Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.47 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance (ECHA R.8, 2012) and ECETOC Technical Report No. 110
Overall assessment factor (AF):
10.2
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
26.44 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used which is also justified by DNEL comparison with the toxicological relvant metabolite. For details, please refer to the discussion.
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).
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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
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:
ECHA REACH Guidance
Overall assessment factor (AF):
0.2
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: DNEL long-term, inhal.
Value:
1.47 mg/m³
Explanation for the modification of the dose descriptor starting point:
According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECHA Guidance and ECETOC Technical Report No. 110
Overall assessment factor (AF):
43.2
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary as a subacute dermal 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:
default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).
AF for interspecies differences (allometric scaling):
2.4
Justification:
Allometric scaling rabbit to humans (ECHA R.8, Table R.8-3; 2012)
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 3 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.2
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: DNEL, long-term, dermal
Value:
0.58 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL inhal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:15 mg/kg bw/d

NOAEL for liver effectsin rats given AMA by oral gavage in a 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;ECHA R.8, 2012)

 

Route-to-Route extrapolation

1

A default oral to inhalation extrapolation factor of 2 (ECHA R.8, 2012) isnot justified when comparing the DNEL with the currently applied factors vs. the DNEL of allyl alcohol as toxicological relevant metabolite (see below)

NAEC worker

26.44 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) and well investigated metabolites 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

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

Remaining uncertainties

1

No remaining uncertainties.

DNELlong-term

 

Based upon a NOAEL of 15 mg/kg bw/d for male rats, for approx. 50 d by the oral route.

1,47 mg/m3

Using a total factor (POD modifier and AF) of 10.2 (/ 0.38 x 10/6.7 m³ x 1 x 1 x 3 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, workerof 1,468 mg/m³ is derived.

DNELshort-term

 

Long-term to short term extrapolation

5

Upper end of value range 1 to 5 according to ECHA R.8 (2012)

Based upon a NOAEL of 15 mg/kg bw/d for rats by the oral route.

7.35 mg/m3

Using a total factor (POD modifier and AF) of 2.0 (/ 0.38 x 10/6.7 m³ x 1 x 1 x 3 x 6 x 1 x 1 x 1 / 5) a DNELshort-term, inhal, workerof 7.35 mg/m³ is derived.

 

 

 

DNEL dermal worker long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:25 mg/kg bw/d

NOAEL for mortality and body weighteffectsin rabbits in a subacute treatment, Val 2 (Siddiqui 1982)

Step 2) Modification of starting point

1

No route-to-route extrapolation required.

NAEL worker

25 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

2.4

Allometric scaling rabbit to humans (ECHA R.8, Table R.8-3; 2012)

Intraspecies

3

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key study is of high quality, being rated K2. No adjustment is required.

Remaining uncertainties

1

No remaining uncertainties

DNEL long-term

 

Based upon a NOAEL of 25 mg/kg bw/d for rabbits, for subacute treatment by the dermal route.

0.58 mg/kg bw/d

Using a total factor (POD modifier and AF) of 43,2 (1 x 2.4 x 3 x 6 x 1 x 1) a DNELlong-term, dermal, workerof 0.58 mg/kg bw/d is derived.

DNELshort-term

 

Long-term to short term extrapolation

5

Upper range of value range 1 to 5 according to ECHA R.8 (2012)

Based upon a NOAEL of 25 mg/kg bw/d for rabbits, for subacute treatment by the dermal route.

2.9 mg/m3

Using a total factor (POD modifier and AF) of 8.6 (1 x 2.4 x 3 x 6 x 1 x 1 / 5) a DNELshort-term, dermal, workerof 2.9 mg/kg bw/d is derived.

 


Discussion/ further considerations

Comparison of DNELlong-term, systemicvalues of AMA and its metabolites on molar base (mmol/m3or mg/kg bw/d)

 

Worker

General Population

Source

 

Inhal

Dermal

Inhal

dermal

oral

 

Substance

AMA, MW 126.1g/mol

0.012

0.005

0.003

0.003

0.001

this CSR

Metabolites

Allyl alcohol, MW 58.1g/mol

0.080

0.002

no data

no data

0.001

ECHA 2018, CAS 107-18-6

Methyl Methacrylate, MW 100.1g/mol

2.1

0.017

0.74

0.08

no data

ECHA 2018, CAS 80-62-6

 

Given a rapid hydrolysis of AMA to its primary metabolites, a comparison of the DNELs of the (parent) substance and the primary metabolites on molar basis show that

-       Allyl alcohol is the toxicological relevant metabolite (as indicated by lower DNEL levels)

-       The hazard levels of AMA is calculated with a suitable margin of safety (as indicated by lower or equal DNEL levels of AMA vs. those of the metabolites, where available)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Technical Report No. 110 and ECHA R.8, 2012
Overall assessment factor (AF):
34.55
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
13.04 mg/m³
Explanation for the modification of the dose descriptor starting point:
There are no relevant experimental data on repeated exposure by inhalation. The recommended approach using oral data and assuming the same absorption for inhalation and oral route is used. For details, please refer to the discussion.
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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).
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:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.2
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: DNEL,long-term, inhalation
Value:
0.43
Explanation for the modification of the dose descriptor starting point:
According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: ECETOC Technical Report No. 110 and ECHA R.8 (2012)
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary as a subacute dermal 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).
AF for interspecies differences (allometric scaling):
2.4
Justification:
Allometric scaling rabbit to humans (ECHA R.8, Table R.8-3; 2012)
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K2. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.75 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.2
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
other: DNEL, long-term, dermal
Value:
0.35 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
15 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary as a subacute oral 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans (ECHA R.8, Table R.8-3; 2012)
AF for other interspecies differences:
1
Justification:
There is no evidence for species differences in the general mode of actions or kinetics.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites makes a lower variability likely, hence the AF of 5 is sufficiently conservative. (ECETOC, 2010)
AF for the quality of the whole database:
1
Justification:
The key study is of high quality, being rated K1. No adjustment is required.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.65 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
0.2
Modified dose descriptor starting point:
other: DNEL, long-term, oral
Value:
0.13 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health", a DNEL for acute systemic toxicity should be derived if an acute systemic toxicity hazard leading to classification is identified.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

