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EC number: 203-652-6
CAS number: 109-16-0
Negative controls in the rat liver
microsome experiments included incubations with heat-inactivated
microsomes, no microsomes and no NADPH. Removal of NADPH made little or
no difference in hydrolysis rates. Heat inactivation significantly
reduced hydrolysis rates, and absence of microsomes resulted in no
TREGDMA was rapidly
converted to MAA in whole rat blood and rat liver microsomes with
hydrolysis half-lives of 3.01 min (liver microsomes) and 5.68 min
This in vitro metabolism study was conducted
to investigate in vitro hydrolysis rates of TREGDMA. Half-lifes were
determined in rat liver microsomes and whole rat blood.
TREGDMA was rapidly converted to MAA in
whole rat blood and rat liver microsomes with hydrolysis half lives of
3.01 min (liver microsomes) and 5.68 min (blood).
Exctretion of triethylene glycol was investigated in male albino rats.
Following administration of 14C-triethyleneglycol to the rat, 86-94% of
the radioactivity was recovered in the urine in the subsequent 5-day
period. The total excretion by way of the urine and faeces amounted to
94-97%. The expired air over a 60-h period contained approximately 1% of
the administered dose. Therefore Triethylene glycol is expected to pass
the organism without further metabolism.
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).
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)
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
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
Based on a molecular
weight of 286.32 g/mol and a log
Kow of 2.3, the predicted flux of TREGDMA is 4.989
dermal absorption is low.
The dermal absorption (steady-state flux) of
TREGDMA has been estimated by calculation using the principles defined
in the Potts and Guy prediction model.
Based on a molecular
weight of 286.32 g/mol and a log
Kow of 2.3, the predicted flux of TREGDMA is 4.989 μg/cm²/h;
dermal absorption is low.
TREGDMA is likely to be readily absorbed by all routes. Due to the
low vapour pressure, the dermal route is the primary route of exposure,
since inhalation is unlikely. The dermal absorption rate however is
calculated to be low.
The ester is rapidly hydrolysed by carboxylesterases to
methacrylic acid (MAA) and the respective alcohol triethylene glycol
(TREG). MAA is metabolized to succinic acid which will be degraded
through the tricarboxylic acid cycle and primarily excreted as CO2.
Orally administered TREG is excreted either unchanged or oxidized to the
di-carbolic acid of TREG, predominantly via urine.
Based on physico chemical properties, no potential for
bioaccumulation is to be expected.
The physico chemical properties of TREGDMA (log Pow = 2.3), the
relatively high water solubility of 3.6 g/L and the molecular weight of
286.32 g/mol are in a range suggestive of absorption from the
gastrointestinal tract subsequent to oral ingestion. For chemical safety
assessment an oral absorption rate of 50% is assumed as a worst case
default value in the absence of other data (ECHA R.8 guidance, 2012).
Based on a QSAR Prediction of Dermal Absorption (extract from
Heylings JR, 2013) TREGDMA 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 4.989 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).
No vapour pressure is available for TREGDMA itself but for the
structurally related substance ET3EGMA which boiling point is lower than
TREGDMA. The vapour pressure of ET3EGMA (0.077 Pa@20 °C) was used to
characterize TREGDMA. Due to the low vapour pressure exposure to TREGDMA
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. However, due to the low log Pow
bioaccumulation in particular tissues is not predicted.
of Methacrylic esters
Di- and monoester 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 triethylene glycol. The metabolic pathway is
described 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
that because of the lower vapour pressure and hence lower likelihood of
inhalation exposure the involvement of the nasal epithelium is less
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.
Hydrolysis of Acrylate
Esters by Porcine Liver Carboxylesterase in vitro (extract from
McCarthy and Witz., 1997):
Ethyl methacrylate (EMA)
Butyl methacrylate (BMA)
Ethyleneglycol dimethacrylate (EGDMA)
Tetraethyleneglycol dimethacrylate (TTEGDMA)
different (p < 0.05) from ethyl acrylate
A recent study, designed to
extend an ealier work on lower alkyl methacrylates (Jones 2002), see
below) to higher and more complex methacrylate esters, studies 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 the 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:
ke: elimination rate
Clint: intrinsic clearance (ke x volume of incubation / mg/mL microsomal
All studied 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. The table above
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 starting concentrations.
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 hydrolysed 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 studies exhibited rat liver microsome hydrolysis rates
approximately 10 fold lower than MMA. For its vers rapid degradation to
MAA, MMA can be understood as suitable donor for MAA as common primary
metabolite of all catergory members.
information on Alkyl methacrylates
above mentioned EMA and n-BMA were also studied in an elaborate series
of in vitro studies 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 vivo clearance for several tissues (blood, liver, skin
and nasal epithelium) from rats and humans, which showed that
methacrylate 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.
