Opinion on the results of the Risk Assessment of: METHYL METHACRYLATE (2-Methyl-2-propenoic acid, methyl ester) - CAS No.: 80-62-6 - EINECS No.: 201-297-1. Report version : Draft of 07.07.2000 carried out in the framework of Council Regulation (EEC) 793/93 on the evaluation and control of the risks of existing substances1. Opinion expressed at the 22nd CSTEE plenary meeting, Brussels, 6/7 March 2001.
Terms of reference
In the context of
Regulation 793/93 (Existing
Substances Regulation), and on
the basis of the examination of
the Risk Assessment Report the
CSTEE is invited to examine the
following issues:
1. Does the CSTEE agree
with the conclusions of the
Risk Assessment Report?
2. If the CSTEE
disagrees with such
conclusions, the CSTEE is
invited to elaborate on the
reasons for this divergence of
opinion.
INTRODUCTION
Methyl methacrylate is
primarily used as a chemical
intermediate that is further
processed to polymers. Main
products are acrylic sheets,
methacrylate esters, moulding,
extrusion, emulsion and
dispersion polymers as well as
reactive resins. The substance
is used in reactive resin
preparations which are applied
in industrial and skilled trade
sectors such as in floor
coatings, adhesives and dental
products. Methyl methacrylate
may be a residual component in
paints, lacquers and varnishes.
Oral intake of small amounts of
residual monomer migrating from
food packaging materials may be
a route for consumer exposure.
Consumers may be exposed to
methyl methacrylate via
variable amounts of residual
monomer in a wide range of
applications. From plastic
products containing the methyl
methacrylate-monomer migration
of methyl methacrylate takes
place.
GENERAL COMMENTS
The health part of the
document is of excellent
quality. The CSTEE agrees with
the general conclusion that
there is a need for limiting
the risks of methyl
methacrylate concerning skin
sensitisation and respiratory
tract irritation at many
workplaces in the chemical
industry, industrial area and
skilled trade, and during use
of casting resins. In addition,
in several inhalation and
combined inhalation and dermal
exposure scenarios systemic
toxicity gives rise to concern.
The CSTEE does not agree with
conclusion ii) for workers, as
there is a need for further
testing (inhalation
sensitisation study and rodent
2-generation reproduction
study).
The environmental part
of the Risk Assessment Report
is written in a clear and
concise form. The documents
follows the recommendations of
the TGD, clarifying whether
default or specific values have
been used in the calculations.
Calculations have been excluded
from the RAR text but included
as appendices. This solution
produces a nice document, the
rationale of which can be
easily followed, and the
required transparency for
decision-making kept. The
conclusions are supported by
the CSTEE.
SPECIFIC COMMENTS
Environment
Exposure assessment
The CSTEE recognises the
efforts of the authors of the
report to use as much as
possible real exposure
estimations. The use of this
information must be encouraged.
The report concludes that
although information on real
emissions has been presented
for different production and/or
processing sites, the
information cannot be
extrapolated to all such sites.
Therefore, generic and specific
assessments have been included
in the report. The CSTEE fully
supports this approach.
Effects assessment
Aquatic organisms
The derivation of the
PNEC for aquatic organisms
follows the TGD rules and it is
acceptable. Considering the
water solubility, potential for
biodegradation, and expected
distribution, this value is
expected to protect sediment
dwelling organisms as mentioned
in the report. The toxicity for
micro-organisms is expected to
be very low.
Terrestrial organisms
Taking into account the
physical-chemical properties
and the toxicological profile
of the molecule, the use of the
equilibrium partitioning method
for the derivation of the PNEC
soil organisms, due to the lack
of toxicity results, is
considered acceptable. The
additional information on
micro-organisms confirms that
the derived value is expected
to provide enough protection.
Due to the low potential for
bioaccumulation and the
expected rapid dissipation,
secondary poisoning is not
likely to be expected.
Risk characterisation
The conclusions of
potential unacceptable risk for
wet polymerisation companies
which have not submitted
information (and therefore the
default scenario must be
applied) and four additional
sites are supported by the
CSTEE. The report suggests that
both exposure and effects
assessment can be refined; this
suggestion is also acceptable.
Although no information
on toxicity for atmospheric
exposures other than for
mammals is available,
considering the exposure
levels, the conclusion of low
risk for the atmosphere can be
supported.
