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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

No carcinogenicity study is available for EGDMA. For the alcohol metabolite ethylene glycol data are available as well as from the methacrylic metabolite donor substance methyl methacrylate (donor for methacrylic acid). More details on the metabolism are available in the chapter Toxicokinetics and in the Category document.

Ethylene Glycol (alcohol metabolite)

Mice, oral, 2 yrs: negative (NTP 1993)

Methyl methacrylate (donor substance for the methacrylic metabolite, methacrylic acid)

Rats, inhalation, 2 yrs: negative (NTP 1986)

Mice, inhalation, 2 yrs: negative (NTP 1986)

Rats, male inhalation, 2 yrs: negative (Lomax 1992)

Rats, oral (Borzelleca, 1964, limited reliability)

In summary there is no evidence of carcinogenicity of the ester hydrolyses products of EGDMA and therefore no carcinogenicity is expected for EGDMA itself.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Principles of method if other than guideline:
NTP standard method
GLP compliance:
yes
Specific details on test material used for the study:
>99% pure
Species:
mouse
Strain:
B6C3F1
Details on species / strain selection:
age 55–63 days
Sex:
male/female
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Dose / conc.:
50 000 ppm
Remarks:
only females (highest dose); corresponds to 12000 mg/kg/d in females (based on measured dietary intakes)
Dose / conc.:
25 000 ppm
Remarks:
males (highest dose) & females; corresponds to 6000 mg/kg/d in both sexes (based on measured dietary intakes)
Dose / conc.:
12 500 ppm
Remarks:
females (lowest dose) & males; corresponds to 3000 mg/kg/d in both sexes (based on measured dietary intakes)
Dose / conc.:
6 250 ppm
Remarks:
only males (lowest dose); corresponds to 3000 mg/kg/d (based on measured dietary intakes)
No. of animals per sex per dose:
60
Control animals:
yes
Details on study design:
Doses for this study were based on results of the NTP 13-week mouse study
Mortality:
no mortality observed
Description (incidence):
The number of surviving animals was 23−37/group/sex by the end of the study; there was no difference in survival between treated and control groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects on bw gain.
Haematological findings:
no effects observed
Description (incidence and severity):
No effects on hematology.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effects on blood chemistry.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The primary effects noted in the 2-year study were: significant hepatocyte hyaline degeneration in the liver of males at the 2 highest doses (3,000 and 6,000 mg/kg bw/day) and in females at the highest dose (12,000 mg/kg bw/day); and medial hyperplasia of the pulmonary arterioles in females at all doses (3,000, 6,000, and 12,000 mg/kg bw/day). Significant treatment-related nephropathic effects were not observed. A few oxalate-like crystals were seen in renal tubules, urethrae, and/or urinary bladders of high-dose males (6,000 mg/kg bw/day).
No significant (p<0.05) increases in incidence of nonneoplastic lesions were seen in reproductive organs of treated males (testes, seminal vesicle, prostate, preputial gland, penis, epididymis, ductus deferens, coagulating gland) or females (ovary, oviduct, uterus).
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No significant (p<0.05) increases in incidence of neoplastic lesions were seen in reproductive organs of treated males (testes, seminal vesicle, prostate, preputial gland, penis, epididymis, ductus deferens, coagulating gland) or females (ovary, oviduct, uterus).
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
LOAEL
Effect level:
3 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
3 000 mg/kg bw/day (nominal)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
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:
stabilzed with 10 ppm t-butyl hydroquinone
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- 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.
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:
Animals: 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.  
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 concetration s 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 saerif1ee of 2-year survivors differed from the eontrols only in signifieantly inereased kidney ratios in female rats receiving 2000 ppm of methyl mcthaerylate.
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
Conclusions:
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 study available

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 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.
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 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:
no effects observed
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.
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.
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
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)
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)

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 methacrylate50 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 hld, 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 rats in the highest doses tested (500 ppm /females, 1000 ppm/males).