DNEL inhal gen pop long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:15 mg/kg bw/d

NOAEL for liver effectsin rats given AMA by oral gavage in a 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

1

A default oral to inhalation extrapolation factor of 2 (ECHA R.8, 2012) is not justified when comparing the DNEL with the currently applied factors vs. the DNEL of allyl alcohol as toxicological relevant metabolite (see below)

NAEC general population

13.04 mg/m3

 

Step 3) Assessment factors

 

 

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) and well investigated metabolites 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

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

Remaining uncertainties

1

No remaining uncertainties

DNEL long-term

 

Based upon a NOAEL of 15 mg/kg bw/d for rats by the oral route.

0,43 mg/m3

Using a total factor (POD modifier and AF) of 34.55 (/ 1.15 m³ x 1 x 1 x 5 x 6 x 1 x 1 x 1) a DNELlong-term, inhal, gen-popof 0.435 mg/m³ is derived.

DNELshort-term

 

 

Long-term to short term extrapolation

5

Upper range of value range 1 to 5 according to ECHA R.8 (2012)

Based upon a NOAEL of 15 mg/kg bw/d for rats by the oral route.

2.15 mg/m3

Using a total factor (POD modifier and AF) of 11.5 (/ 1.15 m³ x 1 x 1 x 5 x 6 x 1 x 1 x 1 /5) a DNELshort-term, inhal, gen-popof 2.15 mg/m³ is derived.

  

DNEL dermal general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:25 mg/kg bw/d

NOAEL for mortality and body weighteffectsin rabbits in a subacute treatment, Val 2 (Siddiqui 1982)

Step 2) Modification of starting point

1

No route-to-route extrapolation required.

NAEL worker

25 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

2.4

Allometric scaling rabbit to humans (ECHA R.8, Table R.8-3; 2012)

Intraspecies

5

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

The key study is of high quality, being rated K2. No adjustment is required.

Remaining uncertainties

1

No remaining uncertainties

DNEL

 

Based upon a NOAEL of 25 mg/kg bw/d for rabbits, for subacute treatment by the dermal route.

0.35 mg/kg bw/d

Using a total factor (POD modifier and AF) of 72 (1 x 2.4 x 5 x 6 x 1 x 1) a DNELlong-term, dermal, gen-popof 0.35 mg/kg bw/d is derived.

DNELshort-term

 

 

Long-term to short term extrapolation

5

Upper range of value range 1 to 5 according to ECHA R.8 (2012)

Based upon a NOAEL of 25 mg/kg bw/d for rabbits, for subacute treatment by the dermal route.

1.75 mg/m3

Using a total factor (POD modifier and AF) of 14.4 (1 x 2.4 x 5 x 6 x 1 x 1 / 5) a DNELlong-term, dermal, gen-popof 1.75 mg/kg bw/d is derived.

  

DNEL oral general population long-term

Description

Value/ factor

Remark

Step 1) Relevant dose-descriptor

NOAEL:15 mg/kg bw/d

NOAEL for liver effectsin rats given AMA by oral gavage in a OECD 422 protocol

Step 2) Modification of starting point

1

No route-to-route extrapolation required.

NAEL general population

15 mg/kg bw/d

 

Step 3) Assessment factors

 

 

Interspecies

4

Allometric scaling rat to humans (ECHA R.8, Table R.8-3; 2012)

Intraspecies

5

Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) and well investigated metabolites 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: default AF 6 for extrapolation from sub-acute to chronic according to ECHA R.8 ( 2012).

Dose response

1

The NOAEL is reliable. No adjustment is required.

Quality of database

1

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

Remaining uncertainties

1

No remaining uncertainties

DNEL

 

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

0,13 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 0.125 mg/kg bw/d is derived.

DNELshort-term

 

 

Long-term to short term extrapolation

5

Upper range of value range 1 to 5 according to ECHA R.8 (2012)

Based upon a NOAEL of 15 mg/kg bw/d for rats by the oral route.

0,65 mg/m3

Using a total factor (POD modifier and AF) 24 (1 x 4 x 5 x 6 x 1 x 1 / 5) a DNELshort-term,oral, gen.pop.of 0.65 mg/kg bw/d is derived.

Discussion/ further considerations

Comparison of DNELlong-term, systemicvalues of AMA and its metabolites on molar base (mmol/m3or mg/kg bw/d)

 

Worker

General Population

Source

 

Inhal

Dermal

Inhal

dermal

oral

 

Substance

AMA, MW 126.1g/mol

0.012

0.005

0.003

0.003

0.001

this CSR

Metabolites

Allyl alcohol, MW 58.1g/mol

0.080

0.002

no data

no data

0.001

ECHA 2018, CAS 107-18-6

Methyl Methacrylate, MW 100.1g/mol

2.1

0.017

0.74

0.08

no data

ECHA 2018, CAS 80-62-6

 

Given a rapid hydrolysis of AMA to its primary metabolites, a comparison of the DNELs of the (parent) substance and the primary metabolites on molar basis show that

-       Allyl alcohol is the toxicological relevant metabolite (as indicated by lower DNEL levels)

-       The hazard levels of AMA is calculated with a suitable margin of safety (as indicated by lower or equal DNEL levels of AMA vs. those of the metabolites, where available)