Hazardous substance assessment - Methyl methacrylate

Identification

Chemical name:
Methyl methacrylate (MMA)

CAS #: 80-62-6

Chemical composition:
CH₅H₈O₂

Synonyms:
2-Propenoic acid, 2-methyl-, methyl ester; Methacrylic acid, methyl ester.

UN #:
1247

Pictograms

Figure 1 - Text description

The symbol within the pictogram is an exclamation mark. This symbol indicates that hazardous products with this pictogram can cause certain health effects, for example:

• skin irritation
• eye irritation
• skin sensitization

Figure 2 - Text description

The symbol within the pictogram is a flame with a line underneath it. This symbol indicates that hazardous products with this pictogram can ignite easily and burn rapidly if they are not stored and handled properly.

WHMIS classification

Health hazards:

Skin Irritation – Category 2

Skin Sensitization: Category 1A

Specific Target Organ Toxicity - Single Exposure – Category 3 (Respiratory Tract Irritation)

Physical hazards:

Flammable Liquids – Category 2

Health hazards

Acute Toxicity (Oral):

Does not meet criteria

Median lethal dose (LD₅₀): 7,940 mg/kg (rat)^Footnote 1.

The available data do not meet the classification criteria for Acute Toxicity (Oral).

Acute Toxicity (Dermal):

Does not meet criteria

LD₅₀: > 5,000 mg/kg (rabbit) (based on study summary^Footnote 2).

The available data do not meet the classification criteria for Acute Toxicity (Dermal).

Acute Toxicity (Inhalation – Gases):

Not applicable

MMA is not a gas. The classification criteria for Acute Toxicity (Inhalation – Gases) do not apply to this substance.

Acute Toxicity (Inhalation – Vapours):

Does not meet criteria

Median lethal concentration (LC₅₀): 29.8 mg/L (rat, 4 hour)^Footnote 3.

The available data do not meet the classification criteria for Acute Toxicity (Inhalation - Vapours).

Acute Toxicity (Inhalation – Dusts and Mists):

No data available

Skin Corrosion / Irritation:

Category 2

The results from a study conducted similarly to the Organisation for Economic Co-operation and Development Test Guideline (OECD TG) 404 suggested that MMA may cause moderate to severe skin irritation^Footnote 4. In this study, 0.5 mL of MMA was applied to the skin of 2 rabbits for 4 hours. One rabbit did not display signs of erythema or edema but the other rabbit experienced eschar formation and blanching of the skin (along with a 4/4 score for erythema and a 3/4 score for edema at 24 hours). Although this is not a standard guideline compliant study, data are sufficient to meet a Category 2 classification [HPR 8.2.2(3)(b)(iii)].

The available data meet the classification criteria for Skin Irritation - Category 2 [HPR 8.2.2(3)(b)(iii)].

Serious Eye Damage / Eye Irritation:

Does not meet criteria

In a 2-rabbit study, the 24-, 48-, and 72-hour scores for corneal opacity and iritis in both animals were 0/4 and 0/2, respectively. Conjunctival redness scores were 2/3 at 24 hours in both animals but full reversal was achieved by 48 hours^Footnote 4. These scores are not severe enough to meet classification criteria.

The available data do not meet classification criteria for Serious Eye Damage / Eye Irritation.

Respiratory Sensitization:

Does not meet criteria

There are several case studies available that report the presence of asthma and/or respiratory distress after workers were exposed to MMA^{Footnote 5,Footnote 6,Footnote 7}. Johnson and colleagues identified that these cases seem to be associated with “end-user” occupations where the pattern of exposure is characterised by high peak levels of short duration^Footnote 7. In these case studies, the bronchial challenge tests were conducted by exposing the volunteers to an atmosphere that mimicked the workplace, rendering it difficult to distinguish whether the effects were from MMA or another workplace substance. The only bronchial challenge test that was specific to MMA had negative results. Thus, the conclusion by the study authors was that there was insufficient evidence of MMA-induced airway hypersensitivity^Footnote 7.

The available data do not meet classification criteria for Respiratory Sensitization.

Skin Sensitization:

Category 1A

Multiple human case reports have shown MMA to be a strong skin sensitizer in occupational settings^{Footnote 8,Footnote 9,Footnote 10,Footnote 11,Footnote 12,Footnote 13,Footnote 14,Footnote 15}. Based on the high frequency of occurrence of sensitization in humans, the available data meet the classification criteria for Category 1A [HPR 8.4.1(4)].

An OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay) study in mice (4/group) exposed to 0, 10, 30, 50, 75 or 100% (neat) solutions in acetone reported stimulation indices (SI) of 0, 1.5, 2.3, 2.0, 4.4 and 7.3, respectively, which meet classification criteria for Category 1^Footnote 2. Strong positive results were obtained in several other guideline studies, including guinea pig maximization tests^{Footnote 16,Footnote 17} and in other local lymph node assays^{Footnote 2,Footnote 18}.

The available data meet the classification criteria for Skin Sensitization - Category 1A [HPR 8.4.1(4)].

Germ Cell Mutagenicity:

Does not meet criteria

In vivo: Negative results were obtained in an inhalation chromosomal aberration test in mice^{Footnote 2,Footnote 19}. In a mouse erythrocyte micronucleus test where mice were exposed to MMA orally, the results were also negative (based on study summary^Footnote 2). There was increased sister chromatid exchange in male workers exposed to MMA, but this was found by the study authors to be unrelated to MMA exposure (based on study summary^Footnote 2).

In vitro: An OECD Guideline 471 (Bacterial Reverse Mutation Assay) study in S. typhimurium strains TA 1535, TA 97, TA 98 and TA 100 was negative with and without metabolic activation^Footnote 2. Another OECD Guideline 471 study in S. typhimurium strains TA 97a, TA 98, TA 100, TA 102 and TA 104 was negative with and without metabolic activation^Footnote 2. Several additional studies in various S. typhimurium strains also reported negative genotoxicity results^Footnote 2. An OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test) in Chinese hamster ovary cells reported ambiguous results without metabolic activation and weakly positive results with metabolic activation^Footnote 2. A pre-guideline mouse lymphoma assay in mouse lymphoma L5178Y cells was positive without and inconclusive with metabolic activation^Footnote 2. Another mouse lymphoma assay in mouse lymphoma L5178Y cells was positive with and negative without metabolic activation, whereas a third study reported ambiguous results without such activation^Footnote 2. A pre-guideline in vitro mammalian cell micronucleus test in Chinese hamster lung fibroblasts was negative without metabolic activation^Footnote 2. An OECD Guideline 479 (Genetic Toxicology: In Vitro Sister Chromatid Exchange Assay in Mammalian Cells) in Chinese hamster ovary cells was ambiguous with and without metabolic activation^Footnote 2. Another sister chromatid exchange assay in human lymphocytes was negative for genotoxicity^Footnote 2.

The available in vivo data do not meet classification criteria. The ambiguous/positive in vitro data are insufficient to evaluate for classification.

The available data do not meet classification criteria for Germ Cell Mutagenicity

Carcinogenicity:

Does not meet criteria

MMA has been classified in Group 3 (not classifiable as to its carcinogenicity to humans) by the International Agency for Research on Cancer (IARC)^Footnote 20. The American Conference of Governmental Industrial Hygienists (ACGIH) has classified MMA in Category 4A (not classifiable as a human carcinogen)^Footnote 21.  The National Toxicology Program (NTP) completed a 2-year inhalation carcinogenicity study and did not find any evidence of carcinogenicity for male rats exposed at 500 or 1,000 ppm MMA or for female rats exposed to 250 or 500 ppm MMA, or for male and female B6C3F1 mice exposed to 500 or 1,000 ppm MMA^Footnote 22. In a 2-year rat study, administration of 6, 60, or 2,000 mg/L MMA in drinking water produced no treatment-related tumors^Footnote 20. A skin painting study, which involved the administration of MMA 3 times/week for 4 months, produced no local tumors throughout the duration of the rats’ lifespans^Footnote 23.

The available data do not meet classification criteria for Carcinogenicity.

Reproductive Toxicity:

Does not meet criteria

Female rats exposed to MMA via whole-body inhalation of up to 2,028 ppm for 6 hours/day on days 5-15 of gestation showed no embryo toxicity, fetal toxicity, or malformations, even at exposure levels that resulted in maternal toxicity^{Footnote 2,Footnote 24,Footnote 25}. In inhalation studies with doses up to 1,000 ppm in rats and up to 400 ppm in mice, no significant reproductive or developmental effects were noted^{Footnote 26,Footnote 27}. In another mouse inhalation study with a dose of 1,330 ppm, no evidence of fetal toxicity or teratogenic effects was found^Footnote 28. MMA did not demonstrate an effect on male fertility when animals had been exposed to concentrations up to 9,000 ppm in another study^Footnote 29. In another study with limited details available, rats were orally administered 4, 8, 16 or 32% MMA (in water) for 8 months. Seven out of 10 rats to which the MMA was administered at a concentration of 32% showed partial seminal vesicle atrophy. The seminal vesicles in the remaining rats showed normal histology. Testis, epididymis and vas deferens showed normal histology in all rats^Footnote 30. Lower doses had no reproductive effects. Effects at the highest dose are insufficient to meet classification criteria.

