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EC number: 202-617-2
CAS number: 97-90-5
All seven methacrylate esters were rapidly converted to MAA in
whole rat blood and rat liver microsomes. Hydrolysis half-lives ranged
from 1.56 to 99 minutes, and from 0.06 to 4.95 minutes for blood and
liver microsomes, respectively. The incubations in whole rat blood and
rat liver microsomes were performed on three separate days with MMA
included as a positive control on each day. Table 6 shows elimination
rates (ke), intrinsic clearance (Clint) and half-life values
for each molecule in whole rat blood and rat liver microsomes at 0.25 mM
Rat liver microsome hydrolysis rates for the positive control
(MMA) were somewhat variable between days. This was likely due to the
rapidity of hydrolysis of MMA. Often, measurable levels of MAA were
present even in the zero minute samples and the substrate was completely
hydrolyzed by 2 minutes. This made it difficult to accurately calculate
hydrolysis rates for MMA in these experiments. However, generally the
calculated rates were similar to rates for hydrolysis for MMA reported
previously (Jones, 2002; Mainwaring et al., 2001) and confirmed that the
in vitro test systems were enzymatically active for each day of
incubation experiments. The remaining six molecules exhibited rat liver
microsome hydrolysis rates approximately 10 fold lower than
MMA. However, all seven molecules were completely, or nearly completely,
hydrolyzed to MAA within 15 minutes incubation.
R. D .O. (2002). Using physiologically based pharmacokinetic modeling to
the pharmacokinetics and toxicity of methacrylate esters. Thesis
to theoffor the degree of Doctor of Philosophy
the Faculty of Medicine, Dentistry, Nursing and Pharmacy.
G., Foster, J. R.,, V., and Green, T. (2001). Methyl methacrylate
in rat nasal epithelium: studies of the mechanism of action and
In a structure-activity relationship investigation of acrylate and methacrylate
the reactivity towards hydrolysis by carboxyl esterase in vitro was studied in order to
elucidate their mechanism(s) of toxicity; the compounds tested included
ethyleneglycol dimethacrylate, the
second order rate constant Km for the carbioxylesterase
hydrolysis of ethyleneglycol dimethacrylate was about
64 ±24* µM and Vmax was 6.9 ± 2.4# nmole/min;
from comparison with the reaction rate of other esters the authors concluded that
increased alcohol chain length increases substrate affinity, yet decreases turnover
for the enzymatic hydrolysis of these esters.
Hydrolysis of acrylate esters by porcine liver carboxylesterase in vitro
Ester | Conc. | n | Km** | Vmax** | Vmax/Km
| [µM] | | [µM] | [nmol/min] | [1/min]
EA 25-2500 4 134 ± 16 8.9 ± 2.0 66
EMA 25-2500 7 159 ± 90 5.2 ± 2.5* 33
BA 5-250 3 33.3 ± 8.5* 1.49 ± 0.83* 45
BMA 5-250 5 72 ± 28* 1.84 ± 0.64* 26
EGDMA 5-250 4 64 ± 24* 6.9 ± 2.4# 108
TEGDMA 5-250 4 39 ± 15* 2.9 ± l.0*° 74
EA = Ethyl acrylate, EMA = Ethyl methacrylate, BA = Butyl acrylate,
BMA = Butyl methacrylate, EGDMA = Ethyleneglycol dimethacrylate,
TEGDMA = Tetraethyleneglycol dimethacrylate
**Mean + standard deviation.
*Significantly different at P 0.05 compared with ethyl acrylate.
#Significantly different at P 0.05 compared with butyl acrylate.
°Significantly different at P 0.05 compared with ethyleneglycol dimethacrylate.
