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Description of key information

Taking into consideration all available data, 2-MEA is readily absorbed following oral, inhalation or dermal exposure, rapidly metabolized and its metabolites are distributed extensively throughout the body, including the developmental fetus.

Key value for chemical safety assessment

Additional information

There are no experimental studies available in which the toxicokinetic properties of 2-methoxyethyl acrylate (2-MEA) were investigated. Therefore, whenever possible, toxicokinetic behaviour was assessed taking into account the available information on physicochemical and toxicological characteristics of 2-MEA according to “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012)”.

2-MEA (130.14 g/mol) is a colourless to pale yellow transparent liquid at room temperature. It is highly soluble in water (144 g/L) and has a vapour pressure of 281 Pa at 25 °C. The low partition coefficient (log Kow) of 0.9 results in a low potential to accumulate in biological systems.


Absorption and distribution

Oral absorption

In an acute oral toxicity study, rats were administered 2 –MEA via gavage (Shapiro, 1980). 5 rats per sex and dose received the following dose levels: 252.5, 353.3, 505.0, 555.5, 606.0 mg/kg bw. The mortality was 0, 2, 2, 4 and 5 for males and 0, 2, 3, 4 and 5 for females, respectively, listed by increasing dose levels. Autopsy of dead animals revealed pulmonary hemorrhages. No clinical signs were noted. The LD50 of the test substance was 404 mg/kg bw.

In another acute oral toxicity study, 5 male rats per dose received the test substance via gavage at dose levels of 252.5, 1010 and 2020 mg/kg bw (Union Carbide Corporation, 1968). Mortalities were observed in 0/5 animals, 4/5 animals and 5/5 animals treated with 252.2, 1010 and 2020 mg/kg bw, respectively. At the lowest dose level, sluggish behaviour was observed during the 14-day observation period. At necropsy, congestion was observed in the lungs and the abdominal viscera of treated animals. The oral LD50 in rats was calculated to be 818 mg/kg bw.

With respect to the dose administered and the effects observed, systemic bioavailability of the test substance is considered to play a significant role after single oral administration of 2-MEA. Moreover,a repeated dose toxicity study according to OECD 422 confirmed that 2-MEA was systemically bioavailable after oral administration (de Raaf-Beekhuijzen, 2012). In this study, 2-MEA led to systemic (blood system, testes, epididymides), reproductive and developmental toxicity at all dose levels tested.


Inhalation absorption

The acute inhalation toxicity of 2-MEA was investigated in male rats (6 per concentration) using a whole body exposure system (Union Carbide Corporation, 1968). The test concentrations used were 5.3, 2.7 and 1.3 mg/L. Each animal was exposed to the test substance for 4 h. At 1.3, 2.7 and 5.3 mg/L, mortalities were observed in 0/6, 3/6 and 6/6 animals, respectively. Clinical signs observed in the animals involved swollen abdomen, laboured breathing and gasping. Furthermore, irritation of the eyes, nose and extremities was noted during exposure to the test substance. Necropsy of rats dying during the study revealed slight haemorrhage of lungs and blood in intestines. In 2/3 surviving rats at 2.7 mg/L areas of focal consolidation scattered throughout the lungs were observed at necropsy. Based on the results, the LC50 in rats was 2.7 mg/L.

As the vapour pressure of 2-MEA is 281 Pa (at 25 °C), there is a potential for inhalation exposure which is confirmed by the acute inhalation toxicity study.


Dermal absorption

The acute dermal toxicity of 2-MEA was assessed in 4 rabbits per dose at dose levels of 126.25, 252.5 and 505 mg/kg bw (Union Carbide Corporation, 1968). The undiluted test substance was applied for 24 h to the clipped trunk under occlusive conditions. After 24 h exposure, residual test substance was washed and animals were observed during a period of 14 days. Mortality occurred at dose levels of 126.25, 252.5 and 500 mg/kg bw in 0/4, 2/4 and 4/4 animals, respectively. No clinical signs were observed in any treated animal, but skin irritation was noted in all surviving animals treated with 252.5 and 505 mg/kg bw. Necropsy revealed mottled liver in the treated animals. Based on the results, the dermal LD50 value in rats was determined to be 252.5 mg/kg bw. Therefore, dermal absorption seems to be a significant route of exposure, as systemic toxicity was found after single dermal application of 2-MEA.

For 2-MEA, a QSAR based modelling published by Potts and Guy (1992), taking into account molecular weight and log Kow, estimated a dermal permeability constant Kp of 4.03E-04 cm/h. Similar to the approach taken by Kroes et al. (2007), the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated, resulting in dermal absorption of 403 µg/cm²/h 2-MEA. Usually, this value is considered as indicator for a dermal absorption of 80% (Mostert and Goergens, 2011).

Taking into consideration all available data on acute and repeated dose toxicity, 2-MEA is readily absorbed following oral, inhalation or dermal exposure and distributed extensively throughout the body, including the developing fetus.


Metabolism and excretion

There are no experimental data available concerning the metabolism of 2-MEA. QSAR estimation using the OECD Toolbox v.2.3 suggests enzymatic cleavage of the ester bond resulting in acrylic acid and 2-methoxyethanol as primary metabolites. Both primary metabolites are described briefly below.

