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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study well documented, meets generally accepted scientific principles, acceptable for assessment. With regard to carcinogenicity testing, the number of animals used in this test is below current guideline requirements. The power of this study and the negative finding have to be placed into perspective with the other three negative in vivo studies, the absence of genotoxicity and the lack of positive evidence in the cancer mortality studies on MMA.
Qualifier:
no guideline followed
GLP compliance:
no
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
Route of administration:
oral: drinking water
Details on exposure:
The rats were individually caged and weighed once a week. The diet consisted of finely ground Purina Dog Chow Kibbled Meal consumed ad libitum. Fluid consumption values were determined over a 3-day period at the end of 1 and 4 weeks,
monthly through 6 months, and on even months thereafter. Food consumptions were measuered over 3-day periods at the same intervals.
The low and medium concentrations in the water were selected with the expectation that the diet equivalents would approximate 10 and 100 ppm. The high concentration was selected following preliminary tests that indicated
that this level would significantly depress fluid consumption.
Details on analytical verification of doses or concentrations:
Food consumptions were measured over 3-day periods at the same time intervals. From the fluid and food consumption measurements, diet equivalents of the monomers consumed in the drinking
water were calculated.
Duration of treatment / exposure:
104 weeks (2 years)
Frequency of treatment:
Daily, ad libitum
Post exposure period:
no
Dose / conc.:
6 ppm
Remarks:
raised after 5 months to 7 ppm
Dose / conc.:
60 ppm
Remarks:
raised after 5 months to 70 ppm,
Dose / conc.:
2 000 ppm
Dose / conc.:
12 other: ppm (on the basis of fluid and food consumption observations)
Remarks:
corresponding to roughly 0.6 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)corresponding to roughly 0.6, 6 and 165 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)
Dose / conc.:
120 other: ppm (on the basis of fluid and food consumption observations)
Remarks:
corresponding to roughly 6 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)
Dose / conc.:
3 000 other: ppm (on the basis of fluid and food consumption observations)
Remarks:
corresponding to roughly 165 mg/kg/bw (based on a conversion factor of 20 (Derelanko, M.J., 2000)
No. of animals per sex per dose:
25
Control animals:
other: yes, concurrent negative control group
Details on study design:
 Twenty-five male and female albino (Wistar) rats were administered 6, 60 or 2000 ppm of methyl methacrylate in the drinking water. The concentrations of the low- and mid-dose groups were increased to 7 and 70 ppm at the beginning of the fifth month of the study. The animals were individually housed and provided food ad libitum.  
Prior to the start of the study, it was apparent that methyl methacrylate was volatilizing at the tip of the water bottles. A special design was employed to reduce the volatilization and measurements showed that the methyl methacrylate concentrations remained within 15% of nominal for 72 hours.
The low and medium concentrations in the water were selected with the expectation that the diet equivalents would approximate 10 and 100 ppm. The high concentration was selected following preliminary tests that indicated that this level would significantly depress fluid consumption.
Observations and examinations performed and frequency:
Body weights were measured prior to study initiation, at weeks 1, 3, 6, 13, 26, 52, 78 and 104. Food and water consumption was measured over a three day period at the end of one and four weeks, monthly through month six and during even months thereafter. Hematological measurements, including hematocrit, hemoglobin, total white and differential white cell counts, were obtained from five rats from each sex in each treatment level at three month intervals. Pooled urine samples were collected from five rats per sex from each treatment group every three months to evaluate urinary concentrations of reducing substances and proteins.
Sacrifice and pathology:
Necropsy: At sacrifice, organ to bodyweight ratios were made for the heart, spleen, kidney, liver and testes. Select tissues collected and preserved from all survivors and decedents included: heart, lung, liver, kidney, urinary bladder, spleen, gastroenteric, skeletal muscle, bone marrow, skin, brain, thyroid, adrenal, pancreas, pituitary and gonads. Histopathological examinations were made in the control and the high-dose group.
Other examinations:
no post-exposure recovery group
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