The available data do not meet classification criteria for Reproductive Toxicity.

Specific Target Organ Toxicity – Single Exposure:

Category 3 (Respiratory Tract Irritation)

Oral Route of Exposure: In an oral toxicity study, rats and rabbits were administered single doses of 8.42, 9.36, 10.30 or 11.23 g/kg (rats), and 0.94, 1.87, 2.81, 3.74, 4.68, 5.8, 6.55, 7.49 or 8.42 g/kg (rabbits) of undiluted MMA^Footnote 1. Effects such as an increased respiration rate and motor weakness were only seen at very high lethal doses. Since these effects are associated with mortality, they are not relevant to classification in this hazard class.

Dermal Route of Exposure: No data available.

Inhalation Route of Exposure:

In humans: No adverse effects were observed following an acute exposure to 50 ppm MMA except minor irritation in the nose^Footnote 31. Another study tested higher concentrations and found that irritation to the respiratory tract occurred among workers exposed to 170 to 248 ppm MMA (based on study summary^Footnote 2). In an area with a spot concentration of 2,300 ppm, workers experienced unbearable discomfort. The study concluded that respiratory tract irritation occurred at concentrations exceeding 100 ppm. In an epidemiological survey, irritation of the eyes and the upper respiratory tract was limited to acute and reversible reactions after short-term peak exposures at concentrations exceeding 100 ppm (based on study summary^Footnote 2). In a study with human volunteers, no effects on cytokine levels that would be indicative of irritation were seen after a 50-ppm exposure to MMA^Footnote 32.

In animals: Irritation to mucous membranes occurred when animals (rats, guinea pigs and rabbits) were exposed to MMA vapour^Footnote 1. Another study exposed rats to 100 ppm MMA and observed interalveolar congestion/hemorrhage, pulmonary vasodilatation, and pulmonary edema after an exposure time of 2 or 4 hours^Footnote 19. A 1-hour exposure time did not cause these same effects. On the other hand, a study conducted by the Methacrylate Producers Association concluded that MMA was not a respiratory irritant in mice at concentrations up to 33,000 ppm^Footnote 33.

Due to the presence of human respiratory tract irritation that is transient, along with animal data that confirm tissue changes, the available data meet the classification criteria for Specific Target Organ Toxicity - Single Exposure – Category 3 (Respiratory Tract Irritation) [HPR 8.8.1(2)].

Specific Target Organ Toxicity – Repeated Exposure:

Does not meet criteria

Oral Route of Exposure: In a 21-day study, rats were fed 500 mg/kg/day of MMA^Footnote 34. Compared to controls, behavioral effects, such as a statistically significant decrease in spontaneous locomotor activity and conditioned avoidance response, and a statistically significant increase in aggression, were observed. The study authors stated that no behavioral effects were noted at 100 and 200 mg/kg/day in a previous unpublished study.

Dermal Route of Exposure: MMA is widely used in prosthetic dentistry and therefore dental technicians are repeatedly exposed to it in their daily work. There have been multiple reports of peripheral nervous system effects, including feelings of numbness, coldness, and pain in fingers, in humans after handling MMA without gloves^{Footnote 35,Footnote 36,Footnote 37,Footnote 38}. In one case, there was evidence of axonal neuropathy with loss of large myelinated fibers and unmyelinated axons in a 58-year old dental technician^Footnote 38. Despite the many case studies available that demonstrate a correlation between dermal MMA exposure and generalized peripheral neuropathy, a causal relation cannot be confirmed due to the many other chemicals present in a dental work place. An experimental physiologic rat study was available that examined the effects of MMA when dermally applied to the tail skin for 8 weeks (3 hours daily)^Footnote 39. It was found that there were reduced amplitudes of the primary response of tail muscles to proximal motor nerve stimulation. However, the dosage applied was not specified. Thus, this study is insufficient for classification purposes.

Inhalation Route of Exposure: Increased chronic cough and mild airway obstruction were observed in humans at mean atmospheric concentrations of MMA vapour between 18.5 and 21.6 ppm^Footnote 40. At a mean atmospheric MMA concentration of 5.3 ppm, there were no significant clinical symptoms or abnormal hematological or serum biochemical findings, with the exception of some workers complaining of throat irritation and frequent cough and sputa^Footnote 41. Details on severity of effects from this study are insufficient for classification. In animals, significant effects, including nasal lesions and lung damage, were seen at MMA vapour exposures of 400 ppm and greater in long-term studies (102 to 104 weeks)^{Footnote 22, Footnote 42, Footnote 43, Footnote 44}. These doses were too high for classification. In a 97-day vapour inhalation study in rats with MMA exposures up to 1,000 ppm, no gross or histopathological changes were observed and no statistically significant differences in mortality or body weights were noted between control and test groups^Footnote 45.

