Fatty acids, C18-36, esters with ethylene glycol

Endpoint summary

Description of key information

Toxicokinetic assessment

 

In accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance 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. There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18-36 esters with ethylene glycol has been investigated.

The substance, Fatty acids, C18-36 esters with ethylene glycol is a UVCB substance and is produced by reacting ethylene glycol with sources of C18-36 fatty acids (hydrogenated rape seed fatty acids and refined montan wax fatty acids, at a ratio of approximately 60:40 by weight respectively).

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 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, 2012).

Absorption, 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) which would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2012).

Fatty acids, C18-36 esters with ethylene glycol has a molecular weight > 500 Da. The substance is solid with an extremely high calculated logKow and a measured water solubility of <0.5 mg/L. The substance’s physico-chemical properties are indicative for a low absorption, but some micellular solubilisation by bile salts in the gastro-intestinal tract an concomitant crossing of lipid biomembranes cannot be excluded.

Fatty acids, C18-36 esters with ethylene glycol is an ester of long-chain (hydroxylated) fatty acids. The ester is expected to be subject to hydrolysis by esterases in the gastro-intestinal tract. The resulting fatty acids (and hydrogenated fatty acids in the substance) are expected to be taken (depending on their carbon chain length, logKow and water solubility). The other hydrolysis product ethylene glycol will be absorbed easily (see Annex I).

The absence of adverse effects in oral acute toxicity test (Huntingdon 1977 see dossier) is either indicative for low absorption and/or low toxicity. No local effects on the membranes of the gastro-intestinal tract lining or irritant effects are reported. Therefore local irritation as potential for enhanced absorption can be excluded.

The oral absorption is set at 100% in view of the expected hydrolysis in the gastro-intestinal tract.

Absorption, 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. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. 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 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, 2012).

The physico-chemical properties (solid, low water solubility and log Pow > 6) of Fatty acids, C18-36 esters with ethylene glycol are in a range suggestive of low absorption through the skin. The substance shows no skin irritating or corrosive properties and therefore no damage to the skin surface, which could lead to increased absorption is expected. Taking this information into account the dermal absorption potential is considered to be rather low and is set at the default value of 10%.

Absorption, inhalation

Fatty acids, C18-36 esters with ethylene glycol is a solid with a vapour pressure of0.00038 Paat 20 °C. Based on these properties under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours is not significant.

Exposure to dust is not expected as the substance is handled in liquid formulations.

However, liquid formulations containing the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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, 2012). As for oral absorption, the molecular weight and physico-chemical properties of Fatty acids, C18-36 esters with ethylene glycol are in a range suggestive of low absorption across the respiratory tract epithelium. Absorption by micellar solubilisation may occur, but this mechanism is more relevant for oral absorption due to the requirement of the emulsifying bile salts.

In conclusion, absorption via inhalation cannot be completely excluded, but is expected to be rather low (set at default value of 10%).

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, 2012).

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidized for energy or they are released into the systemic circulation and returned to the liver. Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2.

No data are available for hydrogenated fatty acids, but a similar process can be expected.

For ethylene glycol distribution in the aqueous compartments of the body is expected (see Annex I).

Metabolism

Fatty acids, C18-36 esters with ethylene glycol is assumed to be metabolised via the standard metabolism pathways for fatty acids.

After hydrolysis by esterases and uptake fatty acids are then degraded by mitochondrial β-oxidation which takes place in the most animal tissues and uses an enzyme complex for a series of oxidation and hydration reactions resulting in the cleavage of acetate groups in form of acetyl CoA. The alkyl chain length is thus reduced by 2 carbon atoms in each β-oxidation cycle. The complete oxidation of unsaturated fatty acids such as oleic acid requires an additional isomerisation step. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Thus iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates and to be metabolised to a large extent by ω-oxidation. Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl CoA, through which they are completely oxidized to CO(Lehninger, 1998; Stryer, 1996).

No data are available for hydrogenated fatty acids, but a similar process can be expected. 

The metabolism of ethylene glycol is described in Annex I.

The results of the in vitro genotoxicity studies did not show any evidence that the addition of the metabolic system either enhances or diminishes the activity of Fatty acids, C18-36 esters with ethylene glycol (Envigo 2017, see dossier) and therefore metabolic conversion to the products as described and concomitant degradation to carbon dioxide and water can be expected.

