Fatty acids, tall-oil, esters with ethylene glycol

Endpoint summary

Description of key information

Fatty acids, tall-oil, esters with ethylene glycol (CAS68187-85-9) is a liquid UVCB substance with calculated log Pow value >10 and calculated vapour pressure < 0.0001 Pa. The dermal absorption rate is expected to be low. Exposure and absorption via the inhalation route is considered to be negligible. Via the oral route of exposure the substance is expected to be absorbed after hydrolysis into saturated and unsaturated fatty acids, and saturated and unsaturated fatty acids with a hydroxyethyl moiety. Further microbial metabolism in the gastrointestinal tract may theoretically lead to the production of ethylene glycol and its breakdown products. However, after oral administration of the parent molecule, no systemic toxicity was observed, indicating limited ethylene glycol metabolism.

Fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons. The alcohol component is highly water-soluble and has low molecular weight and is therefore expected to be distributed and further metabolized in different compartments. The main route of excretion is predicted to be by expired air as carbon dioxide after stepwise metabolic degradation. No bioaccumulation is expected to take place.

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The hazard assessment is based on the data currently available. New studies with the registered substance and/or other member substances of the glycol esters category will be conducted in the future. The finalised studies will be included in the technical dossier as soon as they become available and the hazard assessment will be re-evaluated accordingly.

For further details, please refer to the category concept document attached to the category object (linked under IUCLID section 0.2) showing an overview of the strategy for all substances within the glycol esters category.

There are no studies available in which the toxicokinetic behaviour of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) has been investigated. The substance Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) is a UVCB substance specified by mainly C18 fatty acids esterified with ethylene glycol (EG).

Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) is a liquid at room temperature with a molecular weight range of 585-615 g/mol. Experimental laboratory data on water solubility, vapour pressure and partition coefficient were not available (see IUCLID section 4.8). Log Pow and vapour pressure were calculated for 5 main constituents of the UVCB substance. The calculated log Pow values were >10 and the vapour pressure was calculated to be < 0.0001 Pa.

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).

In vitro studies with propylene glycol distearate (PGDS) demonstrated hydrolysis of the ester (Long et al., 1958). The hydrolysis of fatty acid esters in-vivo was studied in rats dosed with fatty acid esters containing one, two (like ethylene glycol esters) or three ester groups. The studies showed that fatty acid esters with two ester groups are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson and Volpenhein, 1968; 1972). Furthermore, the in-vivo hydrolysis of propylene glycol distearate (PGDS), a structurally related glycol ester, was studied using isotopically labelled PGDS (Long et al., 1958). Oral administration of PGDS showed intestinal hydrolysis into propylene glycol monostearate, propylene glycol and stearic acid, supporting the prediction of the metabolism of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9).

The hydrolysis of fatty acid esters with ethylene glycol was also confirmed by in-vitro studies using a pancreatic lipase preparation (Noda et al., 1977). In the study, the fatty acid release from ethylene dioleate was comparable to those from the triglyceride trioleoylglycerol, which is the natural substrate of the ubiquitously expressed GI lipases.

When assessing the potential of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) to be absorbed in the GI-tract, it has to be considered that fatty acid esters will undergo hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1998; Mattson and Volpenhein, 1972; National technical information service, 1973). Therefore, due to the hydrolysis the predictions based on the physico-chemical characteristics of the intact parent substance as well as the physico-chemical characteristics of the breakdown products of the ester will be relevant. The hydrolysis products are the alcohol ethylene glycol and the corresponding fatty acids, mostly unsaturated C18.

Experimental data on water solubility was not available. the high log Pow value >10 of the parent compound indicates that oral absorption may be limited by the inability to dissolve into GI fluids. However, mi-cellular solubilisation by bile salts may enhance absorption (Aungst and Shen, 1986). The alcohol component ethylene glycol is highly water-soluble and has a low molecular weight (62.07 g/mol) and can therefore dissolve into GI fluids (ATSDR, 2010). Therefore, ethylene glycol will readily be absorbed through the GI tract. The highly lipophilic C18-fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

The acute oral LD50 value in rats and mice was found to be > 2000 mg/kg bw for the source substances Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0), Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1) and Fatty acids, C16-18, esters with diethylene glycol (CAS 85116-97-8).

