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EC number: 212-084-8 | CAS number: 760-93-0
Non-compartmental analysis of the blood concentration data for MAA at the two doses, gives volumes of distribution of 23 ml (10 mg kg-1) and 35 ml (20 mg kg-1). The clearance of MAA was calculated to be 0.324 L hr-1 SRW-1 at the 10 mg kg-1 dose and 0.25 L hr-1 SRW-1 at the 20 mg kg-1 dose. The change in clearance from the lower dose to the higher dose indicates non-linear saturable metabolism in the rat.
Based on that information, the following kinetic parameters were determined from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination (Vss = 0.039 L/SRW; Vmax = 19.8 mg/hrxSRW; Km = 20.3 mg/L; SRW: standard rat weight = 250 g) the half-life of MAA in blood was calculated to 1.7 min.
The PBPK model data were validated by i.v. administration of MAA in rats and subsequent analysis of blood from the tail vein.
In conclusion, from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination, the half-life of MAA in blood was calculated to 1.7 min.
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The presence of methacrylic acid (quantity not determined) was reported in Wistar rat blood serum 10 min after oral gavage administration of 2 ml of a 1 M solution of sodium methacrylate. After 60 min MAA could not anymore be detected in the blood serum (detection limit 0.5 µmol/l).
The algorithm of the OECD toolbox has been used to predict GSH/protein reactiviry.
Test Chemical / Compound Identity
Protein Binding Potency
Slightly reactive (GSH) >> Methacrylates (MA)
No alert found
2-(2-Butoxyethoxy) ethyl methacrylate, Butyldiglycol methacrylate
2-(2-(2-Ethoxy ethoxy)-thoxyethyl methacrylate
Hydroxypropyl methacrylate(propyleneglycol monoester)= isomer mixture of< 80 % 2-Hydroxypropyl methacrylate> 20% 2-Hydroxy-1-methylethyl methacrylate
Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA)
Ethylene glycol dimethacrylate
Ethoxylated bisphenol A dimethacrylate
CC(C)(C1=CC=C(C=C1)O)C2=CC=C(C=C2)O.C=CC(=O)O.C(CO)OID of reference isomer:CC(=C)C(=O)OC1=CC=C(C=C1)C(C)(C)C1=CC=C(OC(=O)C(C)=C)C=C1
4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxy propane, reaction products with methacrylic acid
Bis-GMA NLP (DSM/Akzo/+others)
2-hydroxyethyl methacrylate phosphate
Hydroxyethyl ethylene urea methacrylate
for approximation see Tetraethyleneglycol dimathacrylate
2-Trimethylammoniummethyl methacrylate-chloride2-(Methacryloyloxy)-N,N,N-trimethylethanaminium chloride
A dataset with methacrylic acid derivatives has been assessed using the reactivity profiler in the OECD QSAR Toolbox. This profiler contains structural alerts derived from an analysis of experimental reactivity data as measured using glutathione (the Schultz assay). The profiler assigns chemicals to one of five potency classes (non-reactive, slightly reactive, moderately reactive, highly reactive and extremely reactive) based on the experimental results.
For Methacrylic acid, no alert was found, while the majority of the methacrylate esters are slightly reactive. For methacrylate esters it is well known that the addition of an alkyl group on the alpha-carbon significantly reduces reactivity in the Michael addition reaction.
There are also a group of vinyl carboxamides (methacrylamide derivatives) that have been flagged as being moderately reactive. It should be noted, however, that in the underlying QSAR data in the TB there is no information regarding the effect of an alpha substituent for this class of chemical. In reality this means that no chemicals were tested with glutathione that contained an alpha alkyl substituent thus the prediction is being made based on the un-substituted parent (acrylamide; thus the over-cautious prediction). The investigator indicated that they are likely to be pretty unreactive in reality.
The model output reproduced the published total rat nose deposition data for MAA under unidirectional flow conditions. Comparisons of predicted olfactory tissue concentrations of MAA following simulated exposure of rat, mouse, and human nasal cavities indicated that under identical exposure conditions human olfactory tissue would have a 2 -3 fold lower concentration of MAA than comparable rodent tissue. Conducting the same comparison except using human physiology associated with light physical activity resulted in a range of values based on the extent to which human oral breathing is included in the evaluation. At a reported average of 40% oral breathing at this workload, the human olfactory tissue concentration would be approximately one-half of the concentration of the comparable rat tissue.
Using a valid modeling technique, it is predicted that exposure concentrations for human olfactory tissue relative to rodent tissue would be at least 50 % lower.
MAAH is rapidly hydrolysed to Methacrylic acid (MAA) either by passive physical processes (see chapter "Hydrolysis") and biological processes with the help of ubiquiteous carboxylase enzymes. Based on studies of the toxicikinetic of methacrylic acid, which thus can be understood as the initial hydrolysis product and primary metabolite of methacrylic anhydride, methacrylic acid is readily absorbed by all routes and rapidly cleared from blood. As indicated by studies with methyl methacrylate(MMA), which functions as metabolite donor substance due to its rapid metablism to MAA, this metabolism is by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.
