Reaction mass of 2-hydroxy-1,3-propanediyl bismethacrylate and 101525-90-0

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.35 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):

40.8

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

264.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

--

- 0.38 m³/kg 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)

- Standard route-to-route extrapolation factor oral to inhalation of 2 (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)

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 inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).

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, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.

AF for the quality of the whole database:

1

Justification:

The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

2

Justification:

The starting point is data from the structurally similar chemical (C3 monoester isomers instead of C3 diester isomers, which are at the same time the primary metabolites of the 1,2-GDMA isomer after proposed rapid hydrolysis, with same metabolic pathways). A hazard level analysis of the metabolites and the analogous 1,4-BDDMA has been performed and does generally not indicate remaining uncertainties (see considerations below). A factor of 2 is however temporary considered until experimental data confirm the rapid hydrolysis of GDMA.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

4.17 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

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

--

Standard route-to-route extrapolation factor oral to dermal of 1 (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be moderate (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). 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 studies were of high quality, being rated K1 or K2. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

The current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA).

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)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with HPMA (primary metabolite of 1,3-GDMA) in rats

 

DNEL inhal worker long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:300 mg/kg bw/d	NOAEL for mortality and increased liver weightwith minimal hepatocyte vacuolation in male rats given HPMA by oral gavage in OECD 422 protocol
Step 2) Modification of starting point	0.38 m³/kg   6.7 m^3/10 m^3	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 m^3/6.7 m^3;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	264.6 mg/m^3
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 (C3 monoester isomers instead of C3 diester isomers, which are at the same time the primary metabolites of the 1,2-GDMA isomer after proposed rapid hydrolysis, with same metabolic pathways). A hazard level analysis of the metabolites and the analogous 1,4-BDDMA has been performed and does generally not indicate remaining uncertainties (see considerations below).A factor of 2 is however temporary considered until experimental data confirm the rapid hydrolysis of GDMA.
DNEL
Based upon a NOAEL of 300 mg/kg bw/d for male rats, for 50 d by the oral route.	7.35 mg/m^3		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 7.35 mg/m³ is derived.

 

 

DNEL dermal worker long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:300 mg/kg bw/d	NOAEL for mortality and increased liver weightwith minimal hepatocyte vacuolation in male rats given HPMA 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 conservative approach as the relative dermal absorption is calculated to be moderate (Heylings 2012) and oral absorption is indicated to be higher as indicated by physico-chemical parameters (see above)
NAEL worker	300 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 current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA).
DNEL
Based upon a NOAEL of 300 mg/kg bw/d for male rats, for 50 d by the oral route.	4.17 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 4.17mg/kg bw/d is derived.

Further considerations

AF for remaining differences based on analysis of the toxicological relevant metabolites of GDMA and HPMA including 1,4-BDDMA as analogous methacrylate di-ester from the category

 

There is a high likelihood that GDMA isomers, like other members of the category, are rapidly metabolized to the metabolites MAA and Glycerol within the order of minutes (see category document). A temporary AF of 2 is applied to relevant application routs until the rapid hydrolysis is not experimentally confirmed.

In the case of diol di-methacrylate esters the first step would be hydrolysis of one of the ester bonds to produce the corresponding mono-ester followed by subsequent hydrolysis of the second ester bond to produce methacrylic acid (MAA) and the corresponding alcohol (see Figure 1 in the category document, chapter 5.1.1.1).Here, the HPMA isomers can be understood as primary metabolites for GDMA, especially for the 1,2-GDMA isomer, with the same subsequent metabolic pathways (for structural comparison, see category document, chapter 1.3). As a consequence, there is no remaining difference to be considered as relevant from this perspective for the read across from 1,4-BDDMA to 1,6-HDDMA, leading to a AF of “1”.

While the source substance HPMA consists of methacrylate mono-ester isomers, 1,4-BDDMA as analogous methacrylate di-ester has the same molar composition of moieties and is thus considered for quantitative evaluation of effects of the methacrylic metabolite. The methacrylic metabolite MAA is the common metabolite for all mentioned methacrylate esters. The NOAEL for oral repeated dose toxicity of MMA, (i.e. 124 mg/kg bw/d; Borzelleca 1964) corresponds to 1.24 mM MAA/ kg bw/d on molar basis. Theoretically, this effect level would correspond to a NOAEL of 0.62 mM/ kg bw/d for a methacrylate di-ester like GDMA or 1,4-BDDMA. However, this low effect level does not show up in 1,4-BDDMA, where a NOAEL of 300 mg/kg bw/d = 1,33 mM / kg bw/d was observed under experimental conditions comparable to those used here (oral OECD 422 screening study in rats). It is likely that toxicodynamic aspects of the rapid subsequent metabolism of MAA are responsible for the absence of a pronounced MAA effect in the study with 1,4-BDDMA. The same is concluded for GDMA, so that different MAA molarities from the methacrylate mono-ester HPMA as source substance are not considered as relevant for “remaining differences”.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.35 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):

69

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

130.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

no repeated dose toxicity study via inhalation route is available

--

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

- Standard route-to-route extrapolation factor oral to inhalation of 2 (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)

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:

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

AF for remaining uncertainties:

1

Justification:

Currently, there is certain uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) which is considered with a uncertainty factor higher than 1. For the general population however, an additional uncertainty factor is not considered as adequate, 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.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

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:

2.5 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) and ECETOC (2010)

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no dermal repeated dose toxicity study is available

--

Standard route-to-route extrapolation factor oral to dermal of 1 (ECHA R.8, 2012). This is considered as very conservative approach as the relative dermal absorption is calculated to be moderate (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). 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 studies were of high quality, being rated K1 or K2. No adjustment is required.

