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Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

There was no reliable and relevant information source investigating the absorption/metabolism/excretion of ethoxylated trimethylolpropane triacrylate (TMPeoTA, CAS 28961-43-5). Since no experimental data are available to assess the absorption and metabolism properties of the test substance, the expected toxicokinetic behavior is estimated based on the physicochemical properties. The test substance is a liquid with a low vapour pressure of 0.0032 Pa. The molecular weight varies between approx. 410 and 450 g/mol, depending on the number of ethoxy and acrylic acid units per molecule. The moderate water solubility of 0.8 g/L matches the LogPow of 2.89. Hydrolysis in water can occur but is very slow (half-life 453d at 12°C) and thus not considered relevant in this context.

Absorption:

No systemic toxicity was observed following ingestion of the substance, which is either due to the low toxicity of the substance or due to low GI absorption. Substances with a molecular weight below 500 g/mol and a moderate logPow between -1 and 4 are usually readily absorbed in the gastrointestinal tract. Additionally, the water solubility of 0.8 g/L, which allows dissolution in the GI fluids, and the absence of ionizable elements in the structure favor gastric absorption. In summary, the substance will likely be well absorbed after oral exposure.

Based on the water solubility and low lipophilicity, the substance will probably also be absorbed, if it reaches the lung mucosa. On the other hand, exposure is considered negligible due to the very low vapour pressure of only 0.0032 Pa. Thus, even though absorption cannot be excluded, inhalation is not considered a relevant route of exposure.

Due to the physico-chemical information (moderate water solubility and logPow of 2.89) the substance can assume to be absorbed via skin. The low volatility, the moderate lipophilicity, and the slight irritating effect of the substance points to an increased absorption, but the high molecular weight (approx. 410 and 450 g/mol) and a possible binding to skin, caused by the acrylate group, decreases the absorption potential of the substance. Sensitisation was reported for TMPeoTA with LLNA and Buehler tests (BASF, 2004/2006, Gamer A.O.) and therefore absorption is expected to take place. No toxicity occurred in acute dermal studies, but this might be due to the low toxicity of the substance. The substance causes only very slight skin irritation but caused skin sensitization in animals. The latter proves that dermal absorption is possible, though no information about the percentage is available. In conclusion, although dermal absorption might be lower than GI absorption, it is definitely possible. Moderate to well absorption is assumed for the risk assessment.

Distribution and Metabolism:

No systemic toxicity of the substance was seen in an OECD 422 study using oral gavage administration. NOAEL of 1000 mg/kg bw/day was concluded for systemic effects while a NOAEL of 100 mg/kg bw/day, based on adverse local forestomach effects at 300 mg/kg/day (males) and 1000 mg/kg/day (both sexes) was concluded. Once absorbed the substance is expected to be quickly metabolized by esterases in the liver or other tissues (e.g., the skin after dermal contact) to acrylic acid and the corresponding alcohol. Acrylic acid is first converted to acrylyl-CoA, which is subsequently oxidized to 3-hydroxypropionate. 3-hydroxypropionate is, in turn, metabolized to acetate and carbon dioxide via malonic semialdehyde. The resultant acetate is then incorporated into intermediary metabolism. 

The resulting alcohol is either further metabolized via alcohol – and aldehyde dehydrogenases to the corresponding acid, which is then bound to glutathione prior to excretion, or the tri-alcohol is directly conjugated to glutathione and excreted. Both reactions are believed to be rapid and to compete with one another, so that either way is about equally likely. In any case, the substance will be quickly metabolized and excreted. No accumulation or long half-life is expected. This is also supported by the water solubility of 0.8 g/L, and a logPow of 2.89. Parent compound that reaches the blood is likely not metabolized but directly and very rapidly conjugated to glutathione, as was shown for other acrylates by Miller et al. in 1981.

Excretion:

Due to the physico chemical information (molecular weight, lipophilicity and vapour pressure) the substance is assumed to be excreted via feces (bile) and urine. Specifically, glutathione conjugates of the substance and its break down products are expected to be biliary excreted and may undergo enterohepatic recycling while passing through the intestine before finally excreted via faeces. Small, water soluble metabolites are predominantly excreted via urine. Carbon dioxide as a product of acrylic acid metabolism is exhaled.

Summary:

The bioavailability of the substance can be confirmed for different routes (dermal, oral and inhalation). It can be assumed that the substance is distributed to many different tissues, but the potential to accumulate is low. First step in metabolism may lead, based on the structure, to two metabolites (suspected to be acrylic acid and the alcohol). Reactivity to nucleophilic molecules (e.g., thiol or amine groups of proteins) can be expected. Fast elimination of the substance, mainly via urine, exhaled air (resulting from the conversion into acrylic acid and later to CO2) and faeces, is expected. Nevertheless, due to the high molecular weight also higher amounts excreted via feces/bile are expected.

Reference: Miller, R. R. (1981). Metabolism of Acrylate Esters in Rat Tissue Homogenates.Fundamental and Applied Toxicology, 1, S. 410-414.

 

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