Methyl methacrylate

Carcinogenicity

Description of key information

Inhalation

Groups of 50 male F344/N rats were exposed to methyl methacrylate (purity >99%; containing 0.04 mg/1 equivalent to 10 ppm monomethylethyl ether of hydroquinone as an inhibitor of polymerization) by inhalation at ca. 0, 2.05 and 4.1 mg/L (equivalent to 500 or 1000 ppm), female F344/N rats at ca. 0, 1.03 or 2.05 mg/L (equivalent to 250 or 500 ppm) and male and female B6C3F1 mice at ca. 2.05 or 4.1 mg/L (equivalent to 500 or 1000 ppm), 6 hours a day, 5 days a week for 102 weeks (NTP, 1986). No significant differences of the survival rates were observed between any groups of rats and mice. Reductions in mean body weights of high dosed animals were considered as secondary effects based on the observed inflammations and degenerations of the olfactory epithelium in all MMA treatments. The marginal increase in the incidence of mononuclear-cell leukaemia observed in female rats (control 11/50; low-dose 13/50; high-dose 20/50) fell within the range of values seen in historical controls. Both in mice and rats no treatment-related tumours were observed.

No treatment-related increases in tumour incidence occurred in Golden hamsters with groups of 53-56 males and 56-59 females exposed to ca. 0, 0.103, 0.41 and 1.64 mg/L (0, 25, 100 or 400 ppm) MMA 6 h/d, 5 d/wk for 78 weeks (no interim sacrifice). At the high-dose, body weight decreased and mortality increased in high dose males (Rohm and Haas, 1997). There were no clinical signs or haematological effects attributable to exposure to methyl methacrylate at either the 52- or 78-week sampling times. No gross haematological changes indicative for a possible exposure-related effect were observed.

 

Oral

An early 2-year chronic study on rats treated orally with MMA revealed no adverse effect other than slightly elevated kidney weights in high-dose female rats (Borzelleca et al., 1964) . A similar 2 -year study in dogs suffers from a low number of animals per dose and short study duration, but revealed also no adverse effect other than a lower body weight gain in high-dose animals (Borzelleca et al., 1964).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reason / purpose for cross-reference:

reference to same study

Specific details on test material used for the study:

source: Rohm & Haas company, Philadelphia
stabilized with 10 ppm monomethylether of t-butylhydroquinone

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: "young" (unspecified)
The  animals were individually housed and provided food (finely ground Purina Dog Chow Kibbled Meal; questionable information in the publication) ad libitum
- rats were individually caged and weighed once a week

Details on analytical verification of doses or concentrations:

.

Details on study design:

.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Rats receiving 2000 ppm methyl methacrylate did not continue to loss body weight beyond the first few weeks of the study.

Food consumption and compound intake (if feeding study):

no effects observed

Haematological findings:

no effects observed

Urinalysis findings:

no effects observed

Description (incidence and severity):

Urine concetrations of proteins and reducing substances varied within normal limits in all groups of rats.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Organ to body weight ratios obtaincd at sacrifice of 2-year survivors differed from the controls only in significantly inereased kidney ratios in female rats receiving 2000 ppm of methyl methacrylate.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathologie 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.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Histopathologie 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.

Details on results:

Result (carcinogenicity): negative
With the exception of an increased kidney/body-weight ratio in female rats exposed to ca. 8.2 mg/L (2000 ppm) MMA there were no effects on organ body weight ratios. Histopathological examination of the tissues of exposed rats showed no compound related abnormalities or lesions. The change in kidney/body-weight ratio in the females treated at ca. 8.2 mg/L (2000 ppm) is considered to be a functional adaptation in response to the significantly reduced water intake.

Dose descriptor:

NOAEL

Effect level:

>= 90.3 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects observed

Remarks on result:

other: Effect type: carcinogenicity

Dose descriptor:

NOAEL

Effect level:

>= 193.8 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed

Remarks on result:

other: Effect type: carcinogenicity

Dose descriptor:

NOAEL

Effect level:

>= 2 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Remarks on result:

other: Effect type: carcinogenicity

 

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.

Conclusions:

Methyl methacrylate did not show carcinogenic effects in a 2 years study in rats by oral administration in drinking water.

Executive summary:

A two years toxicity study was performend in 1964 to study the tolerance of animals to chronic ingestion of methyl methacrylate. Methyl methacrylate did not  show carcinogenic effects in a 2 years study in rats by oral administration in drinking water.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

90.3 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Pre guideline study. Only Summary in literature available. One oral 2 years study in rats avaiable. Another oral 2 years study in dogs of the same author, pulished 1964.

