2-Propenoic acid, 2-methyl-, C13-15-branched and linear alkyl esters

Endpoint summary

Description of key information

Based on the molecular weight 268.4 - 296.5 g/mol, the high log Pow of >6.3 and very low water solubility, 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters are not very likely to be observed in the gastrnintestinal (GI) tract. The high log Pow indicates that the substance will not diffuse well across plasma membranes. In addition, gastro-intestinal absorption will not be triggered by passage via passive diffusion through aqueous pores or carriage with the bulk passage of water, which is favoured for small (molecular weight < 200 g/mol), water soluble substances. Therefore, only very low concentrations of these substances are bioavailable. The substances may be taken up by micellular solubilisation since this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), particularly those that are poorly soluble in water. Overall, limited gastrointestinal absorption is expected for the target substance and the source substances based on their physicochemical properties. Moreover, almost no systemic effects were seen in acute toxicity studies after oral administration of 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters demonstrating and supporting that 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters are not very well absorbed in the gastrointestinal tract, and if absorbed reveal a low systemic toxicity. 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters has a low volatility (vapour pressure of 4.5 hPa). Therefore, only a very minimal amount of the substance is available for inhalation and thus, absorption by inhalation can be almost excluded. Moreover, absorption will be limited due to the low water solubility and high Pow of the substances. 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters is a liquid with a low water solubility (<0.5 µg/L) and a molecular weight of 268.4 - 296.5 g/mol, therefore dermal uptake from the stratum corneum into the epidermis is likely to be low. With log Pow > 6.3 the rat of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. In addition, the substances showed effects when tested for skin irritation and skin sensitisation. Based on the physicochemical properties of 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters thy are unlikely to be widely distributed systemically throughout the extracellular compartments of the body after absorption. Particularly due to the low water solubility and the high log Pow values, a long biological half-life in tissues might be expected, but is almost excluded due to the poor absorption and the metabolic cleavage. Thus, the target substance and the source substances have no bioaccumulation potential and only a limited amount of any of these substances come into consideration for distribution into blood or plasma and accumulation in organs and tissues.

2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters and its analogues chemicals, 2-Propylhepty methacrylate (CAS149855-64-1), C17-methacrylate (CAS 1473386-29-6) n-Dodecyl methacrylate (CAS 142-90-5) and Isodecyl methacrylate (CAS 29964-84-9) are higher methacrylate esters and are similar metabolised. For these substances there are no in vivo metabolism data available. However, there is literature available regarding metabolism of methacrylate esters providing sufficient information on the metabolism of 2-Propenoic acid, 2-methyl-, C13-15-branced and linear alkyl esters and its analogues. Metabolism of methacrylate esters occurs by two primary routes, hydrolysis of the ester linkage and conjugation with glutathione (GSH).

The prominent pathway for the metabolism of higher methacrylate esters starts with ester hydrolysis resulting in methacrylic acid (CAS no 79-41-4) and the corresponding alcohol (Jones 2002, McCarthy and Witz 1997). Alkyl esters of methacrylic acid up to C8 (2-ethylhexyl methacrylate) showed rapid metabolism with half lives in rat blood of less than 30 min (Jones, 2002). While the acid is further metabolised via the valine pathway of the citric acid cycle (ECETOC, 1995) the alcohol may be further metabolised by the two standard metabolic pathways for fatty alcohols (1.: oxidation: fatty alcohol -> aldehyde -> acid, and subsequently CoA-mediated fatty acid metabolism or 2.: glucuronidation of the alcohol and excretion).

In addition, a series of in vitro and in vivo studies with a series of methacrylates were used to develop a PBPK model that accurately predicts the metabolism and fate of these monomers. The studies confirmed that alkyl methacrylate esters are rapidly hydrolysed in the organism by ubiquitous carboxylesterases. First pass (local) hydrolysis of the parent esters has been shown to be significant for all routes of exposure. In vivo measurements of rat liver indicated this organ as with the greatest esterase activity. Similar measurements for skin microsomes indicated an approximately 20-fold lower activity than for liver. Nevertheless, this activity was substantial and capable of almost complete first-pass metabolism of the alkyl methacrylates applied on skin. Furthermore, model predictions indicate that esters of ethyl methacrylate or larger would be completely hydrolysed before entering the circulation via skin absorption. This pattern is consistent with a lower rate of absorption for these esters indicating that the rate of metabolism is within the metabolic capacity of the skin. Parent ester also was hydrolysed by S9 fractions from nasal epithelium and was predicted to be effectively hydrolysed following inhalation exposure. These studies showed that any systematically absorbed parent ester will be effectively removed during the first pass through the liver.  In addition, removal of methacrylic acid from the blood also occurs rapidly.

GSH conjugation, the second potential pathway, has only been observed with small alkyl methacrylates (methyl methacrylate/MMA, ethyl methacrylate/EMA) but was no longer measurable with butyl methacrylate. Moreover, GSH conjugation was only detectable with MMA and EMA at high concentrations which are only achievable under laboratory conditions (Elovaara et al., 1983, Mc Carthy et al., 1994).