Registration Dossier

Administrative data

Workers - 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 (2012) & ECETOC (2010)
Overall assessment factor (AF):
20.4
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
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 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 (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations under "Additional Information").
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:
4.2 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
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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerationsunder "Additional considerations").
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 1,4-BDDMA (analogous substance of 1,3-BDDMA) in rats

 

DNEL inhal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:300 mg/kg bw/d

NOAEL for liver and stomach findings given the analogous substance 1,4-BDDMA 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) 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

264.6 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

The starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

14.5 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, workerof 14.5 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 liver and stomach findings given the analogous substance 1,4-BDDMA 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 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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

4.2 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 4.2 mg/kg bw/d is derived.

Further considerations

1. AF for remaining differences based on analysis of the toxicological relevant metabolites of 1,3-BDDMA and 1,4-BDDMA

 

There is clear evidence that 1,3-BDDMA, like other members of the category, is rapidly metabolized to the metabolites MAA and the corresponding alcohol (here: 1,3-BD), as shown by Dow (2017). In this study, comparable metabolism rates of < 5 min in the rat liver were shown for 1,3-BDDMA and the analogous substance 1,4-BDDMA (metabolized to MAA and 1,4-BD), from which the DNEL starting point study is used. With respect to the metabolites, the toxicity of the different alcohol represents a “potential remaining uncertainty” for the DNEL assessment for 1,3-BDDMA.

The underlaying approach for the following consideration is that the toxicological relevant metabolite (TRM) can be identified by comparison of the respective NOAEL values on molar basis. In a second step the hazard risk of the specific metabolite of 1,3-BDDMA, i.e. 1,3-BD, can be assessed with respect to remaining uncertainties in the DNEL calculation process.

Regarding 1,4-BDDMA, the methacrylic metabolite MAA was identified as TRM having a NOAEL for oral repeated dose toxicity of 1.24 mM/ kg bw/d which is almost half of the NOAEL of the alcohol metabolite 1,4-BD on molar basis (see table below). Regarding 1,3-BDDMA, the alcohol metabolite 1,3-BD has a significantly lower toxicity as can be seen with the higher NOAEL. In other words, 1,3-BD is the much less toxic alcohol metabolite when compared to 1,4-BD. As a consequence, also for 1,3-BDDMA MAA is considered as TRM with a high level of confidence. As a final consequence, there is no remaining uncertainty for the hazard assessment of 1,3-BDDMA based on data of 1,4-BDDMA, leading to a AF of “1”.

Table: Summary of NOAELs regarding fertility considering the toxicological relevant metabolite

NOAEL

Repeated dose toxicity, oral

 

1,4-BDDMAa

(MW 226)

 

MMAb

(MW 100)

1,4-BDc

(MW 90)

1,3-BDd

(MW 90)

(mg/kg bw/d)

300

 

124

200

10% in food

(mM/kg bw/d)

1.32

 

1.24

2.2

41

Study type/ species

OECD 422, rat

 

2-yr, pre-guideline, rat

OECD 422, rat

2 yr, pre-guideline, rat feeding

adonor substance for the starting point of DNEL calculations

bdonor substance for the common methacrylic metabolite MAA

cspecific alcohol metabolite of 1,4-BDDMA

dspecific alcohol metabolite of 1,3-BDDMA

ecalculated with a food consumption of 18 d/animal/d and a bw of 350 g/animal (Derelanko & Auletta 2014)

 

 

 

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.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.3 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
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 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 (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations under "Additional Information").
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:
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) & 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
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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations under "Additional 'Information").
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:
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) & 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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations under "Additional information").
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 1,4-BDDMA (analogous substance of 1,3-BDDMA) 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 liver and stomach findings given the analogous substance 1,4-BDDMA 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

130.5 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 (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

4.3 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 4.3 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 liver and stomach findings given the analogous substance 1,4-BDDMA 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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

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 liver and stomach findings given the analogous substance 1,4-BDDMA 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 starting point is data from the structurally similar chemical (1,4- instead of 1,3-BDDMA, read across discussed in the Category document). A DNEL analysis of the metabolites and the analogous 1,4-BDDMA (on molar base) does not indicate relevant remaining uncertainties (see considerations below).

DNEL

 

Based upon a NOAEL of 300 mg/kg bw/d for rats, for 50 d by the oral route, analogous substance.

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

1. AF for remaining differences based on analysis of the toxicological relevant metabolites of 1,3-BDDMA and 1,4-BDDMA

 

There is clear evidence that 1,3-BDDMA, like other members of the category, is rapidly metabolized to the metabolites MAA and the corresponding alcohol (here: 1,3-BD), as shown by Dow (2017). In this study, comparable metabolism rates of < 5 min in the rat liver were shown for 1,3-BDDMA and the analogous substance 1,4-BDDMA (metabolized to MAA and 1,4-BD), from which the DNEL starting point study is used. With respect to the metabolites, the toxicity of the different alcohol represents a “potential remaining uncertainty” for the DNEL assessment for 1,3-BDDMA.

The underlaying approach for the following consideration is that the toxicological relevant metabolite (TRM) can be identified by comparison of the respective NOAEL values on molar basis. In a second step the hazard risk of the specific metabolite of 1,3-BDDMA, i.e. 1,3-BD, can be assessed with respect to remaining uncertainties in the DNEL calculation process.

Regarding 1,4-BDDMA, the methacrylic metabolite MAA was identified as TRM having a NOAEL for oral repeated dose toxicity of 1.24 mM/ kg bw/d which is almost half of the NOAEL of the alcohol metabolite 1,4-BD on molar basis (see table below). Regarding 1,3-BDDMA, the alcohol metabolite 1,3-BD has a significantly lower toxicity as can be seen with the higher NOAEL. In other words, 1,3-BD is the much less toxic alcohol metabolite when compared to 1,4-BD. As a consequence, also for 1,3-BDDMA MAA is considered as TRM with a high level of confidence. As a final consequence, there is no remaining uncertainty for the hazard assessment of 1,3-BDDMA based on data of 1,4-BDDMA, leading to a AF of “1”.

Table: Summary of NOAELs regarding fertility considering the toxicological relevant metabolite

NOAEL

Repeated dose toxicity, oral

 

1,4-BDDMAa

(MW 226)

 

MMAb

(MW 100)

1,4-BDc

(MW 90)

1,3-BDd

(MW 90)

(mg/kg bw/d)

300

 

124

200

10% in food

(mM/kg bw/d)

1.32

 

1.24

2.2

41

Study type/ species

OECD 422, rat

 

2-yr, pre-guideline, rat

OECD 422, rat

2 yr, pre-guideline, rat feeding

adonor substance for the starting point of DNEL calculations

bdonor substance for the common methacrylic metabolite MAA

cspecific alcohol metabolite of 1,4-BDDMA

dspecific alcohol metabolite of 1,3-BDDMA

ecalculated with a food consumption of 18 d/animal/d and a bw of 350 g/animal (Derelanko & Auletta 2014)

 

 

 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.