In a valid scientific study, it was shown that increased alcohol chain
length increases substrate affinity, yet decreases turnover for the
enzymatic hydrolysis of these esters. For the reaction with porcine
liver carboxylesterase the following values were determined for EGDMA:
Km 64 ±24 µM and Vmax was 6.9 ± 2.4 nmole/min; Vmax/Km 108 1/min
Test Chemical / Compound Identity
Predicted Flux (µg/cm2/h)
Relative Dermal Absorption
Multi-func aliph/hydrophob DMA
Ethylene glycol dimethacrylate
Based on the dermal penetration model for human skin the predicted skin
penetration for EGDMA is low (6.109 µg/cm²/h).
likely to be absorbed by all routes. Due to the low vapour pressure, the
is the primary route of exposure, since inhalation is unlikely. The
dermal absorption rate however is calculated to be low.
The ester is
rapidly within a few minutes hydrolysed by carboxylesterases to
methacrylic acid (MAA) and ethylene glycol. Ethylene glycol will be
transformed to glycolic acid and, subsequently, to glyoxylic acid.
Metabolites can be degraded to formate, glycine or malate which can be
broken down to generate respiratory CO2, or to oxalic acid, which is
excreted in the urine. These metabolic steps are partially rate-limited.
metabolized to succinic acid which will be degraded through the
tricarboxylic acid cycle and primarily excreted as CO2.
physicochemical properties of EGDMA (log P = 2.4), the relatively high
water solubility of > 1 g/L and the molecular weight of 198.22 g/mol are
in a range suggestive of absorption from the gastro-intestinal tract
subsequent to oral ingestion (ECHA guidance 7c, 2017). For chemical
safety assessment an oral absorption rate of 50% is assumed as a worst
case default value
(ECHA R.8 guidance, 2012).
Based on a
QSAR Prediction of Dermal Absorption (extract from Heylings JR, 2013)
EGDMA is predicted
on the basis of their molecular weight and lipophilicity to have a
relatively low ability to be absorbed
through the skin. The predicted flux was 6.109 μg/cm²/h. However,
for chemical safety assessment, a dermal absorption
rate of 50% is assumed as a worst case default value
(ECHA R.8 guidance, 2012).
Due to the low vapour pressure of EGDMA (1.0 Pa at 20°C), exposure
via inhalation is unlikely. For chemical safety assessment an inhalative
absorption rate of 100% is assumed as a worst case default value (R8
As a small,
water-soluble molecule with a logP > 0, a wide distribution can be
expected (ECHA guidance 7c, 2017). No information on potential target
organs is available.
of Methacrylic esters
Di- and mono-ester hydrolysis
Ester hydrolysis has been established as the primary step in the
metabolism of methacrylate esters. In the case of diol di-methacrylate
esters the first step would be hydrolysis of one of the ester bonds to
produce the corresponding mono-ester followed by subsequent hydrolysis
of the second ester bond to produce methacrylic acid (MAA) and the
corresponding alcohol Ethylene glycol. The metabolic pathway is
shown in the category document.
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. For
multifunctional methacrylates mostly the same would be the case except,
because of the much lower vapour pressure, inhalation is generally not a
relevant route of exposure and there is a very low likelihood of a
relevant exposure of the nasal epithelium to vapour.
Kinetics data have been reported for the hydrolysis of two
multifunctional methacrylates (EGDMA and TREGDMA) by porcine liver
carboxylesterase in vitro. For comparison reasons, the results from two
lower alkyl methacrylates (EMA and BMA), are also presented in the table
below (McCarthy and Witz, 1997). The four studied substances showed
comparable hydrolysis rates in vitro.
Table: Hydrolysis of
Acrylate Esters by Porcine Liver Carboxylesterasein vitro (extract
from McCarthy and Witz., 1997); supporting data from lower
alkyl methacrylates in grey
Tetraethyleneglycol dimethacrylate (TREGDMA)
Ethyleneglycol dimethacrylate (EGDMA)
Ethyl methacrylate (EMA)
n-Butyl methacrylate (n-BMA)
*Significantly different (p
< 0.05) from ethyl acrylate
A recent study, designed to extend an earlier work on lower alkyl
methacrylates (Jones 2002, see below) to higher and more complex
methacrylate esters, studied the in vitro metabolism of higher and more
complex methacrylate esters in rat blood and liver microsomes. This
study included three esters of the multifunctional methacrylate category
(TREGDMA, EGDMA and 1,4-BDDMA) (DOW, 2013). The results of those studies
are summarized in below table.
