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EC number: 218-465-5 | CAS number: 2157-01-9
- 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
- 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:
- 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:
- rat
- Strain:
- Wistar
- 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 intravenous 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 OMA the half-life was 27.2 minutes and 99.9 % 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 OMA the half-life was 27.2 minutes and 99.9 % was removed by first-pass metabolism in the liver.
- Endpoint:
- dermal absorption in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 428 (Skin Absorption: In Vitro Method)
- GLP compliance:
- no
- Radiolabelling:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Type of coverage:
- open
- Vehicle:
- unchanged (no vehicle)
- Duration of exposure:
- 48 hours
- Doses:
- 100 µl/cm²
- Details on in vitro test system (if applicable):
- The absorption of n-OMA was evaluated through rat and human epidermis in an in vitro system.
- Signs and symptoms of toxicity:
- not examined
- Dermal irritation:
- not examined
- Absorption in different matrices:
- Absorption of OMA through rat epidermis:
Octyl methacrylate readily absorbed through rat epidermis at a constant mean rate of 159 µg cm-2 hr-1. This rate of absorption was constant over the whole 24 hour exposure/sampling period. The total amount of chemical that was absorbed during the time of exposure was 4.2% of the donor reservoir. - Dose:
- 100 µl/cm²
- Parameter:
- percentage
- Absorption:
- 4.2 %
- Remarks on result:
- other: 24 hours
- Remarks:
- Rat epidermis
- Conversion factor human vs. animal skin:
- Human epidermis appears to be several times less permeable to n-OMA than rat epidermis.
- Conclusions:
- Prediction due to the experimental results of analogue substances (n-BMA and 2-EHMA): OMA readily absorbs through rat and human epidermis. Human epidermis appears to be several times less permeable to OMA than rat epidermis.
Human epidermis appears to be 10 times less permeable to 2-EHMA than rat epidermis and 20 times less permeable to n-BMA than rat epidermis. - Executive summary:
The absorption of Octyl methacrylate (OMA) was evaluated through rat and human epidermis in an in vitro system. The technique measures the rate of absorption of OMA across the epidermis. Glass diffusion cells are employed to measure the amount of OMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of OMA to the epidermal surface. OMA absorbed at a constant rate throughoutr the period of exposure/sampling (0 -24 hours). The mean rate of absorption was calculated 159 µg cm-2 hr-1 and the total amount of chemical that was absorbed during the time of exposure was 4.2% (over 24 hours), respectively. OMA appears readily absorbed through rat and human epidermis, but human epideremisc is several times less permeable to OMA than rat epidermis. However, measuring the rate of absorption through rat and human epidermis provides a quantitative estimate for inter-species differences; however, because only the epidermal layer is used, no measure of metabolism during skin absorption is possible.
Referenceopen allclose all
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
The results of the whole-skin penetration studies and the model predictions for
other methacrylate esters are presented in the table.
Table: Summary of the results for the peak rates of absorption of MAA & alkylmethacrylate esters through rat & human epidermis
|
Rat epidermis |
Human epidermis |
|||||||
Ester |
Peak rate of absorption (μg cm-2hr-1) ±SEM |
Period of peak absorption rate (hours) |
% age of applied dose absorbed over x hours |
Peak rate of absorption (μg cm-2hr-1) ±SEM |
Period of peak absorption rate (hours) |
% age of applied dose absorbed over x hours |
|||
MAA |
23825±2839 |
0.5-4 |
93% / 24h |
812 |
- |
- |
|||
MMA |
5888±223 |
2-8 |
46% / 16h |
453±44.5 |
4-24 |
10% / 24h |
|||
EMA |
4421 |
- |
- |
253 |
- |
- |
|||
i-BMA |
1418 |
- |
- |
80 |
- |
- |
|||
n-BMA |
1540±69 |
0-6 |
18% / 24h |
76.7±9.8 |
0-24 |
2% / 24h |
|||
HMA |
147 |
- |
- |
25 |
- |
- |
|||
2EHMA |
234±4.8 |
0-30 |
7.8% / 30h |
22.7 ±3.7 |
3-24 |
0.6% / 24h |
|||
OMA |
159±15 |
0-24 |
- |
7.8 |
- |
- |
Ester
Peak = rate of appearance of the parent ester (µg/cm2/hr)
MAA
Peak = rate of appearance of the hydrolysis product, MAA (µg/cm2/hr)
Period Peak Absorp. = Time (hours) after application for peak absorption
% Applied Dose = total % absorbed
** Predicted rates of MAA from model estimates.
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
Description of key information
Short description of key information on bioaccumulation potential result:
Methacrylate esters, including octyl methacrylate (n-OMA), 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-OMA the half-life was 27.2 minutes and 99.9 % was removed by first-pass metabolism in the liver. Reliable data on the primary metabolites methacrylic acid are available and do not reveal critical properties.
