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EC number: 202-617-2 | CAS number: 97-90-5
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Sep. 2012 - March 2013
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Remarks:
- State of the art metabolism/toxicokinetcs study, GLP
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
- Objective of study:
- metabolism
- toxicokinetics
- Principles of method if other than guideline:
- In vitro metabolism study (rat liver microsomes, rat whole blood) in combination with toxicokinetic modelling (ADME model)
- GLP compliance:
- yes
Test material
- Reference substance name:
- Ethylene dimethacrylate
- EC Number:
- 202-617-2
- EC Name:
- Ethylene dimethacrylate
- Cas Number:
- 97-90-5
- Molecular formula:
- C10H14O4
- IUPAC Name:
- 2-[(2-methylprop-2-enoyl)oxy]ethyl 2-methylprop-2-enoate
- Test material form:
- liquid
Constituent 1
- Radiolabelling:
- no
Test animals
- Details on test animals or test system and environmental conditions:
- in vitro study
Results and discussion
Metabolite characterisation studies
- Details on metabolites:
- By the action of the non-specific carboxylesterases in the microsomes and in whole blood the esters were hydrolysed quantitatively to methacrylic acid and the corresponding alcohols/diols.
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
Seven methacrylate esters (including MMA, which served as a reference chemical) were initially chosen for experimental determination of metabolism rates in whole rat blood and rat liver enzymes at a single substrate concentration (Phase I). All seven methacrylates were quickly hydrolyzed to methacrylic acid (MAA) in, both, whole rat blood and rat liver microsomes. Hydrolysis half-lives of the esters in rat liver microsomes ranged 0.06 minutes to 4.95 minutes. Hydrolysis half-lives of the esters in whole rat blood ranged 1.56 minutes to 99 minutes.
Five methacrylate esters (including MMA, which served as a reference chemical) were chosen for further experiments to determine Km and Vmax values for these in rat liver microsomes. These values, along with QSAR-estimated partition coefficients were used for PBPK modeling to simulate in vivo blood concentrations of each molecule and its MAA hydrolysis product. Resulting blood concentrations were very similar between the five molecules. Differences in parent molecule blood concentrations (mg/L) varied by less than 2-fold and differences in MAA blood concentrations (mg/L) varied by less than 4-fold.
It is important to note that the PBPK model used for this effort was designed for methacrylate esters that have a single ester group, such that for each mol of parent ester hydrolyzed, one mol of methacrylic acid is formed. This is not the case for EGDMA and 1,4-BDDMA, which both contain two ester groups that can be hydrolyzed, resulting in two mol of methacrylic acid for every mol of parent ester. In the Phase II hydrolysis experiments, two mol of methacrylic acid were produced for every mol of methacrylate ester substrate introduced into the incubations. For these molecules, the PBPK model simulates only hydrolysis of the first ester group, resulting in one mol methacrylic acid per mol of parent ester.
Overall, these metabolism data and modeling results show that all five methacrylate esters studied in the definitive experiment are expected to be rapidly hydrolyzed in the rat, with greater than 86-99% cleavage by the oral route. Additionally, these simulated blood levels represent conservative estimates for those that would be expected to occur in the real world. In this study, only hydrolysis in the liver and blood has been considered. In reality, metabolism in other tissues would also be expected to occur (Brebner and Kalow, 1970; Fukami and Yokoi, 2012; Prusakiewicz et al., 2006; Satoh and Hosokawa, 1998; Zhu et al., 2000). Generally, exposures would be expected to occur via dermal, inhalation or oral ingestion. For any of these routes, pre-systemic hydrolysis would be expected to occur, significantly reducing the total amount of material reaching the systemic circulation. This has been illustrated by modeling of an oral dose route. However, even these simulations are expected to be highly conservative in terms of levels of parent ester and MAA metabolite present in the blood as the model assumes an oral bioavailability of 100 percent to the liver with no GI metabolism and no first-pass metabolism of MAA. In reality, esterase enzymes in the gut, as well as the lungs and skin in cases of dermal or inhalation exposure, would be expected to reduce the amount of methacrylate ester available to be absorbed (Brebner and Kalow, 1970; Fukami and Yokoi, 2012; Imai et al., 2003; Inoue et al., 1979; Li et al., 2007; Prusakiewicz et al., 2006). Additionally, further downstream metabolism of MAA, likely with significant first-pass metabolism, would be expected to reduce blood levels of this metabolite. Thus, real in vivo exposures are expected to result in lower blood levels of the methacrylate esters and their metabolic products than those simulated in this study.