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reason / purpose for cross-reference:

reference to same study

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6-5486; 377109
- Expiration date of the lot/batch 28.01.1981
- Purity test date: > 99 %
- water content: < 0.1 %
- Supplier: Rohm&Hass, Co (Philadelphia)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in steel drums at room temperature
- Stability test:periodically analyzed by IR-spectroscopy and gas chromatograpy during the test period, stabel for 2 weeks at 60 °C
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

Route of administration:

inhalation

Post exposure period:

no

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No significant differences were observed in mortality for any of the exposure groups when compared to that of the controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of both male and female mice at both concentrations were lower than those of the controls throughout most of the study (males: up to 16% lower mean body weight; females: up to 17%).

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Acute and chronic inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity occurred at increased incidences in male and female mice exposed to the test substance. Accumulation of homogeneous, eosinophilic material in the cytoplasm of cells, primarily of the respiratory epithelium (cytoplasmic inclusions) was significantly increased in treated animals when compared to that of the controls.
Uterine adenocarcinomas were reduced in animals from both of the treatment groups, but statistical significance was not observed.
In the lungs, interstitial inflammation was increased in the male mice from the high-group, while alveolar/bronchiolar adenomas and alveolar/bronchiolar adenomas and carcinomas (combined) were significantly reduced in the male mice exposed to 500 and 1000 ppm. Pituitary gland adenomas and adenomas and adenocarcinomas (combined) were significantly reduced in the female mice in each of the treatment groups. Hepatocellular adenomas and hepatocellular adenomas and carcinomas (combined) were significantly reduced in males and female mice exposed to the test substance relative to the controls.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related tumors were observed

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed; corresponding to 1000 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no biologically relevant adverse systemic effects observed; corresponding to 1000 ppm

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

ca. 2.05 mg/L air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: inflammation, epithelial hyperplasia, cytoplasmic inclusions in the epithelial cells, and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 500 ppm

Remarks on result:

other:

Remarks:

Effect type: other: local toxicity (migrated information)

Critical effects observed:

no

Effects on body weight gain. Reduced body weights of the high dosed animals by maximum 17% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Conclusions:

In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice methyl methacrylate did not induce neoplasms in the highest doses testd (1000 ppm/males and females)

Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in B6CF31 mice with methyl methacrylate50 males and 50 females of each species male and female mice were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation.

 

Animals were exposed 6 hrs/d, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination performed on all animals . The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in mice in the highest doses tested (1000 ppm, males and females)

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reason / purpose for cross-reference:

reference to same study

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 6-5486; 377109
- Expiration date of the lot/batch 28.01.1981
- Purity test date: > 99 %
- water content: < 0.1 %
- Supplier: Rohm&Hass, Co (Philadelphia)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in steel drums at room temperature
- Stability test:periodically analyzed by IR-spectroscopy and gas chromatograpy during the test period, stabel for 2 weeks at 60 °C
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Post exposure period:

no

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No significant differences were observed for mortality in any of the exposure groups when compared to that of the controls.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of the males in the 1000-ppm group were 5 - 10% reduced from that of the control group after week 81 and the mean body weights of the females in the 500-ppm group decreased by 6 - 11% from that of the controls after week 73.
Remark: Reduced body weights of the high dosed animals by maximum 11% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

A statistically significant positive trend in the incidence of mononuclear cell leukemia occurred in female rats exposed to 500-ppm (incidence of 22%, 26% and 40% for the control, 250 ppm and 500 ppm groups, respectively). However, life table analysis, which can be regarded as more appropriate for life-threatening lesions, showed no difference. The incidence of mononuclear cell leukemia in the three groups of male rats was not statistically different by life table analysis.
Remark: Mononuclear cell leukemia has a high spontaneous incidence in Fischer 344 rats. Based on the lack of statistical significance and the normal occurrence of this neoplasm, the increased incidence was not considered biologically significant. In support of this conclusion, a classification of the leukemia into three stages of severity showed that there were no differences in the characteristics of the leukemia between the exposed and control females, and, further, there 
was no increase in this neoplasm in males exposed to 1000 ppm MMA.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Pituitary and preputial gland adenomas were significantly reduced in the male rats exposed to 1000 ppm test substance.
Serious and suppurative inflammation and degeneration of the olfactory epithelium in the nasal cavity was observed at an increased incidence in the treated rats when compared to the controls. Although alveolar macrophages were observed at an increased incidence treated rats, the severity was considered minimal. An increased incidence of focal or multifocal fibrosis was observed females exposed to 500 ppm of the test substance.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No treatment-related tumors were observed.