Short description of key information on absorption rate of 2-Ethylhexyl methacrylate (2 -EHMA) structural analogue substance and member of the category (C1 -C8 Lower Alkyl Methacrylates):
2-EHMA readily absorbs through rat and human epidermis. Human epidermis appears to be 10 times less permeable to 2-EHMA than rat epidermis.
Key value for chemical safety assessment
Additional information
Read across to stuctural analogue substance 2-Ethylhexyl methacrylate (2 -EHMA) also a member of category (C1 -C8 Lower Alkyl Methacrylates)
In the case of the two octyl esters there is a high degree of confidence that data on the linear, n-octyl ester (n-OMA) can be read across to the branched, 2-Ethylhexyl ester based upon the very similar physical chemical properties, Michael addition reactivity, half-life within the body and ultimate metabolic fate, both of the parent ester as well as the alcohol metabolites. There is only very limited toxicokinetic data for the n-octyl methacrylate ester and the 2-ethyl hexyl methacrylate ester other than for dermal absorption. However, the low volatility of this ester indicates that this is not critical to the overall assessment.
Data availability:
There is some basic information available on 2-EHMA for metabolism in vitro and in vivo, as well as dermal absorption through rat and human skin. Furthermore, 2-EHMA is a member of a category of lower methacrylate esters, of which there are extensive data available for the methyl ester (methyl methacrylate, MMA) and this has been reviewed in the EU Risk Assessment (2002). Sufficient data is available to confirm applicability of this data across all members of the category and this has been reviewed in the OECD SIAR (2009). Data on methacrylic acid (MAA), the common metabolite, has been reviewed in the EU Risk Assessment (2002). The following text relies on these reviews with any addition to the original documents is italicised. Data on the corresponding alcohol metabolite 2-ethyl hexanol have been reviewed by the OECD SIAR process in 2005.
Trends/Results
The OECD SIAR on short chain methacrylate esters concluded that: “Other short chain alkyl-methacrylate esters, like MMA, are initially hydrolysed by non-specific carboxylesterases to methacrylic acid and the structurally corresponding alcohol in several tissues (ECETOC 1995, 1996b). In many regards, therefore, 2-EHMA as well as n-OMA behaves similarly to its close structural analogue MMA.
Taken from the EU Risk Assessment (RA) on MMA; “after oral or inhalation administration, methyl methacrylate is rapidly absorbed and distributed. In vitro skin absorption studies in human skin indicate that methyl methacrylate can be absorbed through human skin, absorption being enhanced under occluded conditions. However, only a very small amount of the applied dose (0.56%) penetrated the skin under unoccluded conditions (presumably due to evaporation of the ester from the skin surface (Syngenta/CEFIC, 1993)). After inhalation exposure to rats 10 to 20% of the substance is deposited in the upper respiratory tract where it is metabolized (by non-specific esterases to the acid, MAA (Morris, 1992)). Activities of local tissue esterases of the nasal epithelial cells appear to be lower in man than in rodents (Green, 1996 later published as Mainwaring, 2001). Toxicokinetics seem to be similar in man and experimental animal. After arthroplasty using methyl methacrylate-based cements, exhalation of unchanged ester occurs to a greater extent than after i. v., i. p. or oral administration. After oral or parenteral administration methyl methacrylate is further metabolised by physiological pathways with the majority of the administered dose being exhaled as CO2(Bratt and Hathway, 1977; ICI, 1977a). Conjugation with GSH or NPSH plays a minor role in methyl methacrylate metabolism and only occurs at high tissue concentrations (McCarthy and Witz, 1991; Elovaara et al., 1983) ”. While the basic metabolic pathway is very similar between MMA, 2 -EHMA and n-OMA, inhalation exposure is much less significant due to an approximately 3 orders of magnitude lower vapour pressure and hence, the threshold of toxic effects in the respiratory tract is unlikely to be reached under normal use patterns.
Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively). The carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin (Satoh & Hosokawa, 1998; Junge & Krish, 1975; Bogdanffy et al., 1987; Frederick et al., 1994). Those organs and tissues that play an important role and/or contribute substantially to the primary metabolism of the short-chain, volatile, alkyl-methacrylate esters are the tissues at the primary point of exposure, namely the nasal epithelia and the skin, and systemically, the liver and blood.
Methacrylate esters can conjugate with glutathione (GSH) in vitro, although they show a low reactivity, since the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group (McCarthy & Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982). There are no data for 2-EHMA and n-OMA itself, although data with MMA, ethyl methacrylate (EMA) and n-butyl methacrylate (n-BMA) indicate that GSH conjugation decreases with increasing chain length and is already negligible with n-BMA (McCarthy et al. 1994). Hence, ester hydrolysis is considered to be the only significant metabolic pathway for 2-EHMA and n-OMA.
Studies completed after the MMA RA have confirmed that all short chain alkyl-methacrylate esters are rapidly hydrolysed by ubiquitous carboxylesterases (see table below, adapted from Jones; 2002). First pass (local) hydrolysis of the parent ester has been shown to be significant for all routes of exposure. For example, no parent ester can be measured systemically following skin exposure to EMA and larger esters (including 2-EHMA), as the lower rate of absorption for these esters is within the metabolic capacity of the skin (Jones, 2002). Parent ester will also be effectively hydrolysed within the G. I. tract and within the tissues of the upper respiratory tract (particularly the olfactory tissue). Systemically absorbed parent ester will be effectively removed during the first pass through the liver (% Liver Blood Flow, LBF; see table below) resulting in their relatively rapid elimination from the body (T50%; see table below).
Table: Rate Constants for ester hydrolysis by rat-liver microsomes and predicted systemic fate kinetics following i.v. administration
Ester |
Rat liver microsomes (100µg ml-1) Vmax Km (nM min-1mg-1) (µM) |
CL (%LBF) |
T50%(min) |
Cmax(MAA) (mg L-1) |
Tmax(MAA) (min) |
|
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 |
HMA – hexyl methacrylate; OMA – octyl methacrylate;; i-BMA - iso-butyl methacrylate.Fate kinetics determined using the “well-stirred” model; CL%LBF – Clearance as percentage removed from liver blood flow i.e. first pass clearance; T50%- time taken for 50% of parent ester to have been eliminated from the body; Cmax– maximum concentration of MAA in circulating blood; Tmax– time in minutes to peak MAA concentration in blood “Jones, 2002”.
Table: Summary of the results for the peak rates of absorption of MAA & alkylmethacrylate esters through rat & human epidermis
|
Rat epidermis |
Human epidermis |
||||
Ester |
Peak rate of absorption (μg cm-2hr-1) ±SEM |
Period of peak absorption rate (hours) |
% age of applied dose absorbed over x hours |
Peak rate of absorption (μg cm-2hr-1) ±SEM |
Period of peak absorption rate (hours) |
% age of applied dose absorbed over x hours |
MAA |
23825±2839 |
0.5-4 |
93% / 24h |
812 |
- |
- |
MMA |
5888±223 |
2-8 |
46% / 16h |
453±44.5 |
4-24 |
10% / 24h |
EMA |
4421 |
- |
- |
253 |
- |
- |
i-BMA |
1418 |
- |
- |
80 |
- |
- |
n-BMA |
1540±69 |
0-6 |
18% / 24h |
76.7±9.8 |
0-24 |
2% / 24h |
HMA |
147 |
- |
- |
25 |
- |
- |
2EHMA |
234±4.8 |
0-30 |
7.8% / 30h |
22.7.7±3.7 |
3-24 |
0.6% / 24h |
OMA |
159±15 |
0-24 |
- |
7.8 |
- |
- |
Key: The values in normal type were obtained experimentally, whilst those in italics, are predicted values based on statistical analysis (single exponential fit) of the experimental data
In terms of MAA, the common metabolite for these esters, another study using intravenous injection of MAA in rats demonstrated very rapid clearance from the blood (half-life <5mins), suggestive of rapid subsequent metabolism (Jones, 2002).
