty derived from the use of data from the structurally similar chemical (HEMA=ethyleneglycol mono instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with the same subsequent metabolic pathways) is compensated for the dermal route by differences in kinetics (the target substance has a higher molecular weight which results in a significantly slower dermal absorption than HEMA).
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:
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 REACH Guidance (2012) & ECETOC (2010)
Overall assessment factor (AF):
120
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 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). The default AF 6 for extrapolation from sub-acute to chronic (ECHA 2012) represents a conservative approach as this study period exceeds a normal 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:
No other factor required, ubiquitous metabolic pathways, equally present in rodents and humans.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative.
AF for the quality of the whole database:
1
Justification:
The key studies were of high quality, being rated K1 or K2. No adjustment required.
AF for remaining uncertainties:
1
Justification:
The uncertainty derived from the use of data from the structurally similar chemical (HEMA=ethyleneglycol mono instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with the same subsequent metabolic pathways) is compensated for the oral route by differences in kinetics (the target substance has a higher molecular weight which results in a slower oral absorption than HEMA).
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

The NOAEL for EGDMA of 100 mg/kg is based on a subacute OECD 422 study with HEMA, the metabolite after the cleavage of the first ester bond of EGDMA. For EGDMA this is a conservative value for several reasons: First of all the NOAEL derived in the HEMA study is based on very slight effects in the kidney and BUN in the absence of histopathology, which is of questionable biological significance and the duration of the study was almost 50 days compare with the 28 d in a typical subacute study. In addition, compared to EGDMA, HEMA is a much smaller molecule for which faster absorption and distribution is predicted. A NOAEL derived for EGDMA from this study is likely to be conservative. The majority of these arguments are also adressed in the tables below.

DNEL inhal gen pop long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:100 mg/kg bw/d

NOAEL for slight effects on kidneys in male rats given HEMA 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)[KK1] . 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. (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 studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The starting point is data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with same metabolic pathways). As a default, an uncertainty factor would be used in this case. On the other hand, 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 100 mg/kg bw/d for male rats, for 50 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

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:100 mg/kg bw/d

NOAEL for slight effects on kidneys in male rats given HEMA 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 very conservative approach as the relative dermal absorption is calculated to be low (Heylings 2012)[KK2] and oral absorption is indicated to be significantly higher (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. (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 studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The uncertainty derived from the use of data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after rapid hydrolysis, with same metabolic pathways) is compensated for the dermal route by differences in kinetics (the target substance has a higher molecular weight which is unfavourable for dermal 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 100 mg/kg bw/d for male rats, for 50 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

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:100 mg/kg bw/d

NOAEL for slight effects on kidneys in male rats given HEMA 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. (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 studies were of high quality, being rated K1 or K2. No adjustment is required.

Remaining uncertainties

1

The uncertainty derived from the use of data from the structurally similar chemical (ethyleneglycol mono- instead of diester, which is at the same time the primary metabolite after 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 100 mg/kg bw/d for male rats, for 50 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. Alternative starting point

A repeated dose/ reproduction toxicity screening study with the primary metabolite served as starting point for the calculation of the long term systemic DNELs above. The available developmental toxicity study with the substance itself (thus reducing metabolism related uncertainties) was considered but neglected as alternative starting point for following reasons: a) the exposure period of the developmental study is approx. only half of a standard subacute study and a suitable AF addressing such short period and accepted by health authorities is not known; b) in the developmental study only female rats were studied; this sex was slightly less sensitive than males in the screening study with the primary metabolite; c) the additional influence of pregnancy is unknown; d) the metabolism of EGDMA is well investigated – the substance hydrolyses to the primary metabolite HEMA in the order of minutes and also the subsequent metabolism is well understood so that the used AFs for remaining differences are considered as additional conservative aspect in current DNEL evaluation.

2. AF for exposure duration

The starting point is the NOAEL of the screening study with an exposure period of approx. 50 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. Moreover, comparison of long term data from the well investigated secondary metabolites MAA/MMA and EG indicate a comparable relation curve between effect levels and exposure periods as expressed in default AFs for exposure duration: when comparing subchronic vs. chronic oral studies, the spacing factors for systemic NOAEL levels of MAA/MMA and EG are 1 (inhalation, rat, BASF 2008 vs. Lomax 1997) and ca. 2 (oral, mouse; both NTP 1993) , respectively, while

the default AF for subchronic to chronic extrapolation is 2.