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EC number: 202-597-5
CAS number: 97-63-2
For EMA, no repeated dose studies are available. However, EMA is
rapidly hydrolyzed to Methacrylic acid (MAA) and Ethanol (see chapter
Toxicokinetics or Category document chapter 5). There are reliable
chronic or subchronic studies from Methyl methacrylate (as MAA donor
substance) and Ethanol which allow the assessment of repeated dose
toxicity of EMA after oral and inhalative administration:
MMA, chronic, rat, drinking water (2 yrs) NOAEL 2000 ppm (124/ 164
mg/kg bw/d for males/ females; no adverse effects observed; Borcelleca
EtOH, subchronic, rat, feed (90 d) NOAEL 2% (2400 mg/kg bw/d due
to histopathological liver findings; Holmberg 1986)
MAA, 90 d rat: NOAEC 100 ppm (BASF 2008)
MMA, chronic, rat (2 yrs) NOAEC 500 ppm (2080 mg/m3; due to
histopathological brain findings; NTP 1986)
For systemic effects, the NOAEC for EMA was not derived. Instead,
the DNEL for EMA is derived by interpolation between the DNELs based
upon the MMA 2-year oral and inhalation studies and the DNELs based upon
the oral 90 d study and the 28 d inhalation study on n-BMA.
MMA, 2 yr rat: NOAEC 25 ppm (104 mg/m3; Lomax 1997); However, the
EU ESR (2002) and SCOEL review (2005) recognised differences between
rodents and humans regarding the physiology of the nasal passages,
metabolic activity result in the greater susceptibility of rodents
compared with humans to inhaled esters. Consequently, a value of 50 ppm
(SCOEL, 2005) is regarded as being the NOAEC(=DNEL) in humans.
n-BMA 28 d rat; 310 ppm (1832 mg/m3; Rohm & Haas 1993)
Ethanol, occupational health assessment, human: 500 ppm (960
mg/m3; BAuA 2017)
For local effects, the NOAEC for EMA is interpolated between the
human NOAEC (IOLV documentation) derived by SCOEL (2005) for MMA and the
NOAEC in the 28 d inhalation study with n-BMA (Rohm & Haas, 1993)
Mortality: A summary of the mortality data for methyl methacrylate
is presented below.
group (ppm) Male Female
(0) 12/25 9/25
6/7 7/25 7/25
2000 12/25 10/25
No statistical differences were noted in the
mortality of the animals exposed to methyl methacrylate and those in the
control group. A statistically significant decrease in body weight was
observed in the first week for the female rats and in weeks one through
three in the male rats administered 2000 ppm methyl methacrylate. Water
consumption was reduced in the animals from the high-dose group;
however, it was reported that this finding tended to regress towards the
end of the study. Food consumption was not affected by the
administration of methyl methacrylate in the drinking water.
Hematologic values varied within normal ranges in all groups of
rats throughout the study, and urine concentrations of protein and
reducing substances showed no trends that appeared relatable to
Organ to body weight ratios obtained at sacrifice of 2-year
survivors differed from the controls only in significantly increased
kidney ratios in female rats receiving 2000 ppm of methyl methacrylate
(controls 0.0082 ± 0.0019; treated 0.0094 ± 0.0011).
Histopathologic findings showed no abnormalities or lesions, in
kind or incidence, not explicable on the basis of naturally occurring
ones in this strain of rat at this age.
Diet equivalents of the test materials were calculated from the
fluid and food consumption data.
these calculations, corrections were not made for evaporation losses of
the test materials from the drinking water, the orders of magnitude of
which are given under methods described above (maximum 15%). Allowing
for such losses, it would appear that the concentrations of test
materials in the drinking water were equivalent to approximately 10,
100, and 3000 ppm in the diet.
No relevant effects were observed after exposure of rats in drinking
water up to the highest dose tested (2000 ppm, limited by palatability).
This study was selected from a larger set of repeated dose studies with
ethanol, as this study was selected by OECD SIDS (2004) as good quality
supporting study with the lowest reliable NOAEL.