Conclusions
2-EHMA, like other, shorter chain esters and MAA are absorbed by all routes. The rate of absorption decreases with increasing ester chain length so it will be absorbed less rapidly than MMA. All esters are rapidly hydrolysed in local tissues as well as in blood by non-specific esterases to methacrylic acid (MAA) and the respective alcohol. There is a trend towards increasing half-life of the ester in blood with increasing ester chain length (see table above). The half life of 2-EHMA is still, however, in the order of minutes (23.8) for n-OMA (27.2) . The primary metabolite, MAA, is subsequently cleared rapidly from blood and, as indicated by studies with MMA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.
Interms of the corresponding alcohol metabolite for these esters, they are subsequently rapidly metabolised, primarily in the liver, by oxidative pathways involving aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase enzymes to the corresponding aldehyde and acid before ultimately being converted to CO2.
Conjugation:
The C=C double bond of methacrylate esters render these chemicals as Michael acceptors capable of electrophilic attack of protein and other cellular macromolecules. This is the mode of action through which a wide range of toxicities including allergic contact dermatitis is thought to be mediated. This reactivity also means, however, that methacrylate esters are capable of conjugating with cellular glutathione (GSH). Quantitative structure activity relationships (QSAR) have been developed for the reaction with glutathione based upon the local charge-limited electrophilicity index ωq(Schwöbel et al., 2010) and the13C chemical shift, of the β-Carbon atom (Fujisawa and Kadoma, 2012) i.e. the unsubstituted end of the double bond in these molecules. The most recent of these models from 2012 is claimed to have a reliability factor (r2) of 0.99 for the prediction of the rate of the Michael addition reaction with GSH for a range of acrylate and methacrylate monomers. This publication includes calculation of the rate constants for EMA and n-BMA. This model was used by Tindale to calculate the rates for the remaining esters in the C1-C8 category (Tindale, 2015). The rate of reaction is low for all members of the C1-C8 methacrylate category (table 10) whether based upon the local charge-limited electrophilicity index ωq(Schwöbel et al., 2010, Cronin, 2012, 2015), or13C chemical shift, of the β-Carbon atom (Fujisawa and Kadoma, 2012; Tindale, 2015) when compared with other esters and unsaturated ketones and aldehydes (McCarthy & Witz, 1991). This is because the addition of a nucleophile at the double bond is hindered by the alpha-methyl side-group in the case of the methacrylates (McCarthy & Witz, 1991; McCarthy et al., 1994; Tanii and Hashimoto, 1982). A minor impact is also exerted by the +I-effect of the alcohol subgroup, but the incremental impact on electrophilicity rapidly decreases with increasing alcohol chain length. Therefore for direct electrophilic reactions the alcohol group will only have a minor, rather monotonic influence with increasing chain length. This is reflected in the very similar GSH reactivity constants for all members of the category. On this basis, ester hydrolysis is considered to be the major metabolic pathway for alkyl-methacrylate esters, with GSH conjugation only playing a minor role in their metabolism, and then possibly only when very high tissue concentrations are achieved. Furthermore, since there is no structural alert for Michael addition reactivity in the case of MAA (Cronin, 2012) or the alcohol metabolites, hydrolysis of the ester is essentially a detoxification process with regard to this MoA.
Like with MMA, local effects resulting from the hydrolysis of the ester to MAA might be expected following inhalation exposure. In the case of MMA this has been shown to be due to the localised concentration of non-specific esterases in nasal olfactory tissues. Data with MMA and n-BMA indicate that the NOEC for this local effect increases with increasing ester chain length within the category. For MMA the NOAEC in rats is 25 ppm while for n-BMA the NOAEC for this lesion is already 310 ppm (LOAEC was 952 ppm) in a subacute study. With 2-EHMA with a saturated vapour density of 50-100 ppm at ambient temperature (64 ppm at 20 °C) it is unlikely that concentrations could ever be reached which cause this effect. In the case of systemic effects the profile of effects is comparable between 2-EHMA and n-BMA. As the systemic NOAEC for n-BMA was 1891 ppm, a concentration approaching the saturated vapour density, in a 28 day study the 30fold lower saturated vapour density of 2-EHMA ensures that systemic effects would not be seen following repeated inhalation exposure to vapour. Hence, based on phys.-chem- properties and toxicokinetic information, the inhalation pathway is not considered a relevant route of exposure.