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References:
Brebner, J., and Kalow, W. (1970). Soluble esterases of human lung. Canadian Journal of Biochemistry 48(9), 970-978.
Fukami, T. and Yokoi, T. (2012). The emerging role of human esterases. Drug Metabolism and Pharmacokinetics 27(5), 466-477.
Imai, T., Yoshigae, Y., Hosokawa, M., Chiba, K., and Otagiri, M. (2003). Evidence for the involvement of a pulmonary first-pass effect via carboxylesterase in the disposition of a propranolol ester derivative after intravenous administration. The Journal of Pharmacology and Experimental Therapeutics 307(3), 1234-1242.
Inoue, M., Morikawa, M., Tsuboi, M., and Sugiura, M. (1979). Species difference and characterization of intestinal esterase on the hydrolizing activity of ester-type drugs. The Japanese Journal of Pharmacology 29, 9-16.
Li, P., Callery, P. S., Gan, L-S., and Balani, S. K. (2007). Esterase inhibition attribute of grapefruit juice leading to a new drug interaction. Drug Metabolism and Disposition 35(7), 1023-1031.
Prusakiewicz, J. J., Ackermann, C., and Voorman, R. (2006). Comparison of skin esterase activities from different species. Pharmaceutical Research 23(7), 1517-1524.
Satoh, T. and Hosokawa, M. (1998). The mammalian carboxylesterases: from molecules to functions. Annual Review of Pharmacology and Toxicology 38, 257-288.
Zhu, W., Song, L., Zhang, H., Matoney, L., LeCluyse, E., and Yan, B. (2000). Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Drug Metabolism and Disposition 28(2), 186-191. - Executive summary:
All seven methacrylate esters were rapidly converted to MAA in whole rat blood and rat liver microsomes. Hydrolysis half-lives ranged from 1.56 to 99 minutes, and from 0.06 to 4.95 minutes for blood and liver microsomes, respectively. The incubations in whole rat blood and rat liver microsomes were performed on three separate days with MMA included as a positive control on each day. Table 6 shows elimination rates (ke), intrinsic clearance (Clint) and half-life values for each molecule in whole rat blood and rat liver microsomes at 0.25 mM starting concentrations.
Rat liver microsome hydrolysis rates for the positive control (MMA) were somewhat variable between days. This was likely due to the rapidity of hydrolysis of MMA. Often, measurable levels of MAA were present even in the zero minute samples and the substrate was completely hydrolyzed by 2 minutes. This made it difficult to accurately calculate hydrolysis rates for MMA in these experiments. However, generally the calculated rates were similar to rates for hydrolysis for MMA reported previously (Jones, 2002; Mainwaring et al., 2001) and confirmed that the in vitro test systems were enzymatically active for each day of incubation experiments. The remaining six molecules exhibited rat liver microsome hydrolysis rates approximately 10 fold lower than MMA. However, all seven molecules were completely, or nearly completely, hydrolyzed to MAA within 15 minutes incubation.
----------------------------
References:
Jones, R. D .O. (2002). Using physiologically based pharmacokinetic modeling to
predict the pharmacokinetics and toxicity of methacrylate esters. Thesis
submitted to theoffor the degree of Doctor of Philosophy
in the Faculty of Medicine, Dentistry, Nursing and Pharmacy.
Mainwaring, G., Foster, J. R.,, V., and Green, T. (2001). Methyl methacrylate
toxicity in rat nasal epithelium: studies of the mechanism of action and
comparisons between species.Toxicology158,109 -118.
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