Methacrylic Acid, Methyl Ester 

Indirect Food Additives and Polymers: Migration and Toxicology V.O. Sheftel 2000

METHACRYLIC ACID, METHYL ESTER Molecular Formula. C₄H₈O₂
M= 100.12
CAS No 80-62-6
RTECS No OZ5075000
Abbreviation. MAM.
Synonyms. Methyl methacrylate; Methyl-2-methyl-2-propenoate.

Properties. Colorless liquid. Water solubility is 1.9% at 20°C. Miscible with alcohol at any ratio. Forms methacrylic acid and methyl alcohol when hydrolyzed. Odor perception threshold is 0.45 mg/l¹ or 0.025 to 0.05 mg/l. ^{02, 010}

Applications. Used for latex coatings and in the production of acrylic polymeric materials, including copolymers with acrylonitrile, a-methyl styrene, and butadiene intended for use in contact with food or drink. 

Acute Toxicity. LD₅₀ was found to be 8.7 g/kg BW for rats and rabbits, 3.6 to 5.2 g/kg BW for mice, 6.3 g/kg BW for guinea pigs, and 5.0 g/kg BW for dogs. The minimum lethal dose is 6.6 g/kg BW for rabbits^1,2 

Repeated Exposure. Rats received 1/5 and 1/10 LD₅₀ for 30 days. At the end of the experiment, LD₅₀ was administered to animals. Slight signs of accumulation were manifested.'

Long-term Toxicity. Rats were dosed by gavage with a total dose of 8.125 g MAM/kg BW (administered twice a week for 8 months). The treatment caused a reduction in the contents of glycoproteins and albumins and an increase in the activity of leucinoaminopeptidase and ß-glucuronidase in the blood serum, and reversible toxic effects on the liver. The kidneys were much less affected (Motoc et al., 1971).

In a 8 to 9-month rat study, there was liver damage; oxidizing enzymes and erythrocytes were affected. The functional condition of the brain cortex was impaired.'

Reproductive Toxicity.

Embryotoxicity and Teratogenicity. Female rats were exposed to MAM at dose levels of 0.13 to 0.44 ml/kg BW by i/p injections on days 5, 10, and 15 of gestations. The treatment caused resorptions, gross and skeletal malformations, fetal death, and decreased fetal size.³ There was no teratogenic effect when polymethylmetacrylate was used for implantation in humans.

Gonadotoxic effect of MAM was found in mice and rats in response to inhalation exposure above MAC 4 Administration of 1/20 LD₅₀ to rats for 2 months did not affect the estrus cycle^s

Allergenic Effect. MAM appeared to be a strong sensitizer, when tested by skin application in olive oil or ethanol. Nevertheless, according to Parker and Turk, methacrylates tested in five different sensitization protocols in guinea pigs were found to be ineffective.⁶

Mutagenicity.

Observations in man. No mutagenic effect was established in humans with polymethylmethacrylate implants.

In vitro genotoxicity. MAM appeared to be positive in Salmonella typhimurium mutagenicity bioassay. It caused a concentration-dependent increase in mutant frequency, producing gross CA in mouse lymphoma cells.'

Carcinogenicity. In a 2-year study, Wistar rats were given drinking water with concentrations of 6.0 to 2000 mg MAM/l. The treatment did not cause tumor development.⁸ IARC considers that the carcinogenic properties of MAM are not proved.

Carcinogenicity classifications. An IARC Working Group concluded that there is sufficient evidence suggesting lack of carcinogenicity of MAM in experimental animals and there is inadequate data available to evaluate the carcinogenicity of MAM in humans.

IARC: 3;

NTP: NE - NE - NE - NE (inhalation).

Chemobiokinetics. Accumulation in the blood, brain, and lungs was observed following acute inhalation exposure. MAM seems to affect the capillary network of the lung tissue (Raje et al., 1985). It is evidently completely oxidized in the body or hydrolyzed to form alcohol that undergoes further oxidation to CO₂ and H₂0. The main part of the dose is removed with the exhaled air in the form of CO₂, irrespective of the route of MAM administration. A smaller part of MAM escapes in the form of methylmelonate, succinate, and possibly, ß-hydroxy- isobutyrate.⁹ According to the data available, MAM metabolites were not found in the urine.¹⁰ MAM's relatively weak toxicity for rats is due to the fact that following oral administration the monomer is rapidly converted to pyruvic acid.

