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Carcinogenicity

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Administrative data

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.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium.
Author:
Chan P.C., Eustis S.L., Huff J.E., Haseman J.K., Ragan H.
Year:
1988
Bibliographic source:
Toxicology, 52, 237-252
Reference Type:
publication
Title:
Unnamed
Year:
1986
Reference Type:
review article or handbook
Title:
The lower alkyl methacrylates: Genotoxic profile of non-carcinogenic compounds
Author:
Albertini, RJ
Year:
2017
Bibliographic source:
Regulatory Toxicology and Pharmacology 84, 77-93

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl methacrylate
EC Number:
201-297-1
EC Name:
Methyl methacrylate
Cas Number:
80-62-6
Molecular formula:
C5H8O2
IUPAC Name:
methyl methacrylate
Test material form:
liquid
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:

Test animals

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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

open allclose all
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)

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

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.



Applicant's summary and conclusion

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)
Test Test Test
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).

 

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