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EC number: 248-666-3 | CAS number: 27813-02-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 14.7 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- other: ECHA (2012) with substance-specific adaptations
- Overall assessment factor (AF):
- 18
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 264.5 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Correction for rat standard breathing volume, 8 hrs (ECHA R.8, 2012): 0.38 m³/kg
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): 6.7 m3/10 m3
Route-to-Route extrapolation factor/ Oral to inhalation extrapolation (ECHA R.8, 2012): 2. 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)
- 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. 54 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 starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
- 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.
- 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:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
- Most sensitive endpoint:
- irritation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- irritation (respiratory tract)
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 (2012) with substance-specific adaptations
- 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:
Oral to dermal extrapolation (ECHA R.8, 2012): AF 1. This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well 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. 54 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 period.
- 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 starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties.
- 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.
- 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:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
- Most sensitive endpoint:
- skin irritation/corrosion
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:
- low hazard (no threshold derived)
Additional information - workers
DNEL inhal worker long-term
Description | Value/ factor | Remark | |
Step 1) Relevant dose-descriptor | NOAEL: 300 mg/kg bw/d | NOAEL due to mortality, clinical biochemistry and increased liver weights at 1000 mg/kg/d 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 |
| 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 | 264.5 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 | 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. | |
Exposure duration | 6 | The NOAEL is based on a subacute study of approx. 54 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 (see additional considerations #2 below). | |
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 | The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below). | |
DNEL |
| ||
Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 d by the oral route. | 14.7 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, worker of 14.7 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 due to mortality, clinical biochemistry and increased liver weights at 1000 mg/kg/d 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 acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well 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. | |
Exposure duration | 6 | The NOAEL is based on an subacute study of approx. 54 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 period (see additional considerations #2 below). | |
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 | The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below). | |
DNEL |
| ||
Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 d by the oral route. | 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 DNEL long-term, dermal, worker of 4.2 mg/kg bw/d is derived.
|
Further considerations: see "general population"
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 (2012) with substance-specific adaptations
- Overall assessment factor (AF):
- 30
- Dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 130.4 mg/m³
- Explanation for the modification of the dose descriptor starting point:
Correction for rat standard breathing volume, 24 hrs (ECHA R.8, 2012): 1.15 m³/kg
Route-to-Route extrapolation: Oral to inhalation extrapolation (ECHA R.8, 2012) AF: 2. 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)
- 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. 54 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 starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
- 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.
- 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:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
- Most sensitive endpoint:
- irritation (respiratory tract)
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
- Most sensitive endpoint:
- irritation (respiratory tract)
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 (2012) with substance-specific adaptations
- 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:
Oral to dermal extrapolation (ECHA R.8, 2012) AF: 1. This is considered as acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well 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. 54 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 period.
- 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 starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
- 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.
- 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:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate 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
- Most sensitive endpoint:
- skin irritation/corrosion
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:
- 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 (2012) with substance-specific adaptations
- 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. 54 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 period.
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Allometric scaling rat to humans AF 4 (ECHA R.8, 2012)
- AF for other interspecies differences:
- 1
- Justification:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
- 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 population.
- 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:
- The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties
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
- AF for remaining differences based on analysis of the toxicological relevant metabolites of HPMA.
- AF for exposure duration
DNEL inhal gen pop long-term (also Man via environment, inhalative)
Description | Value/ factor | Remark | |
Step 1) Relevant dose-descriptor | NOAEL: 300 mg/kg bw/d | NOAEL due to mortality, clinical biochemistry and increased liver weights at 1000 mg/kg/d 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 | 130,4 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. | |
Exposure duration | 6 | The NOAEL is based on a subacute study of approx. 54 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 (see also additional considerations #2 below). | |
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 | The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below). | |
DNEL |
| ||
Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 d by the oral route. | 4.35 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 4.35 mg/m³ is derived.
| |
DNEL dermal general population long-term (also Man via environment, dermal)
Description | Value/ factor | Remark | |
Step 1) Relevant dose-descriptor | NOAEL: 300 mg/kg bw/d | NOAEL due to mortality, clinical biochemistry and increased liver weights at 1000 mg/kg/d 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 acceptable approach as the relative dermal absorption is calculated to be high according to Heylings (2012) and oral absorption is indicated to be high as well as indicated by physico-chemical parameters (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. | |
Exposure duration | 6 | The NOAEL is based on an subacute study of approx. 54 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 period (see also additional considerations #2 below). | |
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 | The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below). | |
DNEL |
| ||
Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 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 (also Man via environment, oral)
Description | Value/ factor | Remark | |
Step 1) Relevant dose-descriptor | NOAEL: 300 mg/kg bw/d | NOAEL due to mortality, clinical biochemistry and increased liver weights at 1000 mg/kg/d 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. | |
Exposure duration | 6 | The NOAEL is based on an subacute study of approx. 54 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 period (see also additional consierations #2 below). | |
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 | The starting point is a screening study with a somewhat higher level of uncertainty. However, a DNEL analysis of the metabolites and the analogous HPMA (on molar base) does not indicate remaining uncertainties (see considerations #1 below). | |
DNEL |
| ||
Based upon a NOAEL of 300 mg/kg bw/d for rats, for approx. 54 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
There is clear evidence that HPMA is rapidly metabolized to the metabolites MAA and the corresponding alcohol (here: PG), as shown by Dow (2017). In these studies, comparable fast metabolism rates of 1-5 min in the rat liver were shown for HPMA.
The underlaying approach for the following consideration is the comparison of a representative DNEL value of the parent ester HPMA against the analogous values of the metabolites on molar basis. For this approach, the oral route was considered due to the suitable data availability of the relevant substances: For HPMA and PG oral data are available while for MAA no oral data are available but reliable data from the donor substance MMA (Methyl Methacrylate; see below table).
While the DNELs cannot be directly compared on explicit number level due to their different starting points (subacute vs. chronic studies), a rough comparison on molar basis identifies the DNEL derived from the screening study of HPMA as sufficiently low to cover the repeated dose hazard of the metabolites when using an AF of 1 for “remaining uncertainties”. As one consequence, an AF of 1 for “remaining uncertainties” (plus all other used AFs) is considered as sufficiently conservative and does not have to be adopted further. As further consequence, the use of the screening study for DNEL purposes is justified even in presence of higher tier studies with the metabolites as the outcome of the screening study results in the lowest DNEL, i.e. represents the most conservative approach.
Table: Summary of NOAELs regarding repeated dose toxicity considering the toxicological relevant metabolite
NOAEL Repeated dose toxicity, oral
| HPMA (MW 144) |
| MMAa (MW 100) | PGb (MW 76) |
NOAEL (mg/kg bw/d) | 300 |
| 124-164 | ≥ 1700 |
NOAEL (mM/kg bw/d) | 2.08 |
| 1.24-1.64 | 22.4 |
Study type/ species | OECD 422, rat |
| 2-yr, pre-guideline, rat | 2-yr, pre-guideline, rat |
Sum of AFs | 120 (see above) |
| 20 (see REACH dossier MMA) | 20 (own assessmentc) |
DNEL (mM/kg bw/d) | 0.017 |
| 0.062-0.082 | 1.12 |
a donor substance for the methacrylic metabolite MAA (no oral studies available for MAA itself)
b specific alcohol metabolite of HPMA
c no oral DNEL calculated in the current REACH dossier
The starting point is the NOAEL of the screening study with an exposure period of approx. 54 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.
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