The repeated dose toxicity potential of the target substance Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) was assessed by applying read across of data from two source substances. In a sub-chronic (90-day) oral repeated dose toxicity study in rats with Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0) the NOAEL was found to be greater than 1000 mg/kg bw/day.

In a sub-chronic (90-day) oral repeated dose toxicity study in rats with stearic acid, monoester with propane-1,2-diol / 2-hydroxypropyl stearate (CAS 1323 -39-3) the NOAEL was found to be greater than 1000 mg/kg bw/day.

The lack of systemic toxicity of the structurally related source substances does not necessarily indicate a lack of absorption but indicates a low absorption rate and/or low toxic potential of glycol esters and their breakdown products.

Dermal

In general, to partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. For substances 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.

There are no data available on the dermal absorption or on acute dermal toxicity of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9). For the source substance Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (CAS 151661-88-0), an acute dermal LD50 value of > 2000 mg/kg body weight in male and female rats is given.

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

Using Dermwin v 2.02, Epiweb 4.1, values relevant for dermal absorption were calculated for the five SMILES codes representing the UVCB substance Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) and using an log Pow value of 10 (see Table 1):

Table 1

Constituent	Structural formula	Molecular weight	estimated water solubility	Kp	Flux
			[mg/cm³]	[cm/h]	[mg/cm²h]
1	C38H66O4	587	5.64e-010	3.52	7.95e-008
2	C38H64O4	585	5.82e-010	3.62	8.3e-008
3	C40H68O4	613	3.81e-010	2.52	4.54e-008
4	C40H70O4	615	3.7e-010	2.45	4.34e-008
5	C38H68O4	589	5.48e-010	3.43	7.61e-008

 

Calculated dermal flux rates indicate a very low dermal absorption potential for Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9).

Based on the available data, the dermal absorption potential of Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) is expected to be low.

Inhalation

Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) is a liquid with a very low calculated vapour pressure of <0.0001 Pa and therefore a low volatility. Therefore, under normal use and handling conditions, inhalation exposure and the availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited (ECHA, 2017). Exposure via the inhalation route and absorption via inhalation route is expected to be negligible.

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

As the parent compound Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) will be hydrolysed prior to absorption (as discussed above); the distribution of the intact substance is less relevant than the distribution of the breakdown products following hydrolysis. The absorbed hydrolysis products, ethylene glycol and the respective fatty acid moieties 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). Substances with high water solubility like ethylene glycol do not have the potential to accumulate in adipose tissue due to its low log Pow.

Like all medium- and long chain fatty acids, the fatty acids may be re-esterified with glycerol into triacylglycerides (TAGs) and transported via chylomicrons or absorbed from the small intestine directly into the bloodstream and transported to the liver. Via chylomicrons, 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). The intact parent compound is not assumed to accumulate 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 as further described in the metabolism section below. At the same time, fatty acids will also be used for energy generation. The stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.

Metabolism

Using OECD QSAR Toolbox v4.2 metabolites were predicted for the 5 main constituents of Fatty acids, tall-oil, esters with ethylene glycol (see table 2). The predicted skin metabolites were mainly saturated and unsaturated fatty acids with hydroxy-ethyl moiety, and saturated and unsaturated C18 fatty acids. Metabolites predicted by rat liver S9 metabolism simulator included the metabolites predicted for skin metabolism, hydroxylation products of the parent substance, and acetic acid. No ethylene glycol was predicted by rat liver S9 metabolism or in vivo rat metabolism simulator for the 5 main constituents assessed. Ethylene glycol was predicted when using the microbial metabolism simulator.

Table 2

Constituent	Molecular formula	Molecular weight	Predicted metabolites
			# of skin metabolites	# of in vivo rat metabolites	# of microbial metabolites
1	C38H66O4	586.90	2	15	128
2	C38H64O4	584.89	4	30	239
3	C40H68O4	628.94	16	58	222
4	C40H70O4	614.96	4	48	227
5	C38H68O4	588.92	4	46	206

 

In general, glycol fatty acid esters are stepwise hydrolysed at the ester bonds by gastrointestinal enzymes resulting in the release of the fatty acid component and the respective alcohol moiety (Long, 1958; Lehninger, 1998; Mattson and Volpenhein, 1972).