Table: Elimination Rates, Intrinsic Clearance and Half-life in Rat Liver
Microsomes and Whole Rat Blood for Five Methacrylate Esters at 0.25 mM
Substrate Concentration (DOW, 2013); data from
supporting substances in grey.
ke: elimination rate
Clint: intrinsic clearance (ke x volume of incubation / mg/mL
MMA: Methyl methacrylate (supporting substance); HEMA: Hydroxyethyl
methacrylate (supporting substance)
All studied methacrylate esters were rapidly converted to MAA in
whole rat blood and rat liver microsomes. Hydrolysis half-lives of the
studied category members were in the order of minutes for blood and
liver microsomes, respectively.
The incubations in whole rat blood and rat liver microsomes were
performed on three separate days with MMA included as a positive control
on each day. Rat liver microsome hydrolysis rates for the positive
control (MMA) were somewhat variable between days. This was likely due
to the rapidity of hydrolysis of MMA. Often, measurable levels of MAA
were present even in the zero minute samples and the substrate was
completely hydrolyzed by 2 minutes. This made it difficult to accurately
calculate hydrolysis rates for MMA in these experiments. However,
generally the calculated rates were similar to rates for hydrolysis for
MMA reported previously (Jones, 2002; Mainwaring et al., 2001) and
confirmed that the in vitro test systems were enzymatically active for
each day of incubation experiments. The other studied methacrylates
exhibited rat liver microsome hydrolysis rates approximately 10 fold
lower than MMA. From its very rapid degradation to MAA, MMA can be
understood as suitable donor substance for MAA as common primary
metabolite of all category members.
Supporting information on Alkyl methacrylates
The above mentioned EMA and n-BMA were also studied in an
elaborate series of in vitrostudies on carboxylesterase activity
with 7 alkyl methacrylates ranging from methyl methacrylate to octyl
methacrylate (with increasing ester size) (Jones, 2002). This was used
to establish a PB-PK model of in vivoclearance for several
tissues (blood, liver, skin and nasal epithelium) from rats and humans,
which showed thatmethacrylate mono-esters are rapidly hydrolyzed by
carboxylesterases to methacrylic acid (MAA) and the respective alcohol.
The validity of the model was verified with targeted in vivo
experiments. Whilst there was a trend of increasing half-life of alkyl
methacrylates with increasing chain length (up to octyl), clearance of
the parent ester from the body was always in the order of minutes.
Although the absolute rate measurements obtained by Jones differ
slightly to those determined by McCarthy and Witz, presumably due to
differences in experimental conditions such as protein content etc., the
rates obtained for the two lower alkyl methacrylates (EMA and BMA) can
be used to draw parallels between the work of the two researchers
indicating that the kinetics for the hydrolysis of EGDMA and TREGDMA
fall within the range observed by Jones for lower alkyl methacrylates.
On this basis the parent ester would be expected to have a short
systemic half–life within the body being effectively cleared from the
blood within the first or second pass through the liver.
Hydrolysis of the di- and monoester would yield the common metabolite
methacrylic acid and the respective alcohol.
Methacrylic acid (MAA, CAS 79-41-4)
From the available extensive toxicokinetic data on lower alkyl
methacrylates it has been established that the common primary metabolite
methacrylic acid is subsequently cleared predominantly via the liver
(valine pathway and the TCA (TriCarboxylic Acid) cycle, respectively;
ECB, 2002; OECD SIAR, 2009). Methyl methacrylate (MMA) is rapidly
degraded in the body to MAA and can thus be understood as metabolite
donor for MAA. The metabolic pathway is shown in the category
CAS 107 -21 -1)
As described in the ATSDR review on ethylene glycol (2010), “Ethylene
glycol is converted to glycolaldehyde by nicotinamide adenine
dinucleotide (NAD)-dependent alcohol dehydrogenase. Subsequent reduction
of NAD results in the formation of lactic acid from pyruvate.