Relevance of carcinogenic effects / potential:

no

Key result

Dose descriptor:

NOAEC

Effect level:

>= 2.05 mg/L air (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed; corresponding to 500 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Key result

Dose descriptor:

NOAEC

Effect level:

>= 4.1 mg/L air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects observed; corresponding to 1000 ppm

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEC

Effect level:

>= 2.05 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: no biologically relevant adverse systemic effects observed; corresponding to 500 ppm

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

ca. 1.03 mg/L air (nominal)

Sex:

male/female

Basis for effect level:

other: Inflammation and degeneration of the olfactory epithelium in the nasal cavity; corresponding to 250 ppm

Remarks on result:

other:

Remarks:

Effect type: other: local toxicity (migrated information)

Critical effects observed:

no

Effects on body weight gain

Reduced body weights of the high dosed animals by maximum 11% are considered as secondary effects following the inflammatory effects in the URT and therefore not relevant for the assessment of a systemic NOAEC.

Hematological effects

Mononuclear cell leukemia has a high spontaneous incidence in Fischer 344 rats. Based on the lack of statistical significance and the normal occurrence of this 

neoplasm, the increased incidence was not considered biologically significant. In support of this conclusion, a classification of the leukemia into three 

stages of severity showed that there were no differences in the characteristics of the leukemia between the exposed and control females, and, further, there 

was no increase in this neoplasm in males exposed to 1000 ppm MMA.

Conclusions:

In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats methyl methacrylate did not induce neoplasms in the highest doses testd (500 ppm /females, 1000 ppm/males)

Executive summary:

In a two years inhalation toxicology and carcinogenesis study (NTP) in F344 rats with methyl methacrylate 50 males and 50 females of each species male rats were exposed to 0, 500, or 1,000 ppm methyl methacrylate by inhalation and female rats were exposed to 0, 250, or 500 ppm methyl methacrylate by inhalation.

Animals were exposed 6 hrs/d, 5 d/wk for 102 wk. Animals were observed twice per day, weighed once per week for the first 13 wk and monthly thereafter; individual clinical examinations were made at weighing.

 

Necropsy and histologic examination was performed on all animals. The following tissues were examined: gross lesions and tissue masses, regional lymph nodes, mandibular lymph node, sternebrae including marrow, thyroid gland, parathyroids, small intestine, rectum, colon, liver, mammary gland, prostate/testes/epididymis or ovaries/uterus, lungs and mainstem bronchi, nasal cavity and turbinates, skin, heart, esophagus, stomach, salivary gland, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, preputial or clitoral gland, and tracheobronchial lymph nodes

 

In this study methyl methacrylate did not induce neoplasms in rats in the highest doses tested (500 ppm /females, 1000 ppm/males).

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

2 050 mg/m³

Study duration:

chronic

Species:

rat

Quality of whole database:

Two chronic NTP studies available in rats and mice in concentrations up to 1000 ppm.

Justification for classification or non-classification

No carcinogenic potential was detected in reliable inhalation studies in rats and mice (NTP 1986) and reliable epidemilogical studies in the United States and Great Britain with a significant sample size of a combined number of over 15,000 employees, with nearly complete follow-up and latency periods of potentially reaching over 60 years

. Therefore, methyl methacrylate has not to be classifed as carcinogen according to 67/548/EEC and UN-GHS requirements, respectively.

Additional information

A not peer-reviewed review on available epidemiological data concluded in 2019 that "A total of 6 epidemiology studies have been conducted on occupational populations with exposure to MMA; four in the MMA-monomer production and/or MMA-polymer sheet production industry and two among orthopedic surgeons. No consistent elevations of specific cancer types were reported. In some studies increased cancer rates were reported, but these findings are most likely attributable to faulty methodology (orthopedic surgeon studies). The conclusion drawn by Tomenson et al in 2005 following a review of the then available epidemiologic literature, that the available human data are not in support of an increased cancer risk from occupational exposure to MMA remains correct. In particular the retrospective cohort studies conducted in the United States, and Great Britain had a significant sample size of a combined number of over 15,000 employees, with nearly complete follow-up and latency periods of potentially reaching over 60 years. These studies evaluated exposure concentrations as high as the 100 ppm range, far in excess of exposures present in industry over the last few decades. These cohorts present the most comprehensive information available on the occurrence of cancer in humans exposed to high concentrations of MMA. Cancer mortality rates in these large cohorts, followed over extensive time periods and with the high MMA concentrations experienced in the early production decades, with longest follow-up, are similar to those in the general population. These results demonstrate that exposure to MMA, even at relatively high concentrations, is not associated with cancer risk." (G. Swaen, 2019, http://static1.1.sqspcdn.com/static/f/1405676/28126984/1557602301267/Epidemiology+studies+on+MMA4-8-19.pdf?token=w4cptUdv95cMRvmFrPlwRVh5vnQ%3D)