Acrylic acid:The primary metabolite acrylic acid is rapidly metabolised by oxidative pathways to carbon dioxide which is formed via acrylyl-CoA by the non-vitamin-B12-dependent pathway of mammalian propionate catabolism (EU RAR, acrylic acid, 2002). About 80% of an ingested dose of acrylic acid is exhaled as carbon dioxide within 24 hours. The kidneys and liver may be major sites of acrylic acid metabolism (Black et al., 1993).In urine poorly characterised substances of a higher polarity than those of acrylic acid are detected. Unmetabolised acrylic acid was not found in urine. However, a small proportion of 3-hydroxypropionic acid as major urinary metabolite of absorbed acrylic acid was identified (EU RAR, acrylic acid, 2002). Epoxidised metabolites of acrylic acid were not detected (EU RAR, acrylic acid, 2002). High dosages of acrylic acid leading to tissue damage caused the formation of small amounts of mercapturic acid derivates (EU RAR, acrylic acid, 2002).

2-Methoxyethanol: The metabolism of 2-methoxyethanol is well studied and the proposed metabolic pathways are outlined in Figure 1 (please refer to the attachment). There are several metabolic pathways identified for 2-methoxyethanol, involving predominantly oxidation. In the first pathway, 2-methoxyethanol is rapidly metabolised via alcohol and aldehyde dehydrogenase to methoxyacetaldehyde, then methoxyacetic acid, the likely active metabolites. Methoxyacetic acid is subsequently conjugated with glycine or O-demethylated and then oxidized to produce carbon dioxide. Some methoxyacetic acid may also undergo Krebs cycle transformation. Alternatively, 2-methoxyethanol may be oxidised via microsomal P450 mixed-function oxidases and O-demethylated to form formaldehyde and ethylene glycol. Subsequently, ethylene glycol will be oxidised via glycolic acid to oxalic acid and formaldehyde to formic acid. 2-Methoxyethanol may also be directly conjugated with sulfate or glucuronic acid.

In general, methoxyacetic acid (in free or conjugated form) was the principal metabolite detected in the urine of rats, mice and humans exposed by ingestion or inhalation (U.S. EPA, 1986). The results of several studies indicated that methoxyacetic acid is either excreted in the urine or further metabolised to the corresponding glycine conjugate or to carbon dioxide, which is exhaled in air (U.S. EPA, 1986). Other urinary metabolites included ethylene glycol, particularly in rats following repeated exposure in drinking-water (Medinsky et al., 1990) and products of the Krebs cycle metabolism. The putatively toxic metabolite methoxyacetic acid is eliminated much more slowly in humans than in (pregnant) rats and (pregnant) monkeys, with half-lives in the blood of 77, 12 and 19 h, respectively (Groeseneken et al., 1989). One study demonstrated that, following a single oral dose of 14C-2-methoxyethanol, urinary radioactivity consisted of 73.1% methoxyacetic acid, 14.8% 2-methoxyethanol, and 8.1% of an unidentified metabolite (U.S. EPA 1986).

The toxicokinetic studies of Miller et al. (1983, 1984) using radiolabelled 2-methoxyethanol showed that approximately 95% of an orally ingested dose is excreted within 48 hours and that the main route of metabolism accounting for more than 50% of the ingested dose is to methoxyacetic acid, which is excreted in urine in its free or conjugated form. A smaller but significant amount is metabolized to carbon dioxide and exhaled in air.

Based on the primary metabolites acrylic acid and 2-methoxyethanol, 2-MEA is predominantly excreted by the kidneys as methoxyacetic acid (in free or conjugated form) and exhaled as carbon dioxide.

In summary, 2-MEA is readily absorbed following oral, inhalation or dermal exposure, rapidly metabolized and its metabolites are distributed extensively throughout the body, including the developmental fetus. Furthermore the test substance is of toxic to harmful acute toxicity following oral, inhalation or dermal exposure. It has a high potential for causing skin or eye corrosion and has been shown to be a skin sensitizer. Based on the screening study (de Raaf-Beekhuijzen, 2012), the key adverse health effects following repeated exposure to 2-MEA are haematological effects as well as reproductive and developmental toxicity, including both impaired fertility and teratogenicity.


References not cited in the IUCLID:

Potts and Guy (1992), Predicting skin permeability. Pharm. Res. 9(5): 663-669

Kroes et al. (2007), Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients. Food Chem. Toxicol. 45, 2533–2562

Mostert and Goergens (2011), Dermal DNEL setting: using QSAR predictions for dermal absorption for a refined route-to-route extrapolation. Society of Toxicology, Annual Meeting, ISSN 1096-6080 (http: //www. toxicology. org/AI/PUB/Toxicologist11. pdf), 120(2): 107

European Union Risk Assessment Report (EU RAR), 2002, Acrylic Acid, CAS 79-10-7, rapporteur: Germany, ISBN 92-894-1272-0

Black et al. (1993), Metabolism of acrylic acid to carbon dioxide in mouse tissues. Fundam. Appl. Toxicol. 21(4): 97-104

Groeseneken et al. (1989) Experimental human exposure to ethylene glycol monomethyl ether. International Archives of Occupational and Environmental Health, 61(4):243–247.

Miller et al. (1983), Comparative metabolism and disposition of ethylene glycol monomethyl ether and propylene glycol monomethyl ether in male rats. Toxicol Appl Pharmacol (67)2, p229-37

Miller et al. (1984), Ethylene glycol monomethyl ether and propylene glycol monomethyl ether: metabolisms, disposition and subchronic inhalation toxicity studies. Env Hlth Persp, 57, 233-9

U.S. EPA (1986), U.S. Environmental Protection Agency. Health and Environmental Effects Profile for 2-Methoxyethanol. Office of Health and Environmental Assessment, U.S. EPA

WHO (2009), Concise International Chemical Assessment Document 67, Selected Alkoxyethanols: 2-Methoxyethanol