Glycolaldehyde has a brief half-life and is rapidly converted to
glycolic acid (and to a lesser extent glyoxal) by aldehyde dehydrogenase
and aldehyde oxidase, respectively. Glycolic acid is oxidized to
glyoxylic acid by glycolic acid oxidase or lactic dehydrogenase.
Glyoxylic acid can be metabolized to formate, glycine, or malate, all of
which may be further broken down to generate respiratory CO2, or to
oxalic acid, which is excreted in the urine. In excess, oxalic acid can
form calcium oxalate crystals. Rate-limiting steps in the metabolism of
ethylene glycol include the initial formation of glycolaldehyde and the
conversion of glycolic acid to glyoxylic acid, both of which are
saturable processes. The conversion of glycolic acid to glyoxylic acid
is the most rate-limiting step in ethylene glycol metabolism.” The
metabolic pathway is shown in the category document.
In rabbits, glucuronic acid conjugation was not observed after
application of 4 mmol/kg bw (Gessner et al., 1960). Enzymatic key
parameters of alcohol dehydrogenase were 1000±60 mM kmand
64±1 nmol/min Vmaxfor EG (Herold et al., 1989).
A QSAR model for the methacrylates in the category predicts only
slight reactivity with glutathione for the category members and no
reactivity for the primary metabolite of the methacrylic moiety,
methacrylic acid (Cronin, 2012).
QSAR prediction of GSH reactivity (Protein Binding Potency; Cronin,
Sat. Water Sol. (µg/mL)
Protein Binding Potency
Studies with methacrylates in vitro confirm low reactivity with
GSH, in particular compared to the corresponding acrylates, and have
proposed that this is due to steric hindrance of the addition of a
nucleophile at the double bond by the alpha-methyl side-group (McCarthy
& Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982). For
example, HEMA as the primary metabolite of EGDMA affected intracellular
GSH depletion only in concentrations of 5 or 10 mM in two different
human cell types (Chang et al. 2005).
Second-Order Rate Constants for the Reaction of Glutathione with
Methacrylate Esters (extract from McCarthy et al., 1994);
data from the supporting substances in grey
App. 2ndorder rate const.Kapp[L/mol/min]
Methyl methacrylate (MMA)
*Bifunctional esters calculated as two independent esters.
In vivo data on category members are absent.
However, in an inhalation study with MMA at an overtly cytotoxic
exposure level off 566 ppm and absolute deposition rates of 35-42μg/min
under unidirectional flow, a 20% lowering of nasal non-protein
sulfhydryl (NPSH) content was observed, indicative of direct protein
reactivity, whereas methacrylic acid exposures had no effect, even at
higher delivered dose rates. Around the local (nasal) LOAEL, at an
exposure concentration of 109 ppm, MMA had no effect on nasal NPSH
levels (Morris and Frederick, 1995).
Hence, ester hydrolysis is considered to be the major metabolic
pathway for alkyl and multifunctional methacrylate esters, with GSH
conjugation only playing a minor role in their metabolism.
As the ester will not survive first pass metabolism in the liver,
excretion of the parent compound is of no relevance. The primary
metabolite, MAA, is cleared rapidly from blood by standard
physiological pathways, with the majority of the administered dose
being exhaled as CO2.
In summary, the metabolism data and modelling results show that
EGDMA would be rapidly hydrolysed in the rat.
Table: QSAR prediction of
dermal absorption (extract from Heylings, 2013)
All members of the MfMA category, but GDMA, are predicted on the
basis of their molecular weight and lipophilicity to have a relatively
low ability to be absorbed through the skin (Heylings, 2013).
MfMA esters are typically predicted to have a relatively low
potential for skin absorption. There is a suggestion of trend for
predicted absorption decreasing with increasing ester chain length and
increasing lipophilicity. The larger members of the category, like
TMPTMA, are extremely unlikely to be absorbed through the skin to any
There are no relevant toxicokinetic data for MfMA in humans.
