2-[2-(2-ethoxyethoxy)ethoxy]ethyl methacrylate

Endpoint summary

Description of key information

ET3EGMA is likely to be readily absorbed by all routes. Due to the low vapour pressure, the dermal route is the primary route of exposure, since inhalation is unlikely. The ester is rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. The primary metabolite, MAA, is subsequently cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2. Based on physicochemical properties, no potential for bioaccumulation is to be expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Absorption

Oral absorption

The physicochemical properties of ET3EGMA (log P = 2.1) and the molecular weight of 246.3 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion.For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data.

Dermal absorption

Based on a QSAR Prediction of Dermal Absorption (extract from Heylings JR, 2013) ET3EGMA has been predicted on the basis of its molecular weight and lipophilicity to have a relatively high ability to be absorbed through the skin. The predicted flux was 103.5μg/cm²/h.

For chemical safety assessment, a dermal absorption rate of 100% was assumed as worst case default value.

Inhalative absorption

Due to the low vapour pressure of ET3EGMA (0.077 Pa at 20°C), exposure via inhalation is unlikely. For chemical safety assessment an inhalative absorption rate of 100% is assumed as a worst case default value in the absence of other data.

Distribution

As a small molecule a wide distribution can be expected. No information on potential target organs is available.

Metabolism

Ester hydrolysis:

Ester hydrolysis has been established as the primary step in the metabolism resulting in methacrylic acid (MAA) and the corresponding alcohol (glycol ether).

 

Carboxylesterases are a group of non-specific enzymes that are widely distributed throughout the body and are known to show high activity within many tissues and organs, including the liver, blood, GI tract, nasal epithelium and skin (Satoh & Hosokawa, 1998; Junge & Krish, 1975; Bogdanffy et al., 1987; Frederick et al., 1994). Those organs and tissues that play an important role and/or contribute substantially to the primary metabolism of the short-chain, volatile, alkyl-methacrylate esters are the tissues at the primary point of exposure, namely the nasal epithelia and the skin, and systemically, the liver and blood. For multifunctional methacrylates mostly the same would be the case except that because of the lower vapour pressure and hence lower likelihood of inhalation exposure the involvement of the nasal epithelium is less likely.

 

An elaborate series of in vitro studies on carboxylesterase activity with 7 alkyl methacrylates ranging from methyl methacrylate to octyl methacrylate (with increasing ester size) was used to construct a PB-PK model of in vivo clearance for several tissues (blood, liver, skin and nasal epithelium) from rats and humans (Jones, 2002). Some of these data for rats are summarised below and demonstrate that methacrylate esters are rapidly hydrolysed by carboxylesterases to methacrylic acid (MAA) and the respective alcohol. Clearance of the parent ester from the body is in the order of minutes.

Kinetics data have been reported for the hydrolysis of two lower alkyl methacrylates (EMA and BMA) and two multifunctional methacrylates (EGDMA and TREGDMA) by porcine liver carboxylesterase in vitro (table 3; McCarthy and Witz, 1997).

Hydrolysis of Acrylate Esters by Porcine Liver Carboxylesterase in vitro (extract from McCarthy and Witz, 1997):

Ester	Km (mM)	Vmax (nmol/min)
Ethyl methacrylate (EMA)	159±90	5.2±2.5*
Butyl methacrylate (BMA)	72±28*	1.8±0.6*
Ethyleneglycol dimethacrylate (EGDMA)	64±24*	6.9±2.4
Tetraethyleneglycol dimethacrylate (TREGDMA)	39±15*	2.9±1.0*

* Significantly different (p < 0.05) from ethyl acrylate

 

Although the absolute rate measurements obtained by McCarthy and Witz differ slightly to those determined by Jones, presumably due to differences in experimental conditions such as protein content etc., the rates obtained for the two lower alkyl methacrylates (EMA and BMA,) can be used to draw parallels between the work of the two researchers indicating that the kinetics for the hydrolysis fall within the range observed by Jones for lower alkyl methacrylates. On this basis the parent ester would be expected to have a short systemic half–life within the body being effectively cleared from the blood within the first or second pass through the liver. Hydrolysis of the di- and mono- ester would yield the common metabolite methacrylic acid and the respective alcohol.

