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EC number: 205-521-9 | CAS number: 142-09-6
- 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
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics, other
- Remarks:
- in vitro and intavenous in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Objective of study:
- metabolism
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- A series of in vitro and PBPK models were used to determine and predict the skin absorption and metabolism of a series of methacrylate monomers. Initial studies were conducted using the rat epidermal membrane model. The results of these studies, when compared to the subsequent rat whole skin model in vitro experiments clearly indicated that the latter studies were more pertinent to the goals of the studies, particularly since the use of epidermal membranes appeared to remove the carboxylesterase activity from the skin samples.
Metabolism, ester hydrolysis, ADME - GLP compliance:
- no
- Species:
- other: rat and human
- Strain:
- other: Wistar/Fischer F344/ not applicable
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- Epidermal membrane absorption studies
Skin was used from male rats of the Wistar-derived strain (supplied by Charles River UK Ltd, Margate, Kent, UK.) aged 28 days ± 2 days
Whole skin absorption studies
Skin was taken from male Fischer F344 (supplied by Harlan Olac) rats weighing between 200 and 250 g.
Human epidermal membrane absorption studies
Extraneous tissue was removed from human abdominal whole skin samples obtained post mortem in accordance with local ethical guidelines. - Route of administration:
- other: in vitro and intavenous in vivo
- Details on study design:
- A series of in vitro and in vivo studies with a series of methacrylates were used to develop PBPK models that accurately predict the metabolism and fate of these monomers. The studies confirmed that alkyl-methacrylate esters are rapidly hydrolyzed by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ has the greatest esterase activity. Similar measurements for skin microsomes indicated approximately 20-fold lower activity than for liver. However, this activity was substantial and capable of almost complete first-pass metabolism of the alkyl-methacrylates. For example, no parent ester penetrated whole rat skin in vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate tested experimentally with only methacrylic acid identified in the receiving fluid. In addition, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolyzed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters such that the rate is within the metabolic capacity of the skin. Parent ester also was hydrolyzed by S9 fractions from nasal epithelium and was predicted to be effectively hydrolyzed following inhalation exposure.
- Type:
- metabolism
- Results:
- Half-life of MMA after i.V. injection: 4.4 min (PBPK estimate)
- Metabolites identified:
- yes
- Details on metabolites:
- Methacrylic acid
- Conclusions:
- Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-HMA the half-life was 18.5 minutes and 99.7 % was removed by first-pass metabolism in the liver.
- Executive summary:
Using a reliable experimental method, the in vivo and in vitro investigations as well as the PBPK models developed from the data showed that alkyl-methacrylate esters are rapidly absorbed and are hydrolyzed at exceptionally high rates to methacrylic acid by high capacity, ubiquitous carboxylesterases. Further, the removal of the hydrolysis product, methacrylic acid, also is very rapid (minutes). For n-HMA the half-life was 18.5 minutes and 99.7 % was removed by first-pass metabolism in the liver.
Reference
A series of in vitro and in vivo studies with a series of methacrylates were
used to develop PBPK models that accurately predict the metabolism and fate of
these monomers. The studies confirmed that alkyl-methacrylate esters are
rapidly hydrolyzed by ubiquitous carboxylesterases. First pass (local)
hydrolysis of the parent ester has been shown to be significant for all routes
of exposure. In vivo measurements of rat liver indicated this organ has the
greatest esterase activity. Similar measurements for skin microsomes indicated
approximately 20-fold lower activity than for liver. However, this activity
was substantial and capable of almost complete first-pass metabolism of the
alkyl-methacrylates. For example, no parent ester penetrated whole rat skin in
vitro for n-butyl methacrylate, octyl methacrylate or lauryl methacrylate
tested experimentally with only methacrylic acid identified in the receiving
fluid. In addition, model predictions indicate that esters of ethyl
methacrylate or larger would be completely hydrolyzed before entering the
circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters
such that the rate is within the metabolic capacity of the skin. Parent ester
also was hydrolyzed by S9 fractions from nasal epithelium and was predicted to
be effectively hydrolyzed following inhalation exposure.
These studies showed that any systemically absorbed parent ester will be effectively removed during the first pass through the liver (CL as % LBF,
see table). In addition, removal of methacrylic acid from the blood also
occurs rapidly (T50%; see table).
Table:
Rate constants for ester hydrolysis by rat-liver microsomes and predicted
systemic fate kinetics for methacrylates following i.v. administration:
Ester Vmax Km CL T50% Cmax Tmax
----------------------------------------------------------
MAA - - 51.6% - - -
MMA 445.8 164.3 98.8% 4.4 14.7 1.7
EMA 699.2 106.2 99.5% 4.5 12.0 1.8
i-BMA 832.9 127.4 99.5% 11.6 7.4 1.6
n-BMA 875.7 77.3 99.7% 7.8 7.9 1.8
HMA 376.4 34.4 99.7% 18.5 5.9 1.2
2EHMA 393.0 17.7 99.9% 23.8 5.0 1.2
OMA 224.8 11.0 99.9% 27.2 5.0 1.2
----------------------------------------------------------
Vmax (nM/min/mg) and Km (µM) from rat-liver microsome (100 µg/ml)
determinations;
CL = clearance as % removed from liver blood flow, T50% = Body elimination time
(min) for 50% parent ester, Cmax = maximum concentration (mg/L) of MAA in
blood, Tmax = time (min) to peak MAA concentration in blood from model
predictions.
Table 2:
Rate constants for ester hydrolysis by human-liver microsome samples:
Ester Vmax (nM/min*mg) Km (mM) CL (µL/min*mg)
-----------------------------------------------
MMA 1721 4103 419
EMA 936 1601 584
i-BMA 80 441 181
n-BMA 211 158 1332
HMA 229 66 3465
2EHMA 53 48 1109
OMA 243 38 6403
----------------------------------------------------------
CL is calculated from the mean Vmax and Km
Description of key information
Short description of key information on bioaccumulation potential result:
Methacrylate esters, including n-hexyl methacrylate, are readily absorbed by all routes and rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes. For n-HMA the half-life was 18.5 minutes and 99.7 % was removed by first-pass metabolism in the liver. Reliable data on the primary metabolite methacrylic acid are available and do not reveal critical properties.
Short description of key information on absorption rate:
n-HMA readily absorbs through rat and human epidermis. Human epidermis appears to be less permeable to n-HMA than rat epidermis.
Human epidermis appears to be 10 times less permeable to structural analogue 2-EHMA than rat epidermis and 20 times less permeable to structural analogue substance n-BMA than rat epidermis.Key value for chemical safety assessment
Additional information
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