 

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 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)

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 hld, 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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Method and results sufficient described, similar to OECD-guideline 453.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
inhalation
Details on exposure:
1. Original study (Reno FE, 1979):  Groups of 70 male and 70 female (total animals = 280 males and  280 females) rats were randomly assigned to either a control or one of  three test groups. The animals were group housed (7/cage) and provided  food and water ad libitum, except during the exposure period. The animals  were exposed to the test substance six hours a day five days per week for  a total of 104 - 106 weeks. The test substance was administered in  6000-liter inhalation chambers with pyramidal tops and bottoms, under  dynamic conditions of 1000 liters/minute of airflow. Control animals were  exposed to filtered room air in the same manner as the treated animals.  
2. Re-Evaluation of the study (Lomax LG et al., 1997): Three hundred male and 300 female rats were received form  Charles River Breeding Laboratories, Inc. (Wilmington, MA, USA). Animals  were maintained under quarantine for 19 days, during such time all rats  were evaluated for clinical signs of disease and an ophthalmoscopic  examination. Following the quarantine period, 70 males and 70 females  were assigned to each of the four exposure groups (including the  control). The animals were housed by sex in wire mesh cages (seven/cage).  Animals were provided feed and water ad libitum, except during the  exposure period.  Exposure conditions: Animals were exposed to the test substance vapor in  6000 liter inhalation chambers under dynamic conditions of 1000  liters/minute of air flow. The control animals were exposed to filtered  room air in a chamber with similar air-flow characteristics.  
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
1. Original study (Reno FE, 1979): Concentrations of the test substance in each chamber were measured hourly  during each exposure period using an infrared analyzer. 
Duration of treatment / exposure:
2 years (104 weeks)
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
25, 100 and 400 ppm (corresponding to ca. 0.10, 0.41 and 164 mg/L, respectively)
Basis:

Control animals:
other: yes, concurrent negative control group
Details on study design:
Post-exposure period: Not applicable
Observations and examinations performed and frequency:
1. Original study (Reno FE, 1979): Animals were observed daily for mortality and moribundity.  Body weights  and clinical observations were recorded prior to study initiation, weekly  during weeks 1 though 12, biweekly from week 14 through 24, every fourth  week from week 28 through 78 and biweekly from week 80 through 104. Ophthalmoscopic exams were performed on all rats prior to treatment using  an indirect ophthalmoscope at weeks 13, 52 and 102.  
2. Re-Evaluation of the study (Lomax LG et al., 1997): All animals were observed for mortality and morbidity daily. Individual body weight data were collected at the start of the study, weekly for the first twelve weeks and biweekly to week 24, every fourth week to week 78 and biweekly until study termination (week 104). At such time, a more detailed evaluation of gross toxicity and tissue masses was performed. Ophthalmoscopic evaluations were conducted at weeks 13, 52 and 102.  
Sacrifice and pathology:
1. Original study (Reno FE, 1979): Blood samples were collected from ten males and ten females in each group at weeks 13, 52 and 102 and from ten males and ten females in the control and high-exposure group at weeks 26 and 78 for hematological evaluation via segmental amputation of the tail. The following parameters were examined: hematocrit, hemoglobin, erythrocyte count, erythrocyte morphology, total leukocyte count and differential leukocyte count. In addition, coagulation and prothrombin times were determined from all blood samples taken at 13, 52 and 104 weeks and from the samples collected from the control and high-exposure groups at week 78. Femoral bone samples were collected from all sacrificed animals at weeks 13 and 52 and from 10 animals/sex/group at termination. The number of myeloid and erythroid cells and the myeloid/erythroid ratios were determined. Blood samples were collected for clinical chemistry evaluations from the abdominal aorta of all animals sacrificed at weeks 13 and 51 and from ten males and ten females per group at study termination. The following parameters were evaluated: fasting glucose, blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase, total protein, total albumin, albumin/globulin ratio. In addition, total cholesterol and triglycerides were also determined from blood samples taken from all animals sacrificed at week 52 and from ten animals/sex/group at week 104. Twenty-four hour urine samples were collected from 10 animals/sex/group at weeks 13, 52 and 104 by individually housing the rats overnight in stainless steel cages. The following parameters were evaluated: appearance, pH, ketones, total protein, specific gravity, bilirubin, glucose and occult blood. Necropsy: Ten rats/sex/group were sacrificed by exsanguination after 13 and 52 weeks of exposure. Animals found moribund during the course of the study were sacrificed at the time of the observation. The remaining animals were sacrificed after 102-104 weeks of exposure to the test substance. A gross necropsy was performed on all animals that were sacrificed and most of the animals that died during the study. Brain, kidneys, lungs, spleen, thyroids, adrenals and testes/ovaries from each animal were weighed and the organ to body weight ratio was calculated. The following tissues were collected and preserved in formalin or Bouin's solution: brain, pituitary, thoracic spinal chord, esophagus, salivary glands, thyroids, lungs, thymus, heart, spleen, kidneys, adrenals, stomach, duodenum, ileum, jejunum, colon, skin, mesenteric lymph nodes, urinary bladder, ovaries, uterus, mammary gland costochondral junction, liver, sciatic nerve, skeletal muscle, pancreas, nasal turbinates, unusual lesions, eyes and the testes with epididymides. Intraperitoneal body fat was recorded without exception at week 52 and by exception at all subsequent intervals. Histopathology was performed on the brain, spinal cord, pituitary, thyroid, adrenal, heart, lung, spleen, liver kidney, and ovaries/testes from 10/animals/sex in the low- and mid-exposure groups; and the nasal turbinates of all low- and mid-level animals. Also, the adrenals, ovaries/testes, heart (with coronary vessels), kidneys, liver, lungs, nasal turbinates, pituitary and thyroid were evaluated from 10 animals/sex/group from the control and high-exposure groups sacrificed at weeks 13 and 52.
2. Re-Evaluation of the study (Lomax LG et al., 1997): Blood samples were collected from 10 males and 10 females per dose group at weeks 13, 52 and 104 and 10 males and 10 females in the control and the high-dose group at weeks 26 and 78. The following hematological parameters were evaluated at each sampling interval: hematocrit, hemoglobin, red blood cells counts, erythrocyte counts, total white blood cell counts, erythrocyte morphology and prothrombin time. Bone marrow samples were collected from the femurs of all rats killed at week 13 and 52 and from 10 males and 10 females from each group at study termination. Blood also was obtained from the abdominal aorta of all rats killed at week 13, 52 and study termination. The following clinical chemistry parameters were evaluated: glucose, blood urea nitrogen, serum glutamic-pyruvic transaminase, alkaline phosphatase, total protein, total albumin, total cholesterol (except for week 13) and triglycerides (except for week 13). Twenty-four hour urine samples were collected from 10 animals per sex per group at weeks 13, 52 and 104. The following parameters were evaluated: appearance, pH, specific gravity, glucose, ketones, total protein, bilirubin, and occult blood. Necropsy: Ten rats per sex per group were sacrificed after 13 and 52 weeks of exposure. The remaining animals were sacrificed after 104 - 106 weeks of exposure. Necropsies were performed on all decedents. The brain, kidneys, lungs spleen, adrenal and thyroid glands and the testis or ovaries were weighed and the organ to body weight ratios were calculated. The following tissues were preserved in buffered 10% formalin: brain, pituitary, spinal cord, esophagus, salivary glands, thyroid glands with parathyroid, lings, mediastinal lymph nodes, thymus, heart, aorta, larynx, spleen, kidneys, adrenals, stomach, duodenum, ileum, jejunum, colon, skin, mesenteric lymph nodes, urinary bladder, uterus, mammary gland, prostate, seminal vesicles, costochondral junction, liver, sciatic nerve, skeletal muscle, pancreas, nasal cavity and gross lesions. The eyes from all rats and the testes with epididymides were preserved in Bouin's fixative. Microscopic evaluations were made using the tissue listed above in the control and the high-dose groups at study termination. The brain, spinal cord, pituitary, thyroid, adrenal, heart, lung, liver, spleen, kidney, and ovaries/testes from 10 animals per sex in the low- and mid-dose groups and the nasal cavities from all animals in the low- and mid-dose groups were evaluated microscopically. Sections from the adrenals, testes or ovaries, heart, kidneys, pituitary, thyroids, liver, nasal cavities and lungs of control and high-dose animals were examined microscopically after the week 13 and 52 interim sacrifices. Following the issuance of the original report, tissue blocks of the nasal cavities from the animals killed at the terminal sacrifice and the control and high-dose dose group at week 13, were obtained and a composite cross-sectional map of representative nasal cavity lesions with the approximate distribution was prepared for the mid- and high-dose groups.
Statistics:
1. Original study (Reno FE, 1979): Data Analysis: Pairwise comparisons of the mean body weights from weeks 12, 24, 36, 48, 52, 60, 72, 78, 90 and 104 were conducted using the F test for equality of two variances and Student's t-test. Clinical laboratory data (except urinalysis and leukocyte differentials), terminal body weights and absolute and relative organ weights (organ/body weight) of all animals sacrificed at weeks 13, 52 and term were subjected to a preliminary test for equality of variance followed by one-way analysis using Bartlett's test for homogeneity and Snedecor and Cochran, respectively. When statistical significances were observed, an additional set of analyses was conducted using Scheffe's method for judging all contrast in analysis of variance.
2. Re-Evaluation of the study (Lomax LG et al., 1997): Data analysis: Pair-wise comparisons of the mean body weights were performed. Clinical laboratory data, with the exception of urinalysis and leukocyte differentials, terminal body weights and absolute and relative organ weights of all animals killed at weeks 13 and 52 and at study termination were subjected to a preliminary test for the equality of variance. To evaluate tumor incidence, Fisher's one-sided exact test was conducted between the control and high-dose groups. For all analyses, statistical significance was determined by a p value < 0.05.
Dose descriptor:
NOAEC
Effect level:
400 ppm
Sex:
male/female
Basis for effect level:
other: No increase in tumour incidence up to the highest concentration tested
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