In a valid guideline study acc OECD 413 (
Subchronic inhalation toxicity: 90 day exposure of rats) methacrylic
acid induced signs of general toxicity as indicated by descreased body
weight, body weight gain, food consumption and transiently food
efficiency in the high concentration male animals. At a concentration as
high as 350 ppm (1232 mg/m³), the local irritating effect was marginal,
indicated by the hypertrophy/hyperplasia of the respiratory epithelium
in the nasal cavity of two female animals. Substance-related changes of
the sexual organs were not noted in any of the exposed animals, nor were
there any changes of sperm mobility and sperm head counts. Under the
current test conditions, the no-observed adverse effect level (NOAEL) in
this study is 100 ppm (352 mg/m³) for the male and female rats.
NOTE: Any of data in this dataset are disseminated by the European
Union on a right-to-know basis and this is not a publication in the same
sense as a book or an article in a journal. The right of ownership in
any part of this information is reserved by the data owner(s). The use
of this information for any other, e.g. commercial purpose is strictly
reserved to the data owners and those persons or legal entities having
paid the respective access fee for the intended purpose.
Mortality: No difference in survival between treated and untreated
Site / Lesion
Nasal Cavity /
Olfactory sensory epithelium /
Focal or multifocal fibrosis
No histopathological findings other than local findings in the
respiratory tract. Systemic histopathological effects, as for example in
the brain in females particularly at 2000 ppm and above in the
subchronic range finding study (Batelle, 1980), are absent in this 104
Body weight: Mean body weight gain was reduced in females at 500 ppm
resulting in 6 -11% lower body weights after week 73 and in males at
1000 ppm which were 5 -10 % lower than controls after week 81.
There was no treatment-related increase in tumour incidence.
In this104-week study
with groups of 50 animals each, male rats were treated with MMA vapour
by whole-body exposure to 500 or 1000 ppm while female rats were exposed
to 250 or 500 ppm.
The primary finding was
inflammation of rat nasal cavity as well as olfactory epithelial
degeneration at all exposure levels in male and female rats. For local
effects the LOAEC was 250 ppm in this study while a NOAEC could not be
In contrast to the 90 d
range finding study with histopathological changes in females at
exposures of 1000 ppm and above (Battelle, 1980), no other significant
histopathological changes were reported in male and female rats after
104-week exposures to MMA vapour in this study. Based on this a NOEC for
systemic effects of 500 ppm is derived.
and female rat body weights were lower at the 1000 ppm (5-10%) and 500
ppm (6-11%) exposure levels, respectively, presumably due to reduced
food consumption due to nasal irritation and damage of olfactory
epithelium. While food consumption was not recorded in this study this
association is confirmed by two other studies, the developmental
toxicity study with MMA with reduced food consumption and reduced body
weight gain at concentrations higher than 99 ppm (Solomon, 1993) and a
subchronic inhalation study with methacrylic acid where there was also
an association of irritative effects in the nose and reduced food
consumption and reduced body weight gain (BASF, 2008). Consequently,
reduced body weight gain, while clearly treatment-related - is
considered to be secondary to the local effects in the nose and not the
result of true systemic toxicity.
1. Original study
(Reno FE, 1979):
The mean analytical
concentration was evaluated. The overall mean concentrations of MMA
vapour were 25.0, 99.8 and 396.1 ppm for the 25, 100 and 400 ppm
exposure groups, respectively.
rates were relatively low through week 78. High mortality was observed
through week 104. The author indicates that the increase in mortality
was probably due to aging, not related to test substance exposure. The
mortality rates for treated groups were comparable to the control group.
A summary of the mortality rates (%) is provided below.
Dose group (ppm)
Negative Control (0)
No signs of test
substance-related toxicity were observed in any of the treated animals
throughout the 104-week exposure period. The most frequent observations
included cloudy eye(s) and bloody crust around one or both eyes. The
author reported that these findings occurred with approximately the same
frequencies in treated and control groups.
