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Description of key information

Reaction mass of 2-hydroxyethyl laurate and ethylene dilaurate (EC 908-917-6) is a solid multi-constituent substance with two main constituents. The substance will be hydrolysed within the gastrointestinal tract. The hydrolysis products (mainly the respective C12 fatty acid and ethylene glycol) are predicted to be readily absorbed via the oral route. The major metabolic pathway for linear fatty acids is the beta-oxidation pathway for energy generation or fatty acids can be re-esterified to triglycerides after absorption and transported via chylomicrons. The absorbed ethylene glycol is expected to be readily distributed throughout the organism and bio-transformed in liver and kidney. Absorption via inhalation and dermal route is expected to be low. The excretion will mainly be as carbon dioxide in expired air; with a smaller fraction of urinary excretion. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In the following the term “Reaction mass” is used as abbreviation for: Reaction mass of 2-hydroxyethyl laurate and ethylene dilaurate (EC 908-917-6). In accordance with Annex VIII, Column 1, Section 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), assessment of the toxicokinetic behaviour of the Reaction mass is 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 Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

There are no studies available in which the toxicokinetic behaviour of the Reaction mass has been investigated.

The substance Reaction mass is a well-defined multi-constituent substance with the two main constituents, 2-hydroxyethylaurate (Molecular Formula C14H28O3) and ethylene dilaurate (Molecular Formula C26H50O4). Both constituents are fatty acid esters belonging to the subgroup of glycol esters. 2-hydroxyethyl laurate is a monoester with ethane-1,2-diol and lauric acid. Ethylene dilaurate is a diester with ethane-1,2-diol and lauric acid.

The constituent 2-hydroxyethyl laurate has a molecular weight of 244.37 and a calculated log Pow of 4.31. The constituent ethylene dilaurate has a molecular weight of 426.67 and calculated log Pow of 10.23.

Reaction mass is a solid at 20°C which has a molecular weight ranging from 244.37 – 426.67 g/mol. Experimental data for water solubility were not available at the time of dossier submission (see IUCLID section 4.8). The calculated log Pow value was in the range of 4.25 to 10.23 (Episuite calculation, 2017) and the vapour pressure was calculated to be between 0.018-0.153 Pa at 25°C (Episuite calculation, 2017).

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 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 may 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 (Aungst and Shen, 1986; ECHA, 2017).

When assessing the potential of Reaction mass to be absorbed in the gastrointestinal (GI) tract, it has to be considered that fatty acid esters will undergo to a high extent hydrolysis by ubiquitous GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). The hydrolysis represents the first chemical step in the absorption, distribution, metabolism and excretion (ADME) pathways likely to be similarly followed by all glycol esters. The hydrolysis is catalysed by classes of enzymes known as carboxylesterases or esterases (Heymann, 1980). Due to the hydrolysis the predictions based on the physico-chemical characteristics of the intact parent substance alone may no longer apply but also the physico-chemical characteristics of the breakdown products of the ester; the alcohol propylene glycol and the corresponding fatty acids (mainly C12). Ethylene glycol is rapidly absorbed from the gastrointestinal tract and subsequently undergoes rapid biotransformation in liver and kidney (IPCS, 2001; WHO, 2002; ATSDR, 2010). The lipophilic fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

In an acute oral gavage toxicity study (2017) according to OECD guideline 420, no adverse toxic effects were seen in female Wistar rats at a single dose of 2000 mg/kg bw.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Reaction mass. On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

No adverse toxic effects were found in two acute dermal toxicity studies with the source substances Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (151661-88-0) and 1,2-Propandiol-mono/di-octanoat (CAS 31565-12-5). The acute LD50 value was found to be > 2000 mg/kg bw in male and female rats in both studies.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a water solubility <1 mg/L, dermal uptake of the substance is likely to be low. In addition, for substances having an octanol/water partition coefficient above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and thus limit absorption across the skin. Furthermore, uptake into the stratum corneum itself may be slow. In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake vie the skin is possible (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 (2012):

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

The Kp was calculated for the 2 main constituents of the substance (please refer to Table 1). Retrieved dermal flux rates indicate only low dermal absorption potential for the two main components of Reaction mass (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1; calculated in Feb 2017).

Table 1: Dermal absorption values for the constituents of Reaction mass (calculated with Dermwin v 2.02, Epiweb 4.1)

Component

Molecular weight

Water solubility (mg/cm³)

Log KOW

Structural formula

Flux (mg/cm2/h)

Dermal absorption potential

2-hydroxyethyl laurate

244.38

3.86e-009

4.31

C14 H28 O3

1.65e-006

very low

ethylene dilaurate

426.69

0.0171

10.23

C26 H50 O4

0.00278

very low

 

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017) The irritation studies with the structurally related substances ethane-1,2-diyl dioctadecanoate (CAS 627-83-8), 2-hydroxyethyl stearate (CAS 111-60-4) and Decanoic acid, mixed diesters with octanoic acid and propylene (CAS 68583-51-7) showed no or only mild irritating effects. No erythema or oedema was seen during an in vivo skin sensitisation (Buehler) study in guinea pigs with the source substance ethane-1,2-diyl dioctadecanoate (627-83-8) after 6 hours of exposure to the undiluted test substance.