For lower alkyl methacrylates there is information indicating that
skin absorption rates are lower in human skin compared to rat skin,
while for MMA it has been demonstrated that human fate kinetics is
similar to those in rats (Jones, 2002).
and discussion on toxicokinetics
esters are absorbed by all routes while the dermal absorption is limited
with the larger members of the category. Due to the low vapour pressure
of the multifunctional methacrylates, the dermal route is the primary
route of exposure, since inhalation is unlikely. The rate of dermal
absorption decreases with increasing ester chain length. All esters are
rapidly hydrolyzed by carboxylesterases to methacrylic acid (MAA) and
the respective alcohol. In the case of di- and triesters the apparent
rate of hydrolysis is highest for the parent ester, but this likely
reflects the higher number of hydrolysable target sites instead as
opposed to any greater specific activity. Ester hydrolysis can occur in
local tissues at the site of contact as well as in blood and other
organs by non-specific carboxylesterases. By far the highest enzyme
activity has been shown in liver microsomes indicating that the parent
ester will be fully metabolized in the liver. Clearance of the parent
ester from the body is in the order of minutes. There is a trend towards
increasing half-life of the ester in blood with increasing ester chain
length, however, none of the esters will survive first pass metabolism
in the liver to any significant extent. The primary methacrylic
metabolite, MAA, is subsequently cleared rapidly from blood by standard
physiological pathways, with the majority of the administered dose being
exhaled as CO2. The respective alcohol moieties will undergo further
metabolism in the liver.
glycol dimethacrylate will rapidly be hydrolyzed by unspecific carboxyl
esterases in the liver
into methacrylic acid and ethylene glycol. Ethylene glycol will be
transformed rapidly by alcohol dehydrogenases
and aldehyde dehydrogenase and aldehyde oxidase, respectively into
glycolic acid (and to a lesser extent glyoxal) and will be converted to
glycolic acid. Glycolic acid is oxidized to glyoxylic acid by glycolic
acid oxidase or lactic dehydrogenase. Glyoxylic acid can be metabolized
to formate, glycine, or malate, all of which may be further broken down
to generate respiratory CO2, or to oxalic acid, which is excreted in the
to REACh requirements
The information requirement is covered with reliable in vitro studies
on the primary metabolism, reliable in vitro/ in vivo studies on
the metabolism of the methacrylic metabolite MAA as well as reliable
publication data on the metabolism of the alcohol metabolite EG. All
mentioned sources are reliable (Reliability 1 or 2) so that the
category/ read across approach can be done with a high level of
ATSDR 2010. Toxicological Profile For Ethylene Glycol. ATSDR TP
No. 96 .S. Department of Health and Human Services; Public Health
Service Agency for Toxic Substances and Disease Registry
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.
H-H. et al.(2005).
Stimulation of glutathione depletion, ROS production and cell cycle
arrest of dental pulp cells and gingival epithelial cells by HEMA.
Biomaterials 26, 745-753
Frederick C. B., Udinsky J. R., Finch L (1994). The regional
hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity.
Toxicology letters, 70: 49-56.
Herold D. A. et al. (1989). Oxidation of polyethylene glycols by
alcohol dehydrogenase. Biochemical Pharmacology 38 (1): 73-76
Jones O (2002). Using physiologically based pharmacokinetic
modelling to predict the pharmacokinetics and toxicity of methacrylate
esters. A Thesis submitted to Univ. of Manchester for the degree of
Doctor of Philosophy.
Junge W, Krisch K (1975) The carboxylesterases/amidases of
mammalian liver and their possible significance. Critical Reviews in
Food Science and Nutrition, 371-434
Gessner PK, ParkeDV, Williams RT (1960). Studies in Detoxication.
80. The metabolism of glycols. Biochemical Journal, 74: 1-5
McCarthy TJ, Witz G (1997). Structure-activity relationships in
the hydrolysis of acrylate and methacrylate esters by carboxylesterase
in vitro. Toxicology 116: 153-158. Owner company: Published.
Satoh T, Hosokawa M (1998). The Mammalian carboxylesterases: From
models to functions. Annual Review of Pharmacology and Toxicology 38,
257-288. Medicine and Biology 283, 333-335
Tanii H., Hashimoto K.(1982); Structure-Toxicity Relationship of
Acrylates and Methacrylates; Toxicol. Lett. 11: 125-129
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