Male body weights were
significantly higher in the mid-level exposure group at week 24, lower
weights in the low-level exposure group at week 104, and lower weights
of the high-level exposure group at weeks 28 and 78. In the females, the
low-level exposure groups showed a significant decrease in body weight
at weeks 60, 72 and 78 and an increase at weeks 12 and 24. The females
in the mid-level exposure group showed a significant decrease at weeks
52, 60 and 78 and in the high-level exposure group at weeks 28, 36, 52,
60, 72, 78 and 90. The author concluded, the body weight reduction
observed in the females exposed to ca. 1.64 mg/L (400 ppm) MMA was test
observations were noted at weeks 13, 52 and 102. The author reports that
no consistent ocular abnormalities were noted at weeks 13 and 52. Ocular
findings noted at week 102 included cataracts, pale coloration, corneal
cloudiness and red discharge. The cataract findings were considered to
be caused by aging.
Evaluation of the
haematology and clinical chemistry data did not reveal any remarkable
trends. Statistical analyses showed numerous significant differences
between the treated and the control groups; however, these differences
were considered sporadic and were considered by the author a reflection
of sampling and biological variability. A transitory appearance of
occult blood was observed in all groups at week 52. All remaining
intervals were generally unremarkable.
significant increase in absolute and relative organ weights of the
females exposed to ca. 1.64 mg/L (400 ppm) MMA was observed in the
lungs, liver, kidneys, and ovaries at week 13. A statistically
significant decrease in absolute and relative thyroid and adrenal
weights were observed in both males and females in the high-level
exposure group at week 52. Absolute thyroid and adrenal weights were
significantly higher in the males exposed to ca. 0.41 mg/L (100 ppm),
MMA for 52 weeks. Other significant differences were noted at weeks 52
and 104; however, the author concluded that no consistent dose-related
pattern was established.
Findings noted in
animals that were sacrificed at weeks 13 and 52 were mainly
discolorations of the lung and liver. None of the findings were
considered treatment-related. Tissue mass findings for animals
sacrificed at week 104 were typical for the age and the species of rats.
No treatment-related differences with respect to the frequency were
histopathological findings were noted in the rats exposed to ca. 1.64
mg/L (400 ppm) MMA for 13 weeks. Findings were consistent among groups
and were typical for rats of this age and strain.
histopathological findings were limited to a very slight increase in the
lesions of mild rhinitis observed in the mucosal lining of the nasal
turbinates. A summary of the lesions is provided below.
Incidence of Lesions
in Nasal Mucosa
No. of Nasal Turbinates Examined
Distended Submucosal Glands
Squamous Metaplasia (focal)
*Groups 1, 2, 3 and 4
were exposed to ca. 0, 0.10, 0.41 and 1.64 mg/L (0, 25, 100 and 400 ppm)
treatment-related effect could be established. Although lesions of mild
rhinitis occurred more often in treated rats than control rats, it could
not be determined if the rhinitis was a result of direct chemical insult
to the turbinate area or whether the presence of MMA vapors predisposed
the rats to an increase in spontaneous disease. [NOTE - Subsequent
evaluation of the nasal lesions (Lomax et al., 1997) indicated that
there were exposure related nasal lesions at ca. 0.10 and 0.41 mg/L (100
and 400 ppm)]. Neoplasms and spontaneous disease lesions were observed
with comparable frequency in control and treated rats. Chronic nephritis
was observed in most rats; however, it was more pronounced in males.
2. Re-Evaluation of
the study (Lomax LG et al. (1997)):
The mean analytical
concentrations of the test substance in the exposure chambers were 25.0,
99.8 and 396.1 ppm less than 10% per dose level.
Mortality rates for
the treated animals were similar to those of the controls. No signs of
treatment-related toxicity were observed. At the 13, 52 and 104-week
observation intervals, cloudy eyes and bloody crusts around one or both
eyes were noted in all of the treatment groups, as well as the control
animals. Body weights for males were lower than the control at various
intervals but overall were considered equivalent over the 104-week
period. Mean body weights for females were lower than the controls at
ca. 1.64 mg/L (400 ppm) after week 52. Haematology, clinical chemistry
and urinalyses did not indicate any treatment-related effects in any of
the parameters evaluated.