Fatty acids, tall-oil, esters with ethylene glycol is expected to be readily hydrolysed at the ester bond resulting in release fatty acid moieties (mainly C18 and C20) and molecules with the alcohol moiety.

In experimental studies metabolites of diethylene glycol (DEG) included carbon dioxide, 2-(hydroxyethoxy) acetic acid (2-HEAA), and oxalic acid. In rats, oxalic acid is not a significant metabolite (NICNAS; 2009; SIAM, 2004). Instead, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Breakdown of DEG into oxalate appears to be a minor route in laboratory animals.

Although the predicted metabolite ethylene glycol is classified as acutely toxic (oral), category 4, according to Regulation (EC) No. 1272/2008, Annex VI, the available data on acute toxicity on source substances [Fatty acids, C16-18, esters with diethylene glycol (CAS 85116-97-8), Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1), and Fatty acids, C18 and C18 unsatd., epoxidized, ester with ethylene glycol (151661-88-0)] of Fatty acids, tall-oil, esters with ethylene glycol do not indicate intrinsic hazardous properties after single exposure up to the limit dose of 2000 mg/kg bw.

Following absorption into the intestinal lumen, fatty acids are re-esterified with glycerol to triacylglycerides (TAGs) and included into chylomicrons for transportation via the lymphatic system and the blood stream to the liver. In the liver, fatty acids can be metabolised in phase I and II metabolism. An important metabolic pathway for fatty acids is the beta-oxidation for energy generation. 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 H2O and CO2 (Lehninger, 1998; Stryer, 1994). The complete oxidation of unsaturated fatty acids such as oleic acid requires an additional isomerisation step (Lehninger, 1998). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999).

Available genotoxicity data from source substances do not show any genotoxic properties. In particular, Ames tests with fatty acids, coco, esters with 1,3-butanediol (CAS 73138-39-3), fatty acids, C14-18 and C16-18 unsaturated, ester with propylenglycol (CAS 84988-75-0, WoE, 1991), with Fatty acid C18 and C18 unsaturated, epoxidized, Ester with ethylene glycol (CAS 151661-88-0, WoE, 1990), and with Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1, WoE, 1991), an in-vitro mammalian gene mutation assay with Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1; key study, 2010), and an in vivo mammalian erythrocyte micronucleus test with Fatty acid C18 and C18 unsaturated, epoxidized, Ester with ethylene glycol (CAS 151661-88-0, key study, 1990) were consistently negative and therefore no indication of a genotoxic reactivity of structurally related glycol esters is indicated.

Excretion

Based on the metabolism described above, Fatty acids, tall-oil, esters with ethylene glycol (CAS 68187-85-9) and its breakdown products will be metabolised in the body to a high extent. In-vivo studies with propylene glycol distearate (PGDS) showed that 94% of the labelled PGDS was recovered from 14CO2 excretion and only ~ 0.4% of the total dose of PGDS was excreted in the urine after 72 h (Long et al., 1958). A similar observation was made for propylene glycol, which was excreted in substantial amounts as 14CO2 during the first 24 h after administration of radioactive labelled substance (National technical information service, 1973).

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, 1998; Stryer, 1994). Therefore, the fatty acid component is not expected to be excreted un-metabolised to a significant degree via the urine or faeces but will be extensively metabolised and excreted via exhaled air as carbon dioxide or stored as described above.

For Diethylene glycol (DEG) it was found that depending on the dose administered, approximately 45-70% of the total DEG dose is excreted unchanged in the urine within 48 hours, with approximately 11-37% as 2-(hydroxyethoxy) acetic acid (2-HEAA) after oxidative metabolism (NICNAS 2009).

For Fatty acids, tall-oil, esters with ethylene glycol(CAS 68187-85-9), the primary route of excretion is expected to be via exhaled air as carbon dioxide.

References

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Mattson, F.H. and Volpenhein, R.A. (1972). Absorbability by rats of compounds containing from one to eight ester groups. J Nutrition, 102: 1171 -1176

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