1. Original study (Reno FE, 1979):
-----------------------------------
The mean analytical concentration was evaluated. The overall mean concentrations of MMA vapor 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)    Week 0-13     Week 0-52      Week 0-104
MALES
-----------------------------------------------------------
Negative Control (0)   0             0              16
25                     0             1.7            20
100                    0             1.7            16
400                    0             0              20
-----------------------------------------------------------
FEMALES
Negative Control (0)   0             0              24
25                     0             3.3            36
100                    1.4           3.3            26
400                    0             5.0            30
-----------------------------------------------------------

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 bodyweight 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. Evaluation of the hematology 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.

Gross pathology: 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.

Histopathology: 
Week 13
No treatment-related histopathological findings were noted in the rats exposed to 400 ppm MMA for 13 weeks. Findings were consistent among groups and were typical for rats of this age and strain.
Week 52
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.
Week 104
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


                         Males               Females
Group No.*             1  2  3  4           1  2  3  4
---------------------------------------------------------
No. of Nasal 
Turbinates Examined    48 49 49 48          44 48 45 46
Serous Exudate          3 11 12 16          15  8 17 23
Purulent Exudate        2  6  4  8           2  9  6  6
Pleocellular Infiltrate 1  4  6 19           3 14  9 11
Distended
Submucosal Glands       5 21 21 12           3 14 12  9
Squamous Metaplasia
(focal)                 2  3  1  5           0  5  1  2
Inflammatory Polyp      0  0  1  2           0  0  0  0
---------------------------------------------------------

Groups 1, 2, 3 and 4 were exposed to ca. 0, 0.10, 0.41 and 1.64 mg/L (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. 0.41 and 1.64 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):
------------------------------------------------------

Observations:
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. Hematology, 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 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 0.41 and 1.64 mg/L (100 and 400 ppm) dose group had dose-dependant 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 ca. 0.41 mg/L (100 ppm) were localized in the more posterior (level 3) portion of the dorsal meatus, while those in animals exposed to 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 25 ppm MMA. No statistically significant differences were observed in the frequency of tumors 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.