Gross necropsy of the
rats sacrificed at weeks 13 and 52 did not show any treatment-related
information was obtained from the reevaluation of the nasal tissues from
this study originally conducted by Reno et al.(1979) - see also summary
for this study in this Dossier. Microscopic evaluation of the nasal
cavity sections obtained from the animals exposed to the test substance
for 13 weeks showed degeneration of the neuroepithelial cell lining of
the dorsal meatus in conjunction with atrophy of Bowman's glands and
focal basal cell hyperplasia. Lesions were identified on the tips of the
maxilloturbinates and nasoturbinates and focally along the nasal septum
in the more anterior regions of the nose. These lesions were
chronic active inflammation, respiratory epithelial hyperplasia and
squamous metaplasia. No microscopic findings were identified in the
ocular tissue or the lungs or other tissues. Blocks of the nasal
cavities of animals from the 52-week sacrifice were unable to be located
and, therefore, were not evaluated. No new findings were identified in
the tissues that were available for animals exposed to the test
substance for 52 weeks. Spontaneous disease lesions included early
respiratory disease in both the control animals and the animals exposed
to 400 ppm of the test substance. Also focal areas of pneumonitis were
observed in two females in the control group.
Gross necropsy after
two years of exposure to the test substance showed no treatment-related
effects. The nasal cavity was the target organ for chronic toxicity.
Rats exposed to the 100 and 400 ppm dose group had dose-dependent
lesions in the anterior portions of the nasal cavity. The olfactory
epithelium lining the dorsal meatus in the anterior region of the nasal
cavity was affected by exposure to higher concentrations of the test
substance. The microscopic changes consisted of degeneration of the
olfactory epithelium and underlying Bowman's glands, hyperplasia of
basal cells, replacement of olfactory epithelium by ciliated epithelium
and inflammation of
the mucosa and/or
submucosa. Lesions tended to be bilateral in distribution. The olfactory
lesions in rats exposed to 100 ppm were localized in the more posterior
(level 3) portion of the dorsal meatus, while those in animals exposed
to ca. 1.64 mg/L (400 ppm) were found in levels 2 and 3. Hyperplasia of
glands in the lamina propria and/or goblet cells and inflammation of the
mucosa/lamina propria were observed in the respiratory epithelium in the
high exposure group animals. No effects were seen in nasal epithelium of
rats exposed to ca. 0.10 mg/L (25 ppm) MMA. No statistically significant
differences were observed in the frequency of tumours between the rats
exposed to ca. 1.64 mg/L (400 ppm) of the test substance and that of the
controls. In female rats exposed to ca. 1.64 mg/L (400 ppm) of the test
substance, a statistically significant decrease in pituitary
adenoma/carcinomas and mammary gland fibroadenomas was recorded. In male
rats, a decreased incidence of pheochromocytoma was observed.
For the assessment by the oral route reference is made to the
2-year study on MMA and the 90 d study on n-BMA.
In an early 2-year chronic drinking water study with 25 male and
25 female rats administered with 6, 60 and 2000 ppm MMA no adverse
effect were observed other than elevated kidney weights without
corresponding histopathology in female rats at 2000 ppm (Borzelleca et
al., 1964). The NOAEC was reported as 2000 ppm (124/164 mg/kg bw/d) in
male and female rats.
In an OECD guideline 408 90-day gavage study in Wistar rats with
n-BMA, with a recovery period of 28 days, revealed general signs of
liver and kidney toxicity at 360 mg/kgbw/d, with a NOAEL of 120 mg/kg
body weight/day for systemic effects in both males and females. Local
degenerative and regenerative effects in the olfactory epithelium of the
nasal cavity were observed in the 360 mg/kg bw/day and 120 mg/kg bw/day
animals. The NOAEL for these effects was 60 mg/kg body weight/day in
both males and females. This substance-related effect was completely
reversible by 28 days after cessation of exposure. Therefore, the no
observed adverse effect level (NOAEL), under the conditions of the
present study, was 120 mg/kg body weight/day for systemic effects and 60
mg/kg body weight/day for local effects in the nose in both sexes.
