Reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate

Endpoint summary

Description of key information

The target substance reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC No. 906-949-5) is expected to be hydrolysed within the human body and the hydrolysis products readily absorbed via the oral route. Absorption via the inhalation route is assumed to be limited. Also low absorption via the dermal route is expected. The absorbed hydrolysis products are readily distributed throughout the organism, with limited distribution in adipose tissue. The hydrolysis products are expected to be rapidly conjugated and excreted via the urine, or metabolised and excreted via air as CO₂. No bioaccumulation will take place, as the parent molecule and metabolites do not have lipophilic groups.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate (EC No. 906 -949 -5) was investigated.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No. 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of the target substance reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017) and taking into account further available information from source substances.

 

Physico-chemical properties

Reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is an UVCB substance, with two major and a number of minor constituents. The substance has a molecular weight of ≥ 442.51 g/mol. It is a liquid at 20 °C with a water solubility of 59.4 mg/L at 20 °C and pH 6.2. The log Pow was estimated to be 3.35 – 3.76 based on the log Pow of the two main constituents. A vapour pressure of 3.14E-04 Pa at 25 °C was measured.

 

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

 

Oral

In general, molecular weights below 500 g/mol and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds can be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017).

The physical state, log Pow and water solubility suggest the substance will be readily absorbed from the GI tract, while the molecular weight is likely to be a limiting factor (≥ 442.51 g/mol).

Although the physico-chemical characteristics of the target substance suggest that some oral absorption will occur, the available data on acute oral toxicity indicate that the substance has low acute toxicity.

An acute oral toxicity study (Ullmann, 1984) was performed with the source substance reaction mass of 7,7,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate and 7,9,9-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diylbismethacrylate (CAS No. 72869-86-4). No mortality was observed in 5 male and 5 female rats that received the test substance at a dose level of 5000 mg/kg bw by gavage. 5/5 males and 5/5 females exhibited dyspnea on Day 1 until 5 h after dosing. Ruffled fur was observed in 5/5 males and 5/5 females 1 - 2 h after administration, and a curved body position was observed in 5/5 males and 5/5 females 1 - 3 h after dosing on Day 1. No clinical signs of toxicity were observed during the rest of the 14-day observation period, no effects on body weight were noted, and the gross necropsy showed no treatment-related macroscopic changes (Ullmann, 1984). The LD50 value was > 5000 mg/kg bw.

The potential of a substance to be absorbed in the GI tract may be influenced by chemical changes taking place in GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply or apply to a lesser extent (ECHA, 2017).

The ester groups may be hydrolysed in the GI tract to form the corresponding alcohol and acid moieties by esterases. The rate of hydrolysis is not known. The smaller molecules of the alcohol and acid moieties may be absorbed faster than the parent molecule. 

 

In conclusion, based on the available information, reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is predicted to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the hydrolysis products rather than (or in addition to) the parent substance is likely. Because the target substance contains ester as well as urethane groups, several hydrolysis products are possible. The absorption rate of the hydrolysis products is expected to be high. Due to the limited information and high complexity on the hydrolysis products of the target substance, as a worst-case approach the oral absorption potential is assumed to be high.  For details on hydrolysis products, please refer to the Analogue Justification.

 

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if the water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The target substance is moderately water soluble (59.4 mg/L) indicating a moderate potential for dermal absorption. Furthermore, the log Pow is in the range indicating dermal absorption is likely to occur. In contrast, the molecular weight of the target substance (≥442.51 g/mol) suggests a low dermal absorption potential (ECHA, 2017).

 

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

Depending on the constituent of the test material, log Pows of 3.35 or 3.76 may enter the equation, leading to a Kp of 0.000867 cm/h or 0.0016 cm/h. Considering the water solubility (0.0594 mg/cm³), the dermal flux is estimated to be in the range of 0.05150 or 0.09491 µg/cm²/h. Both values indicate a low dermal absorption potential.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. The in-vitro skin irritation test (OECD 439) performed with the test substance indicated no irritating properties (Ágh, 2015). The available skin irritation data on the source substance showed no skin irritating effects in the rat (Holalagoudar, 2016). Therefore, no enhanced penetration of the substance due to skin damage is expected. However, two in vitro tests on skin sensitisation gave a positive result, showing that some uptake must have occurred, although it may only have been a small fraction of the applied dose.

Taking all the available information into account, the dermal absorption potential of the target substance is considered to be low.