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

The available data give no concern on carcinogenic properties of the test substance. Thus, classification of EGDMA as carcinogenic is not required according to GHS Regulation EC No 1272/2008 and

therefore labelling is not necessary.

Additional information

No carcinogenicity study is available for EGDMA. For the alcohol metabolite ethylene glycol data are available as well as from the methacrylic metabolite donor substance methyl methacrylate (donor for methacrylic acid). More details on the metabolism are available in the chapter Toxicokinetics and in the Category document.

Ethylene Glycol (alcohol metabolite)

No carcinogenic effects observed in a 2yr feeding study in mice when dosed up to 6,000 mg/kg/d in males and up to 12,000 mg/kg/d in females (NTP 1993). ATSDR (2010) stated: “There is no indication that ethylene glycol is carcinogenic based on results of a limited renal cancer mortality study in chemical plant workers and well-designed chronic oral bioassays in rats (one study) and mice (two studies).”

Methyl methacrylate (donor substance for the methacrylic metabolite, methacrylic acid)

Rats & Mice, inhalation

Groups of 50 male F344/N rats were exposed to methyl methacrylate (purity >99%; containing 0.04 mg/1 equivalent to 10 ppm monomethylethylether 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-cellleukaemiaobserved 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-relatedtumourswere observed.

The combined chronic toxicity and carcinogenicity study on methyl methacrylate of Rohm and Haas (1979a, re-evaluated by Lomax, 1992; Lomax et al. 1997) did not reveal any significant incidence of

tumours or increase of tumour incidence. One male each out of a total of 49, respectively 47 males exposed to 100 and 400 ppm methyl methacrylate had a small solitary polypoid mass attached to the

lateral wall of one side of the anterior nasal cavity. Both masses were composed of well differentiated pseudoglandular structures arising from respiratory epithelium diagnosed as adenomas. Both animals

had chronic inflammation of the respiratory epithelial region. An association of the nasal adenomas to methyl methacrylate inhalation were considered to be unlikely, because the incidence was not

significantly increased in comparison to controls without any nasal tumour and the findings were not confirmed by other studies. However, historical data show that adenomas from respiratory epithelium

are very rare tumours in rats with a spontaneous rate of 0-0.1 % for F344 male and female rats.

Rats, 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).

Sumary and Discussion of carcinogenicity

The substances in this category demonstrate evidence of mutagenicity in some of the in vitro mutagenicity studies only at cytotoxic concentrations, which are unlikely to be achieved in vivo. In deed the esters are non-mutagenic in in vivo studies, presumably due to their rapid metabolism. In summary, the category members including EGDMA are not considered as mutagenic.

 

Furthermore, in chronic dermal cancer studies two members of this category do not cause cancer at the primary site of contact even in the presence ofacanthosis and fibrosis. Although there are no oral cancer bioassays for any member of the category, the relevant metabolites have been shown not to cause cancer of the intestinal tract following chronic ingestion in animals. For γ-butyrolactone, a metabolite donor for 1,4-BDDMA, there was an uncertain association between γ-butyrolactone exposure and hyperplasia and pheochromocytomas of the adrenal medulla on high dose male mice. Based on study results for γ-Butyrolactone and the analogous metabolite 1,3-BD, NTP (1996) concluded that γ-butyrolactone exhibited no carcinogenic potential; therefore it is unlikely that 1,4-butanediol would be carcinogenic in animals and no further evaluation of 1,4-butanediol is needed at this time.

 

MAA as the common methacrylic moiety of the substances has been shown not to cause an excess in cancer in long-time exposed workers.

 

In summary the members of the MfMA category including EGDMA are regarded as non-carcinogenic.

Justification for selection of carcinogenicity via oral route endpoint:

No carcinogenicity study is required. There is no concern for mutagenicity or genotoxicity at physiologically relevant levels. In the available repeated-dose toxicity study there are no indications of

non-specific organ damage or chronic inflammation. Available data give no concern on carcinogenic properties of the test substance.