Most (repeat dose) data available on ethanol is via the oral route
of exposure. Much is at high doses which limits its value to risk
assessment of ethanol as a chemical substance. From the data available,
it is possible to surmise that ethanol is of repeat dose low toxicity by
the oral route, with a lowest reported NOAEL in a 90 d feeding study of
2400 mg/kg for rats (Holmberg et al. 1986, in OECD SIDS, 2004).This
rather continuous administration type is considered as more suitable
than bolus dosing per gavage for both, occupational exposure
considerations and the interpretation of ethanol as a metabolite of EMA.
For the assessment for local effects by the inhalation route
reference is made to the Human NOAEL derived in the SCOEL review and the
28d inhalation study on n-BMA. For systemic effects by the inhalation
route reference is made to the 2-year NTP study on MMA and the 28d
inhalation study on n-BMA.
MAA: In an OECD 413, 90-day vapour inhalation study in Sprague
Dawley rats with MAA revealed general toxicity at 350 ppm (1253 mg/m3)
in male animals. Local, marginal irritation of the respiratory
epithelium in the nasal cavity was observed in two female animals. The
NOAEL was 100 ppm (358 mg/m3) for local irritation effects in male and
females (BASF 2008).
MMA: From the chronic inhalation studies on MMA in rodents the
NOAEC for local effects in the nose was 25ppm and the LOEC was 100 ppm
(Lomax et al. 1997). However, the recognised differences between rodents
and humans regarding the physiology of the nasal passages, metabolic
activity result in the greater susceptibility of rodents compared with
humans to inhaled esters. In the EuRA (2002) these differences were
disregarded and rodents were regarded being of comparable sensitivity to
humans. Subsequently, in the SCOEL review (SCOEL, 2005) greater emphasis
was placed on human data, showing the absence of adverse respiratory
effects up to at least 50 ppm and this was considered to be consistent
with rodents being at least three times more sensitive than humans based
on PBPK considerations (Andersen et al. 2002, Mainwaring et al. 2001).
Ethanol: There are no robust chronic inhalation studies for
ethanol. Major health-based occupational exposure standards are in
excess of 500 ppm (960 mg/m³) indicating that ethanol is of low
inhalation toxicity for both, local and systemic effects (BAuA 2017).
nBMA: In an OECD Guideline 412 Repeated Dose 28-day inhalation
study with n-BMA treatment-related effects included lacrimation, eye
squinting, and laboured breathing in the 952 and 1891 ppm (5626 and
11175 mg/m3) concentration groups throughout the study. Local effects of
inflammation of the olfactory region of the nasal cavity at 952 and 1891
ppm (5626 and 11175 mg/m³) were observed in both sexes. The NOAEC was
310 ppm (1832 mg/m3; Hagan et al., 1993).
MAA: In an OECD 413, 90-day vapour inhalation study in Sprague
Dawley rats with MAA revealed general toxicity at 350 ppm (1253 mg/m3)
in male animals. The NOAEL for systemic effects based upon reduced body
weight gain in the presence of reduced feed intake but no other systemic
effects was 100 ppm (358 mg/m3) in male and females.
MMA: In a two-year chronic inhalation studies of MMA the only
systemic effects observed was reduced mean body weights (6-11 % in week
73) in female rats at 500 ppm (2080 mg/m3) and male rats at 1000 ppm
(NTP, 1986). As this effect was likely the result of reduced food
consumption and therefore not a true adverse effect the observation of
malacia and gliosis of the brain in the 14 week range finder to the NTP
study (Battelle, 1980) is considered being the relevant systemic effect.
This was observed in 5/9 female rats exposed at 2000 ppm and 1/8 females
at 1000 ppm. Therefore, the absence of this effect at 500 ppm (2028
mg/m³) in the corresponding 2-year study (NTP) is considered
representing the NOAEC for chronic systemic effects of MMA.
There are no relevant dermal repeated dose studies. For assessment
purposes the oral data are used with a route-to-route extrapolation
factor of 1.
Repeated dose toxicity: inhalation - systemic effects (target
organ) respiratory: nose
the available information, the potential of ethyl methacrylate for
systemic toxicity after repeated dosing is low. Hazards based on local
effects were covered by the classification for the irritation potential
on skin and respiratory tract (see chapter 7.3). Therefore, no
additional classification is considered as justified.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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