AF for remaining uncertainties:

1

Justification:

The current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA).

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)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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) and ECETOC (2010)

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

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

AF for remaining uncertainties:

1

Justification:

The current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA). 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.

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

Calculation from the oral repeated dose/ repro screening study (OECD 422) study with HPMA (primary metabolite of 1,3-GDMA) in rats

DNEL inhal gen pop long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:300 mg/kg bw/d	NOAEL for mortality and increased liver weightwith minimal hepatocyte vacuolation in male rats given HPMA 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 water solubility and logPow indicate a high oral absorption according to ECHA R.7c (2017)
NAEC general population	130.5 mg/m^3
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 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	Currently, there is certain uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) which is considered with an uncertainty factor higher than 1. For the general population however, an additional uncertainty factor is not considered as adequate, 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 300 mg/kg bw/d for male rats, for 50 d by the oral route.	4.35 mg/m^3		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 4.35 mg/m³ is derived.

 

 DNEL dermal general population long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:300 mg/kg bw/d	NOAEL for mortality and increased liver weightwith minimal hepatocyte vacuolation in male rats given HPMA 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) and oral absorption is indicated to be significantly higher (see above)
NAEL general population	300 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 current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA).
DNEL
Based upon a NOAEL of 300 mg/kg bw/d for male rats, for 50 d by the oral route.	2.5 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 2.5 mg/kg bw/d is derived.

  

DNEL oral general population long-term

Description	Value/ factor	Remark
Step 1) Relevant dose-descriptor	NOAEL:300 mg/kgbw/d	NOAEL for mortality and increased liver weightwith minimal hepatocyte vacuolation in male rats given HPMA by oral gavage in OECD 422 protocol
Step 2) Modification of starting point	1	No route-to-route extrapolation required.
NAEL general population	300 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 current uncertainty on the rapid hydrolysis of GDMA to its metabolites (see long term inhalation DNEL calculation for worker) 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 HPMA). 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 300 mg/kg bw/d for male rats, for 50 d by the oral route.	2.5 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 2.5 mg/kg bw/d is derived.

Further considerations

AF for remaining differences based on analysis of the toxicological relevant metabolites of GDMA and HPMA including 1,4-BDDMA as analogous methacrylate di-ester from the category

 

There is a high likelihood that GDMA isomers, like other members of the category, are rapidly metabolized to the metabolites MAA and Glycerol within the order of minutes (see category document). A temporary AF of 2 is applied to relevant application routs until the rapid hydrolysis is not experimentally confirmed.

In the case of diol di-methacrylate esters the first step would be hydrolysis of one of the ester bonds to produce the corresponding mono-ester followed by subsequent hydrolysis of the second ester bond to produce methacrylic acid (MAA) and the corresponding alcohol (see Figure 1 in the category document, chapter 5.1.1.1).Here, the HPMA isomers can be understood as primary metabolites for GDMA, especially for the 1,2-GDMA isomer, with the same subsequent metabolic pathways (for structural comparison, see category document, chapter 1.3). As a consequence, there is no remaining difference to be considered as relevant from this perspective for the read across from 1,4-BDDMA to 1,6-HDDMA, leading to a AF of “1”.

While the source substance HPMA consists of methacrylate mono-ester isomers, 1,4-BDDMA as analogous methacrylate di-ester has the same molar composition of moieties and is thus considered for quantitative evaluation of effects of the methacrylic metabolite. The methacrylic metabolite MAA is the common metabolite for all mentioned methacrylate esters. The NOAEL for oral repeated dose toxicity of MMA, (i.e. 124 mg/kg bw/d; Borzelleca 1964) corresponds to 1.24 mM MAA/ kg bw/d on molar basis. Theoretically, this effect level would correspond to a NOAEL of 0.62 mM/ kg bw/d for a methacrylate di-ester like GDMA or 1,4-BDDMA. However, this low effect level does not show up in 1,4-BDDMA, where a NOAEL of 300 mg/kg bw/d = 1,33 mM / kg bw/d was observed under experimental conditions comparable to those used here (oral OECD 422 screening study in rats). It is likely that toxicodynamic aspects of the rapid subsequent metabolism of MAA are responsible for the absence of a pronounced MAA effect in the study with 1,4-BDDMA. The same is concluded for GDMA, so that different MAA molarities from the methacrylate mono-ester HPMA as source substance are not considered as relevant for “remaining differences”.