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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 1964)
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. Dose group (ppm) Male Female Negative (0) 12/25 9/25 6/7 7/25 7/25 60/70 10/25 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 treatment.
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.
In 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 groups.
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 week study.
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 found.
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.
Male 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.
Mortality: Mortality 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 substance-related.
Ophthalmoscopic 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.
Haematology/ Clinical chemistry
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.
A statistically 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 observed.
No treatment-related 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.
Treatment-related 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) MMA, respectively.
No clear 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 effects.
The following 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 characterized by 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
Based on 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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