Referenceopen allclose all

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01/1981 to 01/1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
Method and results sufficient described, similar to OECD-guideline 451, NTP-study.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 mice of each sex were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm
- Parameters analyzed/observed: survival, body weight, clinical signs, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung, uterus, liver.
GLP compliance:
not specified
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:
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 8-9 weeks
- Weight at study initiation: males 21.8-23.8 g; females 16.6-20.0 (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 499 ± 17 and 984 ± 36 for the 500 and 1000 ppm exposure groups, respectively.
Duration of treatment / exposure:
2 years (102 weeks)
Frequency of treatment:
6 hours per day, 5 days per week
Post exposure period:
no
Dose / conc.:
2.05 mg/L air (nominal)
Remarks:
male/female(corresponding to 500ppm)
Dose / conc.:
4.1 mg/L air (nominal)
Remarks:
male/female(corresponding to 1000ppm)
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Based on the results of the subchronic study
Positive control:
no
Observations and examinations performed and frequency:
Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly or the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.
Sacrifice and pathology:
Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
A histological evaluation was performed with the following tissues: gross lesions and tissue masses, regional lymph nodes, mandibular lymph nodes, sternebrae including marrow, thyroid glands, 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.
Statistics:
Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test were conducted.
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)

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01/1981 to 01/1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
Method and results sufficient described, similar to OECD-guideline 451, NTP-study.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Principles of method if other than guideline:
- Principle of test: 2 year study, inhalation
- Short description of test conditions: groups of 50 males were exposed for 5 days per week, target conc. of 0, 500 and 1000 ppm, groups of 50 females were exposed for 5 days per week, target conc. 0, 250 and 500 ppm,
- Parameters analyzed/observed: survival, body weight, clinical signs, hematopoietic system, pituitary gland, prepuital gland, nasal cavity and olfactory sensory epithelium, lung
GLP compliance:
not specified
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:

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
- Source: Charles River Breeding Laboratories
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS

- Age at study initiation: 7-8 weeks
- Weight at study initiation: males 151-155g; females 117-119g (mean weights per treatment group)
- Housing: individually in stainless steel cages within the exposure chambers
- Acclimation period: 3 weeks
- Feed and water: both freely avaiable except during exposre period, when only water wa available
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
All animals were exposed to MMA vapors via whole body inhalation. MMA was vaporized at 50 ºC diluted with air and introduced into the chambers.  GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Methyl methacrylate was pumped from a stainless steel reservoir to a vaporizer by a stable micrometering pump with adjustable drift-free pump rates. The vaporizer was heated to 50° ± 2° C, and the study material vapor, along with an air stream, entered the test chamber.

TEST ATMOSPHERE
- Brief description of analytical method used: Methyl methacrylate concentrations were monitored on-line twice during each exposure hour, initially by a photoionization detector and later by gas chromatographic analysis

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Uniformity of the vapor concentration in the chambers was measured periodically throughout the studies. The mean concentrations in the chambers over the two-year study were 249 ± 1, 499 ± 17 and 984 ± 36 ppm for the 250, 500 and 1000 ppm exposure groups, respectively.
Duration of treatment / exposure:
2 years (102 weeks)
Frequency of treatment:
6 hours/day, 5 days/week
Post exposure period:
no
Dose / conc.:
1.03 mg/L air (nominal)
Remarks:
females, corresponding to 250 ppm
Dose / conc.:
2.05 mg/L air (nominal)
Remarks:
males and females, corresponding to 500 ppm
Dose / conc.:
4.1 mg/L air (nominal)
Remarks:
males, corresponding to 1000 ppm
No. of animals per sex per dose:
50
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: based on the results of the subchronic study
Positive control:
no
Observations and examinations performed and frequency:
Observations: Animals were observed twice daily for mortality and morbidity. Body weights were measured prior to study initiation, weekly for the first 13 weeks and monthly thereafter. A more detailed clinical observation was performed on each animal at the time of body weight measurement.
Sacrifice and pathology:
Necropsy: All animals were subjected to a gross necropsy, unless they were excessively autolyzed or cannibalized, missexed, or found missing.
Grosspathology (necropsy) and histologic examination:
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
- Iungs and mainstem bronchi
- nasal cavity and turbinates
- skin
- heart,
- esophagus
- stomach
- salivary gland,
- brain,
- hymus
- trachea
- pancreas
- spleen
- kidneys
- adrenal glands
- urinary bladder
- pituitary gland
- preputial or clitoral gland
Statistics:
Data analysis: Survival probability was estimated using the product limit procedure of Kaplan and Meier (1958). Statistical analysis of survival was completed according to Cox (1972) and to Tarone's life table test (1975). P values for the survival analysis were two-sided and the analysis of the tumor incidence  was evaluated using Mantel and Haenszel (1959). In addition the Fisher Exact Test for pairwise comparisons and the Cochran-Armitage linear trend test was conducted.
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)