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EC number: 230-241-9
CAS number: 6976-93-8
Repr. 1 B
(fertility effects) = 20 mg/kg bw/d (read-across from metabolite 2
experimental data on MTMA are available for the assessment of fertility
effects. However, studies are available for the metabolites
2-methoxyethanol and methacrylic acid. A detailed justification for
read-across is attached to IUCLID section 13.
for the analogue approach
read across hypothesis relies on the observation that alkyl esters are
rapidly hydrolysed by carboxylesterase enzymes within the body to
release methacrylic acid (MAA) and free alcohol. Local effects,
including genotoxicity and sensitisation, if they occur are likely to be
due to electrophilic reactivity of the parent ester 2-methoxyethyl
methacrylate (MTMA). Due to the short half-life of the parent ester
within the body systemic exposure to parent ester is extremely unlikely
so the observed systemic toxicity profile is determined by the systemic
toxicity profile of the primary metabolites Methacrylic acid (MAA) and
read-across hypothesis corresponds to scenario 1 – biotransformation to
common compounds – of the read-across assessment framework) i.e.
properties of the target substance are predicted to be quantitatively
equal to those of the source substance. Namely, the metabolites
Methacrylic acid and 2-methoxyethanol predict the toxicological
properties of the parent compound MTMA.
on the available experimental data, including data from acute toxicity
and genotoxicity studies, the read-across hypothesis is supported by
close structural analogy and similar toxicological profile of the
1.1 Formation of common (identical) compound(s)
focus of this AE is on the scientific explanation and documentation on
how the (bio)transformation from source and target substances to the
common compound(s) occur. It will be shown that biotransformation from
parent ester to primary metabolite occurs rapidly within the body and
that the ensuing metabolism of these primary metabolites is well
understood thereby providing a high confidence in the assertion that the
metabolites alone influence systemic toxicity alone.
oral or inhalation administration, methacrylate esters are expected to
be rapidly absorbed via all routes and distributed. Dermal absorption of
esters is extensive only with occlusion of the site. Heylings (2013)
used a QSPeR model for whole human skin based on that described by Potts
and Guy (1992) to predict the dermal penetration rate of a large number
of methacrylate esters, including MTMA (Heylings, 2013). For MTMA a low
rate of dermal penetration is predicted (1.366µg/cm²/h).
seem to be similar in man and experimental animals. MMA and other short
chain alkyl-methacrylate esters are initially hydrolyzed by non-specific
carboxylesterases to methacrylic acid and the structurally corresponding
alcohol in several tissues, including but not limited to liver,
olfactory epithelium, stratum corneum and blood. This has been shown for
linear alkyl esters, several ether methacrylates, diesters as well as
cycloalkyl and -aryl esters (Jones 2002, DOW 2013, McCarthy and Witz,
1997). Because of the structural similarity of MTMA to the other esters
rapid hydrolysis is expected in the order of minutes.
acid (MAA) is subsequently cleared predominantly via the liver (valine
pathway and the TCA (Tricarboxylic Acid) cycle).
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. 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.
is mainly metabolized to methoxyacetic acid and excreted via the urine
(Mebus et al, 1992; Miller RR, 1987).
pathway: GSH Conjugation
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 (Cronin, 2012, Freidig et al.
1999). Hence, 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.
fast hydrolysis observed for other Methacrylic acid esters is predicted
to occur also for MTMA. Thus, following systemic exposure to MTMA the
organisms will be mainly exposed to the metabolites Methacrylic acid and
this basis the systemic biological targets for the common compound(s)(AE
1.2) and the exposure of these systemic biological target(s) to the
common compound(s) (AE 1.3) will be the same for MTMA as they are for
the primary metabolites.
since carboxylesterases are widely distributed throughout the body and
the half-life of the parent ester is very short the impact of parent
compound (AE 1.4) is unlikely to be significant other than at the site
of initial contact. Indeed, local hydrolysis at the site of contact is
likely to be very rapid thereby minimising exposure to parent ester even
at local targets. Since the source and target compounds are
monoconstituents of high purity there are no impurities worthy of
consideration. Finally, since the hydrolysis of the parent ester to
Methacrylic acid and 2-methoxyethanol is equimolar and does not involve
the formation of non-common compounds (AE 1.5) (including possible
intermediates) their possible impact on the property under consideration
does not have been considered.
experimental data are available for the target substance MTMA. However,
based on the proposed hypothesis read-across from the metabolites
methacrylic acid and 2-methoxyethanol is proposed.