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
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 document.
Triethylene glycol(TREG, CAS 112-27-6)
In an earlier study, oral doses of radio-labelled TREG were
excreted by rats and rabbits in both unchanged and oxidized form. The
data suggest that one of the oxidation products is a monocarboxylic acid
which arises by metabolic oxidation of a single terminal hydroxyl group
of the parent glycol. The rat eliminated only trace quantities of14C
activity as respiratory carbon dioxide. A small but measurable amount of
radioactivity was found in the feces. The major part of the
radioactivity appeared in the urine. The data from fractionation of the
urine indicated that only negligible quantities (if any) of14C
were present as oxalic acid (the completely fragmented acid). The major
metabolic products had properties which suggested that triethylene
glycol is degraded by the route: TREG → mono-carboxylic acid of TREG →
di-carboxylic acid of TREG. The authors concluded that the high degree
of elimination of triethylene glycol and its metabolites by way of the
urine, is consistent with many findings pointing to the low or limited
toxicity of triethylene glycol. The total elimination of radioactivity
(in urine, feces, and expired air) during the 5-day period following a
single oral dose (22.5 mg) was 91–98% (McKennis et al., 1962).
dehydrogenase and aldehyde dehydrogenase were found to be involved in
the metabolism of polyethylene glycols including TREG in humans and
animals. Enzymatic key parameters of alcohol dehydrogenase were 810±50
mM kmand 19±2 nmol/min Vmaxfor TREG (Herold
et al., 1989).
A QSAR model for TREGDMA
predicted only slight reactivity with glutathione for the category
members and no reactivity for the primary metabolite, methacrylic acid. (Cronin,
QSAR prediction of GSH
reactivity (Protein Binding Potency), Cronin,
Sat. Water Sol. (µg/mL)
Protein Binding Potency
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). This is also
confirmed by the publication of Nocca et al. (2011) who found a low
levels of GSH adducts of TREGDMA when erythrocytes and gingival
fibroblasts were exposed to 2 mM (573 mg/L) TREGDMA in vitro.
Apparent Second-Order Rate Constants for the Reaction of Glutathione
with Methacrylate Esters (extract from McCarthy et al.,1994)
App. 2ndorder rate const.Kapp[L/mol/min]
Methyl methacrylate (MMA)
No appreciable reaction rate
esters calculated as two independent esters.
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).
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.
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.
summary, the metabolism data and modelling results show that TREGDMA
would be rapidly hydrolysed in the rat.
QSAR prediction of dermal absorption (extract from Heylings, 2013)
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)
esters are typically predicted to have a relatively low potential for
skin absorption. There
is a suggestion of trend for predicted absorption decreasing with
length and increasing lipophilicity. The larger members of the category,
are extremely unlikely to be absorbed through the skin to any
are no relevant toxicokinetic data for MfMA in humans.
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
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 triethylene glycol.
Excretion of triethylene glycol was investigated in male albino
rats. Following administration of 14C-triethyleneglycol to the rat,
86-94% of the radioactivity was recovered in the urine in the subsequent
5-day period. The total excretion by way of the urine and faeces
amounted to 94-97%. Only
negligible quantities (if any) of14C were present as oxalic
acid (the completely fragmented acid). The expired air over
a 60-h period contained approximately 1% of the administered dose.
Therefore triethylene glycol is expected to pass the organism without
further metabolism. No bioaccumulation of triethyleneglycol is expected.
to REACh requirements
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 passway the alcohol metabolite TREG . All mentioned sources are
reliable (Reliability 1 or 2) so that the category/read
across approach can be done with a high level of confidence.
CAS-Nos and physico chemical properties of the above mentioned
*MW = molecular weight
**BP = boiling point
*** WS = water
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
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
C. B., Udinsky J. R., Finch L (1994). The regional hydrolysis of ethyl
acrylate to acrylic acid in the rat nasal cavity. Toxicology letters,
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
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,
Williams RT (1960). Studies in Detoxication. 80. The metabolism of
glycols. Biochemical Journal, 74: 1-5
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.
H. et al. (1961) The Excretion and Metabolism of Triethylene Glycol,
International Journal of Toxicology 25 (2), 121 - 138
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
H., Hashimoto K.(1982); Structure-Toxicity Relationship of Acrylates and
Methacrylates; Toxicol. Lett. 11: 125-129
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