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EC number: 201-204-4
CAS number: 79-41-4
extensive data available for the methyl ester (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, 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.
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 450 μg/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
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 HPCL. The
maximum concentration was found after 10 min, whereas after 60 min no
more methacrylic acid was detectable (Bereznowski et al., 1994).
no studies which specifically address the metabolism of exogenously
applied methacrylic acid. However it is generally accepted that
methacrylic acid-coenzyme-A is a naturally occurring intermediate of the
valine pathway. Methacrylic acid-CoA is rapidly converted into
(S)-3-hydroxyisobutyryl-CoA by the enzyme enoyl-CoA-hydratase. This
pathway joins the citrate cycle, carbon dioxide, and water being the
final products (Rawn, 1983; Shimomura et al., 1994; Boehringer, 1992).”
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 GHS concentrations in URT tissues up to inhaled MAA
concentrations of 410 ppm, a concentration which causes tissue damage in
the URT in inhalation experiments.
Summary of the results for the peak rates of absorption of MAA & alkyl
methacrylate esters through rat & human epidermis
Peak rate of absorption (μg cm-2hr-1) ±SEM
Period of peak absorption rate (hours)
% age of applied dose absorbed over x hours
93% / 24h
46% / 16h
10% / 24h
18% / 24h
2% / 24h
7.8% / 30h
0.6% / 24h
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
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).
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.
readily absorbed by all routes and 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 may
be observed at the site of contact, because of the irritating/corrosive
properties of MAA.
References quoted from the EU
ESR on MAA, but not copied into the IUCLID dataset:
(1992). Biochemical Pathways,.
DJ (1983). Biochemistry, catabolism of amino acids, succinyl-CoA family.
Harper and Row Pub., 843-845.
Y, Murakami T, Fujitsuka N, Nakai N, Sato Y, Sugiyama S, Shimomura N,
Irwin J, Hawes JW, Harris RA
(1994). Purification and partial characterization of
3-Hydroxyisobutyryl-Coenzyme-A hydrolase of rat-liver, J. Biol.
Chem., 269, 14248-14253.
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