Excretion

In general, fatty acids are catabolised entirely by oxidative physiologic pathways ultimately leading to the production of carbon dioxide and water. Small amounts of ketone bodies resulting from the oxidation of fatty acids are excreted via the urine (Lehninger, 1998; Stryer, 1996). Elimination of ethylene glycol occurs via exhaled carbon dioxide and urinary elimination of both ethylene glycol and glycolic acid (see Annex). Any material that is not absorbed will be excreted in the faeces.

Conclusion

For Fatty acids, C18-36 esters with ethylene glycol absorption via the oral route is expected only after hydrolysis. Dermal absorption is expected to be minimal. If absorbed, fatty acids are expected to be distributed, metabolised and excreted via a mechanism similar to that for fatty acids.

Ethylene glycol is rapidly taken up and metabolised as described in Annex I

In conclusion the human dermal, oral and inhalation absorption, and subsequent human metabolism, distribution and elimination profile of Fatty acids, C18-36 esters with ethylene glycol is predicted to mirror those of mammalian derived dietary lipids and to utilise the same biochemical pathways and cycles. However the metabolic pathway for the glycol moiety differs from that of glycerol.

 

References (not cited in IUCLID)

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

ECHA (2012). Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance.

Annex I(taken from ATSDR Toxicological Profile for Ethylene Glycol, November 2010)

Ethylene glycol is quickly and extensively absorbed through the gastrointestinal tract of many species, but dermal absorption is slow in rodents and is expected to be slow in humans. Limited information is available on absorption of inhaled ethylene glycol, but the existing toxicity studies suggest absorption via the respiratory tract by both humans and rodents. Following absorption, ethylene glycol is distributed in aqueous compartments throughout the body. Ethylene glycol is initially metabolized to glycolaldehyde by alcohol dehydrogenase (with possible contribution from cytochrome P-450 enzymes). Glycolaldehyde is rapidly converted to glycolate and glyoxal by aldehyde oxidase and aldehyde dehydrogenase. Metabolism of glycolate by glycolate oxidase or lactate dehydrogenase results in the formation of glyoxylate, which may be further metabolized to formate, oxalate, glycine, and carbon dioxide. Elimination of ethylene glycol occurs via exhaled carbon dioxide and urinary elimination of both ethylene glycol and glycolic acid. The half-life for elimination in humans has been estimated to be in the range of 2.5–8.4 hours.

Animal studies indicate that oral exposure to ethylene glycol can cause effects in a number of different organ systems, although the developing foetus and kidneys are particularly sensitive and well-documented targets of toxicity.

The developmental toxicity of ethylene glycol in animals has been assessed by inhalation, oral, and dermal exposure in acute-duration studies and by oral exposure in intermediate-duration studies. The short-term oral studies indicate that developmental effects (a skeletal variation and total malformations) occur at doses of ≥500 mg/kg/day when administered by gavage during gestation days (Gd) 6–15 to CD-1 mice. Reduced foetal body weight occurred in mice given gavage doses of ≥750 mg/kg/day. In CD rats, doses of ≥1,000 mg/kg/day by gavage on Gd 6–15 have resulted in increased incidences of skeletal malformations. In F344 rats dosed on Gd 6–15 with 1,000 mg/kg/day in feed, skeletal malformations were not observed, suggesting the possible importance of dose-rate in producing developmental effects; however, strain differences in response cannot be ruled out. No teratogenic effects were observed in rabbits exposed to maternally lethal oral doses of 2,000 mg/kg/day during gestation. In the only dermal exposure study, no developmental toxicity occurred in pregnant CD-1 mice that were treated with 6-hour daily exposures to ethylene glycol (estimated doses up to 3,549 mg/kg/day) by occluded cutaneous application on Gd 6–15.

The kidney is clearly identified as the most sensitive target organ in rats and mice after intermediate duration oral exposure. Typical renal effects included oxalate crystal deposition and renal tubular dilation, vacuolation, and degeneration. Oxalate, a metabolite of glycolic acid, forms a precipitate in the presence of calcium, and the deposition of these crystals in the renal tubules are hallmarks of ethylene glycol toxicity. Glycolic acid accumulation and metabolic acidosis do not contribute to renal toxicity, which is solely caused by oxalate crystal accumulation. Males were more sensitive than females, and rats were more sensitive than mice. In general no effects are observed at 150 mg/kg bw and below.Chronic oral studies confirm that the kidney is a main target organ in male rats, although a minor liver effect (slight fatty metamorphosis) occurred in female rats at doses lower than those inducing kidney effects. No hepatic effects were observed in intermediate-duration studies. There is no indication that ethylene glycol is carcinogenic based on results of a limited renal cancer mortality study in chemical plant workers and well-designed chronic oral bioassays in rats (one study) and mice (two studies).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10