 

Inhalation

Reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is a liquid with a low vapour pressure (3.14E-4 Pa at 20 °C), and therefore very low volatility. Consequently, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapour, gases or mists is not significant (ECHA, 2017). However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed, for example in formulated products. In humans, particles with aerodynamic diameters below 100 µm have the potential to be inhaled. Particles with aerodynamic diameters below 50 µm may reach the thoracic region and those below 15 µm the alveolar region of the respiratory tract (ECHA, 2017). The log Pow and water solubility indicate that the target substance may be absorbed across the respiratory tract epithelium to a certain extent. However, the high molecular weight may have a limiting effect on the absorption rate. There is no experimental data on the effects of acute or long-term inhalation exposure to the target and source substance. The systemic bioavailability of the registered substance in humans cannot be excluded, e.g. after inhalation of aerosols with an aerodynamic diameter below 15 µm. In applying a worst-case scenario due to the above mentioned uncertainty, the absorption potential via the inhalation route of exposure is assumed to be the same as via the oral route of exposure for reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than its extracellular concentration, particularly in fatty tissues (ECHA, 2017).

The transient clinical signs observed in the acute oral toxicity study on the source substance indicate that the source substance, and thereby also the target substance, is systemically available. The macroscopic examination during necropsy did not show any target organ for acute toxicity and no lasting effects were seen for any parameters.

As discussed under oral absorption, reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is expected to undergo enzymatic hydrolysis in the GI tract to some extent prior to absorption. After being absorbed, the hydrolysis products are expected to be widely distributed, due to the size and the functional groups that increase their water solubility. The substances absorbed from the GI tract will be transported via the portal vein to the liver, where further metabolism can take place. Substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before they are transported to the liver where metabolism will take place. The substances are not expected to accumulate in adipose tissue due to the lack of lipophilic groups. 

 

Metabolism

Reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate has functional groups that are suitable particularly for phase I reactions. The ester and urethane groups may be enzymatically hydrolysed by esterases, which are expressed in most tissues and particularly in the liver (Fukami and Yokoi, 2012). The hydrolysis products may be conjugated (e.g. glucuronidation) to form a polar molecule suitable for excretion. The acrylate group that may be derived by ester group hydrolysis is expected to be rapidly metabolised. Literature shows that in rats and mice acrylic acid administered via the oral or dermal route will rapidly be metabolised via the beta-oxidation pathway of propionate catabolism to acetyl-CoA and CO₂ (Black et al., 1995).

The potential metabolites following enzymatic metabolism of the main isomers of the test substance were predicted using the QSAR OECD toolbox v3.3 (OECD, 2014). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the GI tract. Simplified, two dermal metabolites and 20 hepatic metabolites were predicted for each of the main components. The metabolites are mainly the result of hydrolysis of the ester groups and of a hydroxyl group being added to, or substituted with, a methyl group, and furthermore the hydrolysis of the amino group. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The smaller molecules resulting from hydrolysis of the ester group are also expected to have higher water solubility. The metabolites formed in the skin are relatively few, compared with the liver, due to the lower level of enzymes in the skin. The skin metabolites and any absorbed parent substance will enter the blood circulation and have the same fate as the hepatic metabolites. Up to 99 metabolites were predicted to result from microbiological metabolism. The high number includes many minor variations in the c-chain length and number of carbonyl- and hydroxyl groups; reflecting the many microbial enzymes identified. Not all of these reactions are expected to take place in the human GI-tract. A detailed discussion on the simulated metabolites is given in the Analogue Justification. The results of the OECD Toolbox prediction substantiate the information on metabolism known from the general literature (Lehninger, 1993).

There is no indication that reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate is activated to mutagenic intermediates under the relevant test conditions. All three experimental studies performed on genotoxicity (Ames test, micronucleus test and mouse lymphoma assay) were negative, with and without metabolic activation (Vertesi, 2019a/b and Parmantier, 2019). Two in vitro studies on skin sensitisation were positive, showing that the test substance is likely to be metabolised to a reactive molecule, leading ultimately to skin sensitisation (Katona, 2019 a/b).

 

Excretion

The hydrolysis products of reaction product of 2,2'-oxydiethanol and 2-hydroxyethyl acrylate and 2-hydroxyethyl methacrylate and hexan-6-olide and trimethylhexa-1,6-diyl diisocyanate will be conjugated with e.g. glutathione to form more water-soluble compounds and excreted via the urine.

The fraction of the target substance that is not absorbed in the GI tract, will be excreted via the faeces. If microbial metabolism occurs, the smaller metabolites may be absorbed, entering the systemic circulation. The metabolites are expected to be conjugated as described above and excreted via the urine.

 

References

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0.

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases.Drug Metab Pharmacokinet 27(5): 466-477

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993). Principles of Biochemistry. Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

OECD (2014). (Q)SAR Toolbox v3.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Prediction performed 21 June 2016.http://toolbox.oasis-lmc.org/?section=overview

Black, K.A., Beskitt, J.L., Finch, L., Tallant, M.J., Udinsky, J.R. and Frantz, S.W. (1995). Disposition and metabolism of acrylic acid in C3H mice and Fischer 344 rats after oral or cutaneous administration. J Toxicol Environ Health Jul;45(3):291-311

US EPA (2014).Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA.Downloaded from: http://www.epa.gov/oppt/exposure/pubs/episuite.htm