Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.2 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (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, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 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:
1
Justification:
No remaining uncertainties. Modification of starting point (100 mg/m³) is already considered in field dose descriptor starting point of 88.2 mg/m³ (value of AF is 0.67).
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
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
AF for extrapolation from Sub-chronic to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (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, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 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:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Long-term exposure –systemic effects, dermal

Description

Value

Remark

Step 1) Relevant dose-descriptor

100 mg/kg

NOAEL for effects on kidney weight and kidney histopathology in rats given HEMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Conversion of rat oral exposure to human dermal exposure using ECHA Ch R8, Ex. B5, page 69.. Human NOAEC = Oral NOAEL X 1 (Absorption factor for oral to dermal route =1; ECHA Ch R8. page 25.)

Allometric scaling factor of 4 is necessary because conversion is from rat oral to human dermal (Ch R8. p.30)

Intraspecies

3

A combined interspecies and intraspecies assessment factor of 3 is applied as developed in the ECETOC review of appropriate AFs for workers

Exposure duration

6

The key studies were subacute toxicity studies in animals which require extrapolation to a working lifetime in humans.

Dose response

1

The NOAEC is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality.No adjustment is required.

DNEL

Value

 

Using a total AF of 72 a DNELlong-term,workerof 1.3 mg/kg is derived.

Long-term exposure –systemic effects, inhalation

Description

Value

Remark

Step 1) Relevant dose-descriptor

100 mg/kg

NOAEL for effects on kidney weight and kidney histopathology in rats given HEMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

88.2 mg/m3

Modification of starting point involves conversion of rat oral exposure to human inhalation exposure using ECHA Ch R8, Fig. 8.3. Human NOAEC = Oral NOAEL X 1/0.38 m3/kg/d X 0.5 absn. Default X 6.7/10

Step 3) Assessment factors

 

 

Interspecies

1

Allometric scaling factor of 4 is not necessary because conversion is from rat oral to human inhalation (Ch R8. p.30)

Intraspecies

3

A combined interspecies and intraspecies assessment factor of 3 is applied as developed in the ECETOC review of appropriate AFs for workers

Exposure duration

6

The key studies were subacute toxicity studies in animals which require extrapolation to a working lifetime in humans.

Dose response

1

The NOAEC is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality.No adjustment is required.

DNEL

Value

 

Using a total AF of 18 a DNELlong-term,workerof 4.9 mg/m3 is derived.*

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.2 mg/m³
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation (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:
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 by ECETOC (2010) is sufficiently conservative for general public.
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:
1
Justification:
No remaining uncertainties. Modification of starting point (100 mg/m³) is already considered in field dose descriptor starting point of 88.2 mg/m³ (value of AF is 0.67).
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
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (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:
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 by ECETOC (2010) is sufficiently conservative for general public.
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:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

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
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The NOAEC is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
Sub-acute to chronic (ECHA 2008)
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (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:
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 by ECETOC (2010) is sufficiently conservative for general public.
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:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Long-term exposure –systemic effects, dermal

Description

Value

Remark

Step 1) Relevant dose-descriptor

100 mg/kg

NOAEL for effects on kidney weight and kidney histopathology in rats given HEMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

 Conversion of rat oral exposure to human dermal exposure using ECHA Ch R8, Ex. B5, page 69.. Human NOAEC = Oral NOAEL X 1 (Absorption factor for oral to dermal route =1; ECHA Ch R8. page 25.) Allometric scaling factor of 4 is necessary because conversion is from rat oral to human dermal (Ch R8. p.30)

Intraspecies

5

A combined interspecies and intraspecies assessment factor of 5 is applied as developed in the ECETOC review of appropriate AFs for workers

Exposure duration

6

The key studies were subacute toxicity studies in animals which require extrapolation to a working lifetime in humans.

Dose response

1

The NOAEC is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality.No adjustment is required.

DNEL

Value

 

Using a total AF of 120 a DNELlong-term,publicof 0.83 mg/kg is derived.

Long-term exposure -systemic effects, inhalation

Description

Value

Remark

Step 1) Relevant dose-descriptor

100 mg/kg

NOAEL for effects on kidney weight and kidney histopathology in rats given HEMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

88.2 mg/m3

Modification of starting point involves conversion of rat oral exposure to human inhalation exposure using ECHA Ch R8, Fig. 8.3. Human NOAEC = Oral NOAEL X 1/0.38 m3/kg/d X 0.5 absn. Default X 6.7/10

Step 3) Assessment factors

 

 

Interspecies

1

Allometric scaling factor of 4 is not necessary because conversion is from rat oral to human inhalation (Ch R8. p.30)

Remaining interspecies default AF of 2.5 is not necessary because a combined inter- and intra-species factor is applied.

Intraspecies

5

A combined interspecies and intraspecies assessment factor of 5 is applied as developed in the ECETOC review of appropriate AFs for general public

Exposure duration

6

The key studies were subacute toxicity studies in animals which require extrapolation to a working lifetime in humans.

Dose response

1

The NOAEC is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality.No adjustment is required.

DNEL

Value

 

Using a total AF of 30 a DNELlong-term,publicof 2.9 mg/m3 is derived.

Long-term exposure –systemic effects, oral

Description

Value

Remark

Step 1) Relevant dose-descriptor

100 mg/kg

NOAEL for effects on kidney weight and kidney histopathology in rats given HEMA by oral gavage in OECD 422 protocol

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Conversion of rat oral exposure to human oral exposure using ECHA Ch R8, Table 8.3. Human Oral NOAEl= Rat Oral NOAEL / 4 Additional allometric scaling factor of 2.5 interspecies factor is not necessary because incorporated into a combined inter-intraspecies factor

Intraspecies

5

A combined interspecies and intraspecies assessment factor of 5 is applied as developed in the ECETOC review of appropriate AFs for the general population

Exposure duration

6

The key studies were subacute toxicity studies in animals which require extrapolation to a working lifetime in humans.

Dose response

1

The NOAEC is reliable. No adjustment is required.

Quality of database

1

The key studies were of high quality.No adjustment is required.

DNEL

Value

 

Using a total AF of 120 a DNELlong-term,publicof 0.83 mg/kg is derived.