Since residual methyl
methacrylate may through
seepage, as other chemicals
with a potential to leach,
reach groundwater, the CSTEE
emphasises the need for data on
possible groundwater
contamination.
Human Health
Exposure assessment
Occupational: Methyl methacrylate is primarily used as a chemical intermediate which is further processed to polymers. Main products are acrylic sheets, methacrylate esters, moulding, extrusion, emulsion and dispersion polymers and reactive resins. The formulations applied in the industrial and skilled trade sector contain up to 80% methyl methacrylate as a reactive component or as a diluent, e.g. adhesives, floor coatings and resins. Other formulations such as paints and varnishes contain residual methyl methacrylate up to a maximum 0.5%. As an input for the exposure calculations, an annual production tonnage of 470 000 within the EU has been used in the report. Of this, approximately 68% were used by producers and 15% by customers. In 1993, ca. 79 000 tonnes were exported outside the EU. Occupational exposure occurs both via the inhalative and the dermal routes. The highest inhalative exposures have been noted in various production processes and especially during floor coating. High short-term exposures may also occur in relation to certain medical applications and in dentistry.
Consumers: Polymers
manufactured with methyl
methacrylate are used in
consumer products for private
use. The sum of all types of
exposure is expected to be in
the range of 1-10 m g/kg bw/d.
Indirect: The indirect
exposure to humans via the
environment through food,
drinking water and air has been
estimated for a local and a
regional approach. The main
route of exposure is the air
with drinking water as the
second most important exposure
medium. The total dose
calculated for local exposures
is 0.13 mg/kg bw/d whereas the
total dose for regional
exposure was minimal.
Effects assessment
Methyl methacrylate is a
skin irritant in animals and
respiratory irritant in humans
and animals. Methyl
methacrylate has not been
adequately tested for skin
irritation in humans. The
comparison of the rat and human
data with respect to
respiratory tract sensitivity
do not indicate substantial
species differences. The rat
irritation threshold level of
25 ppm (100 mg/m3) does not
contradict human evidence
indicating no olfactory or
respiratory dysfunction up to
50 ppm.
There are numerous reports showing that methyl methacrylate is a skin sensitiser in certain occupational environments. The substance has also shown skin sensitisation in animal tests. There are some reports linking exposure of methyl methacrylate to respiratory allergy, but these are not convincing. The CSTEE agrees with the conclusions of the RAR that most of the respiratory symptoms and alterations in lung function that have been reported in conjunction with methyl methacrylate exposure, are due to respiratory irritation and not an immunological mechanism. However, because of the skin sensitising potential of methyl methacrylate, more studies on the mechanisms underlying asthmatic responses from exposure to methyl methacrylate should be undertaken. It is important to note that respiratory hypersensitivity is not necessarily an immediate reaction mediated by IgE, but may also be mediated by T-cells resulting in late asthmatic reactions.
In repeated dose inhalation studies with methyl methacrylate in rats and mice, the predominant target organ was the respiratory tract. In rats, the primary target tissue was the olfactory epithelium showing degeneration/necrosis at 100 ppm (equivalent to 410 mg/m3) and higher. The No-Observable-Adverse-Effect-Concentration (NOAC) was determined to be 25 ppm (equivalent to 100 mg/m3). The NOAC for systemic effects outside the respiratory tract (growth retardation) is stated in the RAR to be 100 ppm (equivalent to 410 mg/3), with a LOAEL of 400 ppm in female rats (equivalent to 1700 mg/m3) based on Rohm and Haas (1997). However, in a similar inhalation study (NTP, 1986), no growth retardation was found in female rats at 250 ppm (equivalent to 1000 mg/m3), whereas this effect was seen at 500 ppm (equivalent to 2100 mg/m3). The CSTEE finds that the NOAEL of 250 ppm determined in the NTP-study should be used as a basis for risk assessment for systemic effects, since this value reflects better the dose-response relationships in the low dose range than the Rohm and Haas-study. In shorter term experiments, neurotoxic effects were noted at inhalation concentrations of 1000 ppm (equivalent to 4200 mg/m3) and higher.
Methyl methacrylate does
not cause bacterial mutations
but induces chromosomal
aberrations at high, cytotoxic
concentrations in cultured
mammalian cells. An in vivo
micronucleus assay after oral
administration of methyl
methacrylate in mice was
negative. Three studies in rats
(one oral, two by inhalation)
could not be evaluated properly
to due deficiencies in
conducting and reporting. A
dominant lethal inhalation
study in mice was negative. The
CSTEE supports the conclusion
of the RAR that the potential
of methyl methacrylate for
clastogenic effects noted in
vitro, is probably not
expressed in vivo.
