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EC number: 201-297-1 | CAS number: 80-62-6
- 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

Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- other: experimental result and PBPK model
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans.
- GLP compliance:
- not specified
- 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 Fisher 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 - Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Duration of exposure:
- up to 48 h
- Doses:
- 100 µL/cm2
- No. of animals per group:
- 3 (human: 2)
- Time point:
- 8 h
- Dose:
- 100 µL/cm2
- Parameter:
- percentage
- Absorption:
- ca. 45 %
- Remarks on result:
- other: rat epidermis
- Remarks:
- linear absorption during this time period
- Time point:
- 16 h
- Dose:
- 100 µL/cm2
- Parameter:
- percentage
- Absorption:
- ca. 55 %
- Remarks on result:
- other: rat epidermis
- Time point:
- 8 h
- Dose:
- 100 µl/cm2
- Parameter:
- rate
- Absorption:
- 5 888 mg cm-2 h-1
- Remarks on result:
- other: rat epidermis
- Time point:
- 24 h
- Dose:
- 100 µL/m2
- Parameter:
- percentage
- Absorption:
- ca. 10 %
- Remarks on result:
- other: human epidermis
- Remarks:
- linear absorption for >= 24 h
- Time point:
- 24 h
- Dose:
- 100 µL/cm2
- Parameter:
- rate
- Absorption:
- 453 mg cm-2 h-1
- Remarks on result:
- other: human epidermis
- Time point:
- 24 h
- Dose:
- 100 µL/cm2
- Parameter:
- rate
- Absorption:
- 360 mg cm-2 h-1
- Remarks on result:
- other: rat skin
- Conclusions:
- 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).
- Executive summary:
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).
The fastest rate of absorption of MMA through rat epidermal membrane was recorded as being 5688 μg /cm²/hr and this occurred between 2 and 8 hrs following application of the chemical. Absorption through human epidermal membrane was slower with a peak rate of 453 μg/cm²/hr, between 4 and 24 hrs, with 10.2% of the applied dose having been absorbed during this time. There appears to be a lag time with the rate of absorption between 0-4 hrs calculated to be 259 μg /cm²/hr.
Penetration of alkyl methacrylate through whole rat skin was slower than through separated epidermal membrane. MMA was the most rapidly absorbed chemical of the alkyl methacrylates studied. Carboxylesterases present in the viable tissue mediate the hydrolysis of these esters, producing the acid metabolite, together with the structurally corresponding alcohol. In contrast to the larger esters, MMA is not completely hydrolysed during the absorption process; this is substantiated by the appearance of both the parent ester and the metabolite MAA in the receptor fluid. Appearance of both chemicals in the receptor fluid can be explained by MMA possessing a rate of absorption that is higher than the rate with which it is hydrolysed.
The peak rate of appearance of MMA, which occurred between 2.5-24 hrs was calculated to be 360 μg /cm²/hr. This compares to a peak rate of appearance for the metabolite MAA, which occurred between 4-24 hrs and was calculated as 108 μg /cm²/hr. Of the original dose applied to the whole skin, 8.7% appeared as MMA in the receptor chamber, while 2.6% appeared as MAA. Therefore in total, 11.3% of the ester was depleted from the donor reservoir.
Rat epidermis
The fastest rate of absorption of MMA through rat epidermal membrane was recorded as being 5688 μg*cm-2*hr-1 and this occurred between 2 and 8 hrs following application of the chemical. The rate slowed considerably after 8 hours, falling to virtually zero by 16 hours. Nearly half (45.5%) of the donor reservoir had been depleted by 8 hours with 55% of the chemical appearing in the receptor chamber by 16 hours. The rate plateaus after eight hours, which is indicative of the donor reservoir being depleted.
Human epidermis
Methyl methacrylate absorbed at a peak rate of 453 μg*cm-2*hr-1, between 4 and 24 hrs, with 10.2% of the applied dose having been absorbed during this time. There appears to be a lag time with the rate of absorption between 0-4 hrs calculated to be 259 μg cm-2 hr-1. The rates of absorption through human epidermis are considerably slower than those measured for MMA through rat epidermis.
Whole rat skin
Of the alkyl-methacrylate esters whose rate of absorption through whole rat skin was investigated, methyl methacrylate is the most rapidly absorbed chemical. Carboxylesterases present in the viable tissue mediate the hydrolysis of these esters, producing the acid metabolite, together with the structurally corresponding alcohol. In contrast to the larger esters, MMA is not completely hydrolysed during the absorption process; this is substantiated by the appearance of both the parent ester and the metabolite MAA in the receptor fluid. Appearance of both chemicals in the receptor fluid can be explained by MMA possessing a rate of absorption that is higher than the rate with which it is hydrolysed.