Overall, taking into account the physico-chemical properties of 2-hydroxyethylaurate (CAS 4219-48-1) and ethylene dilaurate (CAS 624-04-4) and the QSAR calculations, the dermal absorption potential of the substance is predicted to be low.

Inhalation

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).

Reaction mass is sold in solid form (solidified melt) and has a very low calculated vapour pressure of 0.018-0.153, indicating low volatility (Episuite calculation, 2017). Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not significant.

The potential for exposure via the inhalation route is considered to be negligible.

Distribution and accumulation

As the glycol esters of Reaction mass are considered to be hydrolysed before absorption, the distribution of the intact glycol esters is less relevant than the distribution of the breakdown products of intestinal hydrolysis.

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 extracellular concentration, particularly in fatty tissues (ECHA, 2017).

The absorbed hydrolysis products, the free fatty acids and the highly water-soluble alcohols can be distributed within the body. Ethylene glycol has a low molecular weight (62.07 g/mol) and high water solubility and will therefore be broadly distributed within the body (ECHA Homepage; ATSDR, 2010; IPCS, 2001). Furthermore, substances with high water solubility like ethylene glycol, do not have the potential to accumulate in adipose tissue due to their low log Pow. Medium chain fatty acids like those in the Reaction mass with fatty acid chain length of C12, may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons after absorption in the GI tract. The fatty acids are transported via the lymphatic system and the blood stream to the liver and to extrahepatic tissue for storage e.g. in adipose tissue (Stryer, 1994).

Glycol esters of Reaction mass are not assumed to bio-accumulate in the body, as hydrolysis takes place before absorption and distribution. However, accumulation of the fatty acids in triglycerides in adipose tissue or the incorporation into cell membranes is possible. At the same time, fatty acids may also be used for energy generation.

Metabolism

Metabolism of Reaction mass initially occurs via stepwise enzymatic hydrolysis of the ester , resulting in the corresponding monoester (ethylene glycol monolaurate), and via further metabolism the free fatty acids (C12) and ethylene glycol.

Ethylene glycol is first metabolised by alcohol dehydrogenase to glycoaldehyde, which is then further oxidised successively to glycolic acid, glyoxylic acid, oxalic acids by mitochondrial aldehyde dehydrogenase and cytosolic aldehyde oxidase (ATSDR, 2010; WHO, 2002). The anabolism of fatty acids occurs in the cytosol, where fatty acids esterified into cellular lipids that are the most important storage form of fatty acids (Stryer, 1994). The catabolism of fatty acids occurs in the cellular organelles, mitochondria and peroxisomes via a completely different set of enzymes. The process is termed β-oxidation and involves the sequential cleavage of two-carbon units, released as acetyl-CoA through a cyclic series of reaction catalysed by several distinct enzyme activities rather than a multi-enzyme complex (Tocher, 2003). In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems. In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of water and carbon dioxide.

 

Excretion

Glycol esters and the breakdown products will be metabolised in the body to a high extent. The fatty acid components, will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1994). Therefore, the fatty acid component is not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as carbon dioxide or stored as described above. As ethylene glycol will be highly metabolised as well, the primary route of excretion will be via exhaled air as carbon dioxide and as parent compound and glycolic acid in the urine. High doses of ethylene glycol lead to the excretion of the metabolite oxalate via the urine (ATSDR, 2010).

References

Agency for Toxic Substances and Disease Registry (ATSDR, 2010): Toxicological Profile for Ethylene Glycol. US Department of Health and Human Services. US.

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

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

Heymann, E. (1980): Carboxylesterases and amidases. In: Jakoby, W.B., Bend, J.R. & Caldwell, J., eds., Enzymatic Basis of Detoxication, 2nd Ed., New York: Academic Press, 291-323.

International Programme on Chemical Safety (IPCS) (2001): Ethylene Glycol. Poisons Information Monograph. PIM 227.

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Long, C.L. et al. (1958). Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys, 77(2):428-439.

Mattson F.H. and Volpenhein R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lip Res 9, 79-84.

Mattson F.H. and Nolen G.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171 -1175

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

Tocher, D.R. (2003): Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish. Reviews in Fisheries Science 11(2), 107-184.

US EPA (2012). 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

WHO (2002): Ethylene Glycol: Human Health Aspects. Concise International Chemical Assessment Document 45.