The available data do not meet classification criteria for Specific Target Organ Toxicity – Repeated Exposure.

Aspiration Hazard:

No data available

No human data are available for MMA. This substance is not a liquid hydrocarbon.

Biohazardous Infectious Materials:

Not applicable

MMA is not a microorganism, protein, or nucleic acid.

Physical hazards

Explosives:

Not evaluated*

* Explosives are excluded from the HPA and its regulations. Explosives are regulated under the Explosives Act. For more information, visit Natural Resources Canada.

Flammable Gases:

Not applicable

MMA is not a gas. The classification criteria for Flammable Gases do not apply to this substance.

(Flammable) Aerosols:

Not evaluated

Classification of a hazardous product in the Flammable Aerosols or Aerosols hazard class is product dependent.

Oxidizing Gases:

Not applicable

MMA is not a gas. The classification criteria for Oxidizing Gases do not apply to this substance.

Gases Under Pressure:

Not applicable

MMA is not a gas. The classification criteria for Gases Under Pressure do not apply to this substance.

Flammable Liquids:

Category 2

MMA has a flashpoint of 10 °C and a boiling point of 100.36 °C at standard pressure (based on study summary^Footnote 2).

The available data meet the classification criteria for Flammable Liquids – Category 2 [HPR 7.6.1(2)].

Flammable Solids:

Not applicable

MMA is not a solid. The classification criteria for Flammable Solids do not apply to this substance.

Self-Reactive Substances and Mixtures:

Does not meet criteria

MMA has an auto-ignition temperature of 435 °C^Footnote 46. Self-Reactive Substances and Mixtures must have a self-accelerating decomposition temperature (SADT) of ≤75 °C to meet the minimum classification in this hazard class.

The available data do not meet the classification criteria for Self-Reactive Substances and Mixtures.

Pyrophoric Liquids:

Does not meet criteria

MMA has an auto-ignition temperature of 435 °C^Footnote 46. Pyrophoric Liquids react at room temperature.

The available data do not meet the classification criteria for Pyrophoric liquids.

Pyrophoric Solids:

Not applicable

MMA is not a solid. The classification criteria for Pyrophoric Solids do not apply to this substance.

Self-Heating Substances and Mixtures:

Does not meet criteria

MMA has an auto-ignition temperature of 435 °C^Footnote 46, which is well above the maximum spontaneous ignition temperature of 140 °C for classification.

The available data do not meet the classification criteria for Self-heating Substances and Mixtures.

Substances and Mixtures which, in Contact with Water, Emit Flammable Gases:

Not applicable

MMA has a chemical structure that does not contain metals or metalloids and is, therefore, excluded from classification [HPR 7.12.1(1)].

Oxidizing Liquids:

Not applicable

Paragraph 7.13.1(1)(b) of the HPR excludes from classification any organic liquid that contains oxygen, fluorine or chlorine if those elements are chemically bonded only to carbon or hydrogen. MMA contains oxygen chemically bonded only to carbon.

Oxidizing Solids:

Not applicable

MMA is not a solid. The classification criteria for Oxidizing Solids do not apply to this substance.

Organic Peroxides:

Not applicable

MMA is not an organic peroxide. The classification criteria for Organic Peroxides do not apply to this substance.

Corrosive to Metals:

No data available

No data are available to determine whether MMA meets the classification criteria for Corrosive to Metals.

Combustible Dusts:

Not applicable

MMA is not a solid. The classification criteria for Combustible Dusts do not apply to this substance.

Simple Asphyxiants:

Not applicable

MMA is not a gas. The classification criteria for Simple Asphyxiants do not apply to this substance.

Pyrophoric Gases:

Not applicable

MMA is not a gas. The classification criteria for Pyrophoric Gases do not apply to this substance.

Chemicals Under Pressure:

Not evaluated

Classification of a hazardous product in the Chemicals Under Pressure hazard class is product dependent.

Regulatory and other information

Regulatory information:

Hazardous substance assessments are prepared by Health Canada as educational and information resources. Under the HPA, suppliers of hazardous products must, upon the sale or importation of a hazardous product, provide a label and safety data sheet that meet the requirements set out in the HPR.

Other information:

The information and classifications contained in these hazardous substance assessments are based on publicly available sources, such as peer-reviewed literature or reports by international bodies. New information, including proprietary information, could have an impact on the classification of substances or hazardous products containing them. It is the responsibility of the supplier to ensure the accuracy, sufficiency, and reliability of their hazardous product classifications.

Last updated: 2022

Prepared by: Workplace Hazardous Materials Bureau, Health Canada