It has been demonstrated in a physicochemical hydrolysis study that methacrylic anhydride has a half-life of a few minutes under the conditions of passive hydrolysis. In addition MAAH is stuturally related to an ester which makes it a substrate for carboxylesterase-catalysed hydrolysis in vivo. As methacrylic acid (MAA) thus can be understood as the initial hydrolysis product and primary metabolite of methacrylic anhydride, evaluation of toxicokinetics and fate is primarily based on methacrylic acid. While the properties of the original substance are relevant for local effects (absorption, irritation, sensitisation), systemic effects are most likely the result of the primary metabolite, methacrylic acid.
There are extensive data available for the methyl ester (MMA) which 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, including MAA, and this has been reviewed in the OECD SIAR (2009). Data on 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. Due to the very short half-life of the parent ester in the body and ester hydrolysis being the first step in metabolism, several endpoints in the later parts of the assessment are satisfied by read-across to methyl methacrylate.
Taken from the EU Risk Assessment on MAA: “Deposition of methacrylic acid vapours in the surgically isolated upper respiratory tract (URT) of anaesthetised rats was studied after inhalation of 450μg/l (133 ppm) using a unidirectional respiratory flow technique (cyclic flow studies were not possible due to vapour absorption on the cyclic flow pump) for 60 min (Morris and Frederick, 1995). Deposition of methacrylic acid was measured throughout exposure determining the difference in vapour concentration of methacrylic acid in the inspired and the URT expiring air. Deposition rates (from 30 to 60 min of exposure) of about 95% were observed under 200 ml/min unidirectional flow conditions. However, the degree of penetration to underlying cells could not be derived from this experiment. ”
Further from the EU Risk Assessment on MAA: “After a single oral administration of the sodium salt of methacrylic acid to Wistar rats (540 mg/kg bw) methacrylic acid was detected in the blood serum by means of HPLC. The maximum concentration was found after 10 min, whereas after 60 min no more methacrylic acid was detectable (Bereznowski et al., 1994).
As taken from the OECD SIAR: “Methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively).”As methyl methacrylate (MMA) is rapidly degraded in the body to MAA, it can thus be understood as metabolite donor for MAA, with MAA as common metabolite of MAAH and MMA
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). For MAA, by analogy with acrylic acid and its esters, it can be predicted that the free carboxyl group will reduce the already low reactivity of methacrylates with GSH even further, so that GSH conjugation will only play an insignificant role in MAA metabolism, and then possibly only when very high tissue concentrations are achieved. Morris (1992) did not find any effect on GSH concentrations in URT tissues up to inhaled MAA concentrations of 410 ppm, a concentration which causes tissue damage in the URT in inhalation experiments.
Table: Summary of the results for the peak rates of absorption of MMA through rat & human epidermis
Peak rate of absorption (μg/cm²/hr) ±SEM
Period of peak absorption rate (hours)
% age of applied dose absorbed over x hours
93% / 24h
46% / 16h
10% / 24h
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
Studies completed after the EU ESR on MAA indicate rapid absorption through skin and subsequent clearance from blood. Topically applied MAA absorbs rapidly through intact rat epidermis and viable whole skin in-vitro (Jones, 2002). In another study intravenous injection of MAA in rats demonstrated very rapid clearance from the blood (half-life <5mins), suggestive of rapid subsequent metabolism (Jones, 2002).
A comparison of measured blood concentration data after i. v. administration of 10 and 20 mg/kg MAA and a simulation based on a one-compartment model shows good agreement. Based on that information, the following kinetic parameters were determined from a simultaneous fit of the in vivo data to a one-compartment model with non-linear elimination (Vss = 0.039 L/SRW; Vmax = 19.8 mg/hr x SRW; Km = 20.3 mg/L; SRW: standard rat weight = 250 g) the half-life of MAA in blood was calculated to 1.7 min.
For methacrylic anhydride no in vivo absorption data exist. The rate of dermal absorption has been calculated with a human skin model (Heylings, 2012).
Predicted Flux (µg/cm2/h)
Relative Dermal Absorption
Alkyl basic MA tier 1
Multi-func hydrophil spec / single
In comparison, the predicted absorption rate for MAAH is substantially lower than that of the reference chemical methyl methacrylate in the same model. In relation, the predicted absorption rate for MMA is lower than the epidermal permeation rate shown above but is consistent with the only slightly lower absorption rate for human whole skin (33 µg/cm²/h) predicted from the experimental, epidermal data in the study by Jones(2002).
MAA is absorbed by all routes, while the actual absorption rates may be lower than for the reference chemicals methacrylic acid and methyl methacrylate. Due to the short half-life MAAH is rapidly converted to methacrylaic acid which, in turn, is rapidly cleared 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.
Local effects at the site of contact due to MAAH, but also because of the irritating/corrosive properties of MAA.
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