Methyl methacrylate has
been tested for carcinogenicity
after inhalation exposure in
mice, rats and hamsters. None
of the experiments showed
evidence of increased tumour
responses. Two retrospective
mortality studies and one
cohort study of persons
occupationally exposed to
methyl methacrylate showed
small excesses of some cancers
(respiratory cancer, stomach
cancer), but were of limited
reliability and cannot be
related to methyl methacrylate
as the sole causal agent. The
CSTEE agrees with the RAR
conclusion that there are no
reasons to assume that methyl
methacrylate should be
considered to be carcinogenic
in humans.
Several inhalation studies with methyl methacrylate have been conducted in rats to address developmental toxicity. No teratogenicity, embryotoxicity or fetotoxicity has been observed at exposure levels up to 2028 ppm (8300 mg/m3). Results from studies of intraperitoneal administration in rats and rabbits could not be evaluated due to deficiencies in conduct and reporting. Guideline fertility studies of methyl methacrylate are not available. However, a 2-generation study is being planned in the USA for the near future. The CSTEE agrees with the conclusion of the RAR that the available human data on reproductive toxicity in male and female workers are of questionable quality to be used in risk assessment. At present there is no evidence for a reproductive toxic potential of methyl methacrylate. This should be reassessed when the results of the 2-generation fertility study become available.
Risk characterisation
Workers: The CSTEE agrees that Margin of Safety (MOS) values with respect to respiratory irritation greater than 1 are not considered of concern, given the similar dose threshold for this effect in rats and humans. Based on MOS values equal to or less than 1, the RAR concludes that there is a need for limiting the risks for the following occupational settings due to acute respiratory irritation: Cast sheet production, production of reactive resins, production of adhesives without ventilation, production of paints, use of adhesives without ventilation, floor coating, medical applications, orthopaedic workshops without ventilation, dental laboratories and surgeries without ventilation, and ornamental decoration. There is also a need to limit the risks for most of the dermal exposure scenario. The conclusion iii) is also indicated for long-term exposure with respect to respiratory irritation for the following occupational settings: Cast sheet production, production of reactive resins, production of adhesives without ventilation, production of paints, use of adhesives without ventilation, orthopaedic workshops without ventilation, and dental laboratories and surgeries without ventilation. The CSTEE is in agreement with these conclusions.
The RAR also pointed to occupational settings where there is a concern for non-irritative systemic effects after inhalation exposure or after combined inhalation and dermal exposure. The RAR states that MOS values below 3 are judged to be of concern for systemic toxicity in occupational risk assessment and finds that there is a need to reduce the risks in the following occupational settings: Cast sheet production, production of adhesives without ventilation, production of paints, floor coating, orthopaedic workshops without ventilation, and ornamental decoration. The CSTEE finds that a revised MOS value of 7.5 (NOAEL of 250 ppm rather than 100 ppm) or less is still too low to be protective with respect to systemic effects, even for an occupational workforce. Thus, there are more occupational exposure settings which give rise for concern. However, for these settings there is also a need to reduce the risks due to respiratory irritation and to dermal sensitisation, so these additional settings are already covered by conclusion iii).
In view of the
uncertainty whether the
reported cases of asthma by
methyl methacrylate exposure
are due to irritation of the
airways or due to
sensitisation, the possibility
of inhalatory sensitisation
should be investigated in an
animal study [conclusion i)].
Since the possibility of a
reproductive toxic potential of
methyl methacrylate at present
cannot be properly assessed,
there is a need for further
testing with a rat 2-generation
study [conclusion i)].
Consumers: The CSTEE
agrees to the conclusion ii) of
the RAR for consumer exposures
and all effect types.
Indirect exposure: The
CSTEE agrees to the conclusion
ii) of the RAR for all exposure
scenarios and effect types.
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1 Regulation 793/93
provides a systematic framework
for the evaluation of the risks
to human health and the
environment of those substances
if they are produced or
imported into the Community in
volumes above 10 tonnes per
year. The methods for carrying
out an in-depth Risk Assessment
at Community level are laid
down in Commission Regulation
(EC) 1488/94, which is
supported by a technical
guidance document.