The peak rate of appearance of MMA, which occurred between 2.5-24 hrs was calculated to be 360 μg*cm-2*hr-1. This compares to a peak rate of appearance for the metabolite MAA, which occurred between 4-24 hrs and was calculated as 108 μg cm-2 hr-1. Of the original dose applied to the whole skin, 8.7% appeared as MMA in the receptor chamber, while 2.6% appeared as MAA. Therefore in total, 11.3% of the ester was depleted from the donor reservoir.
---
The results of the whole-skin penetration studies and the model predictions for
other methacrylate esters are presented in the table.
Summary of the peak rates of absorption of MAA & alkyl-methacrylate esters through whole rat and human skin
Substance |
Molecular volume |
Rat whole rat |
Human whole skin |
|||
Peak rate of appearance (µg*cm-2*h-1)+- SEM |
Period of peak absorption rate (hours) |
% age of applied dose absorbed over x hours |
Rate of absorption of ester/MAA (μg*cm-2 *hr-1) |
|||
Ester |
MAA |
|||||
MAA |
78.96 |
|
4584+-344 |
5-8 |
70%/24 |
327 |
MMA |
93.1978 |
360+-20.9 |
108+-4.59 |
2.5-24 |
11.3%/24 |
33.4** |
EMA |
107.436 |
|
190** |
|
|
13.6** |
iBMA |
135.646 |
|
56** |
|
|
4** |
nBMA |
135.856 |
|
40+-9.4 |
2-10 |
0.4%/10 |
2.9** |
6HMA |
164.277 |
|
20** |
|
|
1.4** |
2EHMA |
191.66 |
|
9** |
|
|
0.6** |
OMA |
192.696 |
|
10.3+-0.65 |
8-24 |
0.24%/24 |
0.7** |
12LMA |
249.536 |
|
11.8+-2.11 |
8-24 |
0.26%/24 |
0.8** |
The values in normal type were obtained experimentally, whilst those in italics are predicted values.
** Values are predicted rates of appearance of total chemical including parent ester and metabolite
Data source
Reference
- Reference Type:
- other: Thesis
- Title:
- Unnamed
- Year:
- 2 002
Materials and methods
- Objective of study:
- absorption
- metabolism
Test guideline
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- A physiologically based pharmacokinetic model has been formulated to predict the pharmacokinetics and systemic disposition of alkylmethacrylate esters in rats and humans.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Methyl methacrylate
- EC Number:
- 201-297-1
- EC Name:
- Methyl methacrylate
- Cas Number:
- 80-62-6
- Molecular formula:
- C5H8O2
- IUPAC Name:
- methyl 2-methylprop-2-enoate
- Test material form:
- liquid
Constituent 1
Test animals
- 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.
Administration / exposure
- Route of administration:
- intravenous
- 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.
Results and discussion
Main ADME results
- Type:
- metabolism
- Results:
- Half-life of MMA after i.V. injection: 4.4 min (PBPK estimate)
Toxicokinetic / pharmacokinetic studies
Toxicokinetic parametersopen allclose all
- Test no.:
- #1
- Toxicokinetic parameters:
- half-life 1st: 4.4 min
- Remarks:
- i.v./ rat liver microsomes
- Test no.:
- #1
- Toxicokinetic parameters:
- other: 98.8% removed from liver blood flow i.e. by first pass liver clearance
- Remarks:
- clearance/ i.v./ rat liver microsomes
- Test no.:
- #1
- Toxicokinetic parameters:
- Cmax: 14.7 (mg/L) of MAA in blood
- Remarks:
- i.v./ rat liver microsomes
- Test no.:
- #1
- Toxicokinetic parameters:
- Tmax: 1.7 min to peak MAA concentration in blood from model predictions
- Remarks:
- i.v./rat liver microsomes
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Methacrylic acid
Any other information on results incl. tables
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 1:
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
Applicant's summary and conclusion
- Conclusions:
- The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.
- Executive summary:
The in vivo and in vitro investigations as well as the PBPK models developed from the data showed that MMA, like other alkyl-methacrylate esters, is rapidly absorbed and 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 (within minutes). The half-time after i.v. application in rat liver is 4.4 min for MMA.
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