 

Elimination Rates, Intrinsic Clearance and Half-life in Rat Liver Microsomes and Whole Rat Blood for Seven Methacrylate Esters at 0.25 mM Substrate Concentration:

	Liver Microsomes			Whole Blood
Molecule	Clint (μl/min/mg)	ke	Half‐Life (min)	Clint (μl/min)	ke	Half‐Life (min)
MMA	1192	2.38	0.29	19	0.01	63.00
HEMA	74	0.15	4.62	12	0.01	99.00
MTMA	5800	11.60	0.06	70	0.04	17.77
EGDMA	142	0.28	2.45	796	0.44	1.56
1,4-BDDMA	78	0.16	4.46	304	0.17	4.10
ET3EGMA	69	0.14	4.95	44	0.03	27.72
TREGDMA	116	0.23	3.01	219	0.12	5.68

ke: elimination rate
Clint: intrinsic clearance (ke x volume of incubation / mg/mL microsomal protein)
HEMA: Hydroxyethyl methacrylate; MTMA: Methoxyethyl methacrylate; EGDMA: Ethyleneglycol dimethacrylate; 1,4-BDDMA: 1,4-Butanediol dimethacrylate: TREGDMA: Triethylenglycol dimethacrylate

 

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. The table above shows elimination rates (ke), intrinsic clearance (Cl_int) 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 hydrolysed 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.

 

Subsequent metabolism:

For the lower alkyl methacrylates it has been established that the primary metabolites, methacrylic acid and the corresponding alcohol are subsequently cleared predominantly via the liver (valine pathway and the TCA (Tricarboxylic Acid) cycle, respectively). Triethyleneglycol is known to be primarily excreted either in its original form or with one terminal hydroxyl group oxidised to a carboxyl group by alcohol dehydrogenases.

 

Glutathione reactivity:

A QSAR model for ET3EGMA predicted only slight reactivity with glutathione for the ester and no reactivity for the primary metabolite, methacrylic acid.

 

Studies with methacrylates in vitro confirm low reactivity with GSH, in particular compared to the corresponding acrylates, and have proposed that this is due to steric hindrance of the addition of a nucleophile at the double bond by the alpha-methyl side-group (McCarthy & Witz, 1991, McCarthy et al., 1994, Tanii and Hashimoto, 1982). This is also confirmed by the publication of Nocca et al. (2011) who found a low levels of GSH adducts of triethyleneglycol methacrylate (TREGDMA) when erythrocytes and gingival fibroblasts were exposed to 2 mM (573 mg/L) TREGDMA in vitro.

Apparent Second-Order Rate Constants for the Reaction of Glutathione with Methacrylate Esters (extract from McCarthy et al., 1994)

Ester	App. 2^ndorder rate const. Kapp[L/mol/min]
Methyl methacrylate (MMA)	0.325±0.059
Ethyl methacrylate (EMA)	0.139±0.022
Butyl methacrylate (BMA)	No appreciable reaction rate
Ethyleneglycol dimethacrylate (EGDMA)	0.83±0.12 (0.406±0.059
Tetraethyleneglycol dimethacrylate (TTEGDMA)	1.45±1.0 (0.725±0087)*

           *Bifunctional esters calculated as two independent esters.

In conclusion, ester hydrolysis is considered to be the major metabolic pathway for alkyl and multifunctional methacrylate esters, with GSH conjugation only playing a minor role in their metabolism.

 

Excretion

While first pass metabolism in the liver is the main metabolic pathway, a small part of the ester, may be excreted via the kidneys. Excretion via the kidneys is also the main elimination pathway for ethyltriglycol and its subsequent metabolites. The primary metabolite, MAA, is cleared rapidly from blood by standard physiological pathways, with the majority of the administered dose being exhaled as CO2.