References quoted from the EU RA on MMA and other documents, but not copied into the IUCLID dataset:
Bogdanffy MS, Randall HW, Morgan KT (1987) Biochemical quantitation and histochemical localization of carboxylesterase in the nasal passages of the Fischer-344 rat and B6C3F1 mouse. Toxicology and Applied Pharmacology 88: 183-194
Bratt H,(1977). Fate of methyl methacrylate in rats. Brit. J. Cancer 36, 114-119.
CEFIC (1993). Methyl methacrylate: in vitro absorption through human epidermis: Ward RJ and Heylings JR, Zeneca Central Toxicology Lab., Unpublished study on behalf of CEFIC Methacrylates Toxicology Committee, Brussels
European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methacrylic Acid.European Union - Risk Assessment Report, Vol. 25, Doc. No. EUR 19837 EN
European Chemicals Bureau (2002). European Union - Risk Assessment Report on Methyl methacrylate. European Union - Risk Assessment Report, Vol. 22. Doc. No. EUR 19832 EN
ECETOC (1995) Joint Assessment of Commodity Chemicals No 30 ; Methyl Methacrylate, CAS No. 80-62-6. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-30
ECETOC (1996a) Joint Assessment of Commodity Chemicals No 35 ; Methacrylic acid, CAS No. 79-41-4. European Centre for Ecotoxicology and Toxicology of Chemicals, Avenue Van Nieuwenhuyse 4, (Bte 6) B-1160,. ISSN-0773-6339-35
Elovaara E, Kivistoe H, Vainio H (1983).Effects of methyl Methacrylate on non-protein thiols and drug metabolizing enzymes in rat liver and kidneys. Arch. Toxicol. 52, 109-121.Hext PM., Pinto PJ, Gaskell BA. (2001) Methyl methacrylate toxicity in rat nasal epithelium: investigation of the time course of lesion development and recovery from short term vapour inhalation.Toxicology 156: 119-128
FrederickCB (1998). Interim report on interspecies dosimetry comparisons with a hybrid computational fluid dynamics and physiologically-based pharmacokinetic inhalation model. Rohm and Haas Co.,.
ICI (1977). The biological fate of methylmethacrylate in rats; Rep. CTL/R/396 by Hathaway DE and Bratt H; Zeneca, Alderly Park, Macclesfield, Cheshire.
Junge W, Krisch K (1975) The carboxylesterases/amidases of mammalian liver and their possible significance. Critical Reviews in Food Science and Nutrition, 371-434.Mainwaring G, Foster JR, Lund V, Green T (2001) Methyl methacrylate toxicity in rat nasal epithelium: Studies of the mechanism of action and comparisons between species. Toxicology 158, 109-118
Mainwaring G, Foster JR, Lund V, Green T (2001) Methyl methacrylate toxicity in rat nasal epithelium: Studies of the mechanism of action and comparisons between species. Toxicology 158, 109-118
Morris JB (1992). Uptake of Inspired Methyl Methacrylate and Methacrylic Acid Vapors in the Upper Respiratory Tract of the F344 Rat. Prepared byof, Univ.for US Methacrylate Producers Association (MPA).Washington, DC
OECD (2004) SIDS Initial Assessment Report for18: Short-Chain Alkyl Methacrylates;http://webnet.oecd.org/hpv/UI/handler.axd?id=1da0a7af-3b11-45b7-865f-acad8b19c6c3
Tanii H, Hashimoto K (1982). Structure-toxicity relationship of acrylates and methacrylates. Toxicol Lett. 11: 125 129
Discussion on absorption rate:
The absorption of 2-EHMA was evaluated through rat and human epidermis in an in vitro system. The technique measures the rate of absorption of 2 -EHMA across the epidermis. Glass diffusion cells are employed to measure the amount of 2 -EHMA that is received into a receptor chamber with respect to time, following the application of 100 µl/cm² of 2 -EHMA to the epidermal surface. The mean rate of absorption through rat and human separated epidermis was 234 and 7.72 µg/cm²/hr and the total amount of chemical that was absorbed during the time of exposure was 7.8 % (over 30 hours) and 0.56 % (over 24 hours), respectively. 2-EHMA appears to be readily absorbed through rat and human epidermis, but human epidermis is at least 10 times less permeable to 2-EHMA than rat epidermis. However, measuring the rate of absorption through rat and human epidermis provides a quantitative estimate for inter-species differences; however, because only the epidermal layer is used, no measure of metabolism during skin absorption is possible.
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