2,3-epoxypropyl methacrylate

Endpoint summary

Additional information

Genetic toxicity

Bacterial test

[SIDS data] Glycidyl methacrylate was mutagenic to Salmonella typhimurium TA97, TA100, TA1535 with and without metabolic activation but not to TA98 (Dorothy et al.: 1986, The Goodyear Tire & Rubber Company: 1981, OuYang et al.: 1988).

Glycidyl methacrylate was mutagenic to Klebsiella pneumoniae without metabolic activation (Voogd et al.: 1981). In Escherichia coli, this chemical induced SOS repair with and without metabolic activation (von der Hude et al.: 1990). This chemical was shown to react with the DNA of the gene governing tetracycline resistance in the plasmid pBR322. The modified DNA was transferred to a receptor cell (Escherichia coli HB 101) to screen for mutations based on alterations in phenotypic changes. Results showed the mutations caused by reactions of glycidyl methacrylate with the plasmid were stable and heritable (Xie et al.: 1990a).

Non-bacterial test in vitro

[SIDS data] In chromosomal aberration test of glycidyl methacrylate, using cultured Chinese hamster lung (CHL/IU) cells, both structural abnormality and polyploidy were induced with and without metabolic activation. However, a trend test showed no dose-dependency for the induction of polyploidy with the 24 hours continuous treatment and the short-term treatment with the metabolic activation system. (MHW, Japan: 1997)

In cell cultures, glycidyl methacrylate induced hypoxanthine-guanine-phosphoribosyl transferase forward gene mutation with metabolic activation in Chinese hamster ovary cell (Linscombe and Engle: 1995), very slight increase of unscheduled DNA synthesis in lymphocytes of human and/or rat (Xie et al.: 1990b), non-reverse type inhibition of the DNA replication in lymphocytes of human and/or rat (Xie et al.: 1989), sister-chromatid exchange without metabolic activation in Chinese hamster V79 cells (von der Hude et al.: 1991), transformation of Syrian hamster embryonic cells (SHE) (Xie et al., 1992) and transformation in diploid golden Syrian hamster embryo (SHE) cells (Yang et al.; 1996). This chemical was strongly and covalently bound with calf thymus DNA in vitro (Xie et al.: 1990b).

in vivo test

[SIDS data] In micronucleus assay, mice were administered by gavage with glycidyl methacrylate at a single dose of 188, 375 and 750 mg/kg in males and 250, 500 and 1000 mg/kg in females. The frequency of micronucleated polychromatic erythrocytes in both sexes was significantly increased only at the highest doses 48 hour after administration. (MHW, Japan: 1997)

Three additional mouse bone marrow micronucleus tests by intraperitoneal (ip) administration have been reported. In one study,this chemical produced a 2-3 fold increase in micronuclei at all administered doses relative to the control although it showed an inverse dose response(Ou-Yang et al., 1988). On the other hand, this chemical did not cause an increase in the number of cells containing micronuclei in two other ip injection studies with GMA doses of 75, 150, and 300 mg/kg (Lick et al., 1995) or doses of 42.2, 133, 422, and 464 mg/kg (INBIFO: 1979).

This chemical increased unscheduled DNA synthesis in germ cell of male mice but this effect was very slight (~25% above controls for all doses administered) and not dose-related (Xie et al.: 1990b).

GMA was evaluated in an in vivo assay for the induction of gene mutations at the lacI locus of transgenic Big Blue Fischer 344 (F-344) rats. The rats (15 males/group) were exposed to GMA vapors by inhalation at targeted concentrations of 0 (negative control), 1, 10, and 25 ppm for 2 weeks, 6 hrs/day, 5 days/week. There were no statistically significant increases in the frequencies of lacI mutants in either the olfactory or respiratory epithelium of rats exposed at all doses tested including 25 ppm (145.5 mg/cm3) (17.7. mg/kg/day) when compared to the corresponding negative control values. Based upon these results, the authors concluded that GMA was not mutagenic to the nasal epithelium of rats under the conditions of the study (Gollapudi et al., 1999).

In view of the fact that glycidyl methacrylate is metabolised to glycidol, information is being provided below on the genotoxicity of glycidol, as supporting data for an evaluation of the genotoxic potential of glycidyl methacrylate.

Glycidol was evaluated for the potential to cause micronuclei in mouse bone marrowin vivo (NTP, 1990). Male mice were given two intraperitoneal injections of 37.5, 75 and 150 mg/kg, 24 hours apart, with the glycidol dissolved in phosphate-buffered saline; the total dose volume was 0.4 ml. Solvent control animals were injected with 0.4 ml phosphate-buffered saline only. The positive control mice received injections of mitomycin C. Twenty-four hours after the second injection, the mice were killed by cervical dislocation, and smears were prepared of the bone marrow cells obtained from the femurs. Air-dried smears were fixed and stained; 2,000 PCEs were scored for the number of micronucleated cells in each of five animals per dose group. The results were tabulated as the mean of the pooled results from all animals within a dose group +/- standard error of the mean.

Preliminary range-finding studies were performed to determine appropriate doses for thein vivo micronucleus test. Dose selection in this study was based on animal lethality; no decrease in the percentage of polychromatic erythrocytes (PCEs) in the bone marrow was observed in any of the dose groups. In the first trial, the incidence of micronuclei was increased statistically above concurrent phosphate-buffered saline controls. Micronuclei incidence was increased at doses of 75 and 150 mg/kg. In a second trial, incidences of micronuclei were statistically increased above concurrent control values at 37.5 and 150 mg/kg but not at 75 mg/kg. (It is noted that the control for the second trial was lower that the control in the first trial.)

 

Genotoxicity studies on glycidyl methacrylate in vitro showed positive results. In micronucleus tests in vivo, oral administration of glycidyl methacrylate increased the frequency of micronucleated polychromatic erythrocytes at the highest dose only, while mostly negative results were shown in other in vivo genotoxicity studies including micronucleus tests by intraperitoneal administration and including the gene mutation study using trangenic Big Blue Fischer 344 rats. Glycidol, a metabolite of glycidyl methacrylate, is classified as a Category 2 germ cell mutagen under REACH and CLP. Based on the available studies for glycidyl methacrylate itself and data for glycidol , glycidyl methacrylate is considered to be a substance with genotoxic potential.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

Based on the available studies glycidyl methacrylate is classified under REACH and CLP as:

Germ cell mutagen category 2 (H341)