Assessment by Continuous Breeding" (RACB) protocol was originally
designed using mice as the test species. The purpose of the present
study was to develop a RACB protocol in CD Sprague-Dawley rats.
2-methoxyethanol, a known reproductive toxicant, was used as the test
Toxicity of 2-methoxyethanol in Sprague-Dawley Rats, Litter Two:
levels selected were 0.01, 0.03, and 0.10%, administered via drinking
water. In a modification of the standard protocol, male and female rats
~20 pairs per treatment group, 40 pairs of control animals) were
cohabited for approximately 6 weeks, separated to allow delivery,
nursing and weaning of the second litter, then re- cohabited for
approximately nine more weeks. The weaned second litter was used for F1
reproductive testing. The control and 0.03% F0 pairs were also utilized
for a crossover mating trial to determine the affected sex.
one litter was born in the 0.10% dose group, and no pups were available
for F1 testing. At 0.03% level of EGMME, number of live pups per litter
and proportion of pups born alive decreased significantly, both in F0
and F1 testing. In the crossover mating, proportion of pups born alive
decreased significantly in the 0.03% male X control female group.
Declining control F0 fertility and productivity noted in this study
indicate that the standard RACB design (weaning last rather than second
litter) is better suited to use with rats.
Toxicity of 2-methoxyethanol in Sprague-Dawley Rats, Litter Five:
levels selected were 0.006, 0.012, and 0.024%, administered via drinking
water. Male and female rats (20 pairs per treatment group, 40 pairs of
control animals) were continuously exposed for a 7-day pre-cohabitation
period and 112-day cohabitation (Task 2).
there was no decrease in average litter size with increased dose, the
number of live male pups per litter and the total number of pups per
litter were decreased in the 0.024% group. Both absolute and adjusted
live pup weight were increased in all EGMME groups, but this was not
dose-related. During the cross-over mating to determine the affected
sex, there were fewer live male pups born to the 0.024% male X control
female pairs. During the mating trial for the second generation, fewer
male and total pups were delivered in the high-dose group, and both
absolute and adjusted pup weight were increased in the middle and high
dose groups. Low control fertility (63% fertile) during the cross-over
mating is a cause for concern, however suggested protocol changes should
alleviate some of this problem.
NOAEL of 2-methoxyethanol was 0.01% in drinking water (11 mg/kg bw/d) in
when administered to male rabbits for 12 weeks via drinking water
produced a marked inhibition of normal spermatogenesis. The
effect is marked with a NOAEL of 12.5 mg/kg and a LOAEL of 25 mg/kg. The
effect is very specific with no clear effects on sperm morphology and no
effect on the ability of the sperm that remain to fertilize a female
other adverse effects that could be attributed to treatment were
observed at the LOAEL.
a 90 d inhalation study with methacrylic acid histopathology of the
sexual organs and additional fertility parameters were investigated. Up
to 350 ppm (1232 mg/m³) no effects were seen on gross pathology
including organ weights, histopathology, sperm motility or sperm
metabolite mainly determining reproductive toxicity is 2-methoxyethanol.
Thus, the overall NOAEL for the endpoint toxicity to reproduction
(fertility effects) is based on the NOAEL of 11 mg/kg bw/d obtained in a
study according to the Continuous breeding protocol. The NOAEL of MTMA
for effects to fertility is 20 mg/kg bw/d (extrapolated based on
are no data gaps for the endpoint fertility. There is no reason to
believe that the results would not be relevant to humans.
(embryotoxicity) = 20 mg/kg bw/d (read-across from the metabolite
experimental data on MTMA are available for the assessment of
developmental toxicity. However, studies are available for the
metabolites 2-methoxyethanol and methacrylic acid. A detailed
justification for read-across is attached to IUCLID section 13.
No significant increase in embryo/fetal lethality or fetal
malformations were observed after exposure to methacrylic acid.
While maternal toxicity was observed, methacrylic acid caused no
evidence of developmental toxicity up to 300 ppm.
metabolite mainly determining developmental toxicity is
2-methoxyethanol. Thus, the overall NOAEL for the endpoint toxicity to
reproduction (developmental toxicity) is based on the NOAEL of 11 mg/kg
bw/d obtained in a study according to the Continuous breeding protocol.
The NOAEL of MTMA for effects to fertility is 20 mg/kg bw/d
(extrapolated based on molecular weight).
are no data gaps for the endpoint prenatal developmental toxicity. There
is no reason to believe that the results would not be relevant to
on the available data, MTMA is classified as Repr. 1B (H360FD)
according to the criteria given in regulation (EC) 1272/2008
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