U.S. FDA (1998) regulates the use of MAM (1) as a monomer in adhesives as a component of articles intended for use in packaging, transporting, or holding food in accordance with the conditions prescribed in 21 CFR part 175.105; (2) as an ingredient in the manufacture of resinous and polymeric coatings of food-contact surface, subject to the conditions prescribed in 21 CFR part 175.300; (3) in acrylic and modified acrylic plastics for single and repeated use in contact with food in accordance with the conditions prescribed in 21 CFR part 177.1010; (4) in cross-linked polyester resins for repeated use as articles or components of articles coming in contact with food, subject to the provisions prescribed in 21 CFR part 177.2420; (5) as a component (a monomer) of the uncoated or coated food-contact surface of paper and paperboard intended for use in producing, manufacturing, packaging, processing, preparing, treating, packing, transporting, or holding dry food of the type identified in 21 CFR part 176.170 (c); (6) as a monomer in the manufacture of semirigid and rigid acrylic and modified acrylic plastics in the manufacture of articles intended for use in contact with food in accordance with the conditions prescribed in 21 CFR part 177.1010; (7) as a component (a monomer) of paper and paperboard used in contact with food in accordance with the conditions prescribed in 21 CFR part 176.180; the MAM contents in styrene-MAM copolymers used as components of paper and paperboard in contact with fatty foods were limited to 0.5%; and (8) as a monomer in the manufacture of polyethylene phthalate polymers used as, or components of plastics (films, articles, or fabric) intended for use in contact with food in accordance with the conditions prescribed in 21 CFR part 177.1630.

EU (1990). MAM is available in the List of authorized monomers and other starting substances which shall be used for the manufacture of plastic materials and articles intended to come into contact with foodstuffs (Section A).

Great Britain (1998). MAM is authorized without time limit for use in the production of polymeric materials and articles in contact with food or drink or intended for such contact.

Standards. Russia (1995). MAC and PML in drinking water: 0.01 mg/l; PML in food: 0.25 mg/l. 

References:

1. Klimkina, N. V., Ekhina, R. S., and Sergeev, A. N., Experimental data on MAC of methyl and butyl ether of methacrylic acid, Gig. Sanit., 4, 6, 1976 (in Russian).

2. Deichmann, W., Toxicity of methyl, ethyl and n-butyl methacrylate, J. Ind Hyg. Toxicol., 23, 343, 3. Singh, A. R., Lawrence, W. H., and Autian, J., Embryonic-fetal toxicity and teratogenic effects of a group of methacrylate esters in rats, J Dent. Res., 51, 1632, 1972.

4. Solovyeva, M. S., Smirnova, Ye. S., and Blagodatin V. M., Effect of methyl methacrylate on the specific female functions and sex functions of experimental animals, in Basic Problems of Delayed Consequences of Exposure to Industrial Poisons, Proc. Research Institute Occup. Diseases, A. K. Plyasunov and G. M. Pashkova, Eds., Moscow, 1976, 149 (in Russian).

5. Sheftel', V. O., Hygienic Aspects of the Use of Polymeric Materials in Water Supply, Author's abstract of thesis, All-Union Research Institute of Hygiene and Toxicology of Pesticides, Polymers and Plastic Materials, Kiyv, 1977, 158 (in Russian).

6. Parker, D. and Turk, J. L., Contact sensitivity to acrylate compounds in guinea pigs, Contact Dermat., 9, 55, 1983.

7. Moore, M. M., Amtower, A., Doerr, C. L., Brock, K. H., and Dearfield, K. L., Genotoxicity of acrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate in L5178Y mouse lymphoma cells, Environ. Molec. Mutagen., 11, 49, 1988.

8. Borzelleca, J. F., Larson, P. S., Henniger, G. R., et al., Studies on the chronic oral toxicity of monomeric ethylacrylate and methyl methacrylate, Toxicol. Appl. Pharmacol., 6, 29, 1964.

9. Bratt, H. and Hathway, D. E., Fate of methyl methacrylate in rats, Brit. J. Cancer, 36, 114, 1977. 10. Pantucek, M., Methylmethacrylate metabolism, Food Cosmet. Toxicol., 8, 105, 1970.

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