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Description of key information

Absorption of propane-1,2,3-triyl 2-ethylhexanoate may be the highest after oral exposure, but may be limited at all due to the low water solubility. After enzymatic hydrolysis, the hydrolysis products may be absorbed and well distributed within the body. Glycerol is incorporated in standard metabolic pathways. 2-Ethylhexanoic acid may be metabolised by omega and omega-1 oxidation or by glucuronidation and subsequent renal excretion.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No. 1907/2006 (REACH) and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of propane-1,2,3-triyl 2-ethylhexanoate (CAS 7360-38-5) was conducted to the extent that can be derived from the relevant available information on physico-chemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance. Only limited information is available for the hydrolysis product 2-ethylhexanoic acid.

Absorption

Absorption is a function of the potential of 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).

No measured data are available regarding absorption, hydrolysis (before and after absorption), and the resulting systemic availability (concentration in blood) of propane-1,2,3-triyl 2-ethylhexanoate or its hydrolysis products. Therefore, no conclusion based on analytical data is possible regarding the correlation of propane-1,2,3-triyl 2-ethylhexanoate dosed to amount absorbed (parent compound/hydrolysis products).

Oral

When assessing the potential of propane-1,2,3-triyl 2-ethylhexanoate to be absorbed in the gastrointestinal (GI) tract, it has to be considered that carboxylic acid esters will undergo enzymatic hydrolysis by ubiquitously expressed GI esterases (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). The rate of hydrolysis is depending on the structure of the ester, and may therefore be rapid or rather slow. Thus, due to hydrolysis, predictions on oral absorption based on the physico-chemical characteristics of the intact parent substance alone may no longer apply. Instead, the physico-chemical characteristics of the hydrolysis products (glycerol and 2-ethylhexanoic acid as well as the mono- and diesters) may become relevant. The molecular weight of propane-1,2,3-triyl 2-ethylhexanoate (470.7 g/mol) does favour absorption. In contrast, its low water solubility (< 0.05 mg/L, column elution method, EU A.6) and the high log Pow value (8.98, QSAR calculation with KOWWIN (v1.68)) indicate that the absorption may be limited by the inability to dissolve into GI fluids. However, micellar solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with log Pow > 4 and low water solubility (Aungst and Shen, 1986).

When considering the hydrolysis product glycerol, absorption is favoured based on passive and active absorption of glycerol (Lin, 1977; Yuasa, 2003). The other hydrolysis product 2-ethylhexanoic acid (molecular weight 144.21 g/mol; water solubility approx. 2 g/L; log Pow approx. 2.7; Danish (Q)SAR Database, 2019) is well absorbed via the GI tract. Peak plasma concentrations of 85.1 µg 2-ethylhexanoic acid equivalents per g blood were reached after 18.8 minutes following oral administration of 100 mg/kg bw of 2-ethylhexanoic acid (EPA, 1986). Mono- and diester could also be absorbed after micellar solubilisation by bile salts, similar to mono- and diester of fatty acids with glycerol.

In summary, while absorption of the parent compound propane-1,2,3-triyl 2-ethylhexanoate is considered to be limited after oral application, its hydrolysis products glycerol and 2-ethylhexanoic acid are anticipated to be absorbed to a high degree.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of propane-1,2,3-triyl 2-ethylhexanoate. On the basis of the following considerations, its dermal absorption is considered to be low. Regarding the molecular weight of 470.7 g/mol and an octanol/water partition coefficient of 8.98 in combination with the low water solubility, a low dermal absorption rate is anticipated. Log Pow values above 6, will decrease the rate of transfer between the stratum corneum and the epidermis and therefore absorption across the skin will be limited and uptake into the stratum corneum itself is slow (ECHA, 2017).

Inhalation

Propane-1,2,3-triyl 2-ethylhexanoate has a very low vapour pressure of < 0.0001 Pa at 20 °C (QSAR evaluation) thus being of low volatility. 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. However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the formulated substance is sprayed. 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).

As discussed above, absorption after oral administration of propane-1,2,3-triyl 2-ethylhexanoate may mainly be driven by enzymatic hydrolysis of the ester bonds to the respective hydrolysis products and subsequent absorption of the hydrolysis products. As the presence of esterases and lipases in the mucus lining fluid of the respiratory tract is expected to be lower in comparison to the GI tract, absorption of the hydrolysis products in the respiratory tract is considered to be less effective than in the GI tract. Nevertheless, absorption of the parent substance itself cannot be excluded if the propane-1,2,3-triyl 2-ethylhexanoate reaches the alveolar region. Therefore, inhalative absorption of propane-1,2,3-triyl 2-ethylhexanoate is considered to be not higher than through the intestinal epithelium, but still likely to occur.

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 propane-1,2,3-triyl 2-ethylhexanoate may be hydrolysed before or after absorption as discussed above, the distribution of intact propane-1,2,3-triyl 2-ethylhexanoate as well as the distribution of the hydrolysis products needs to be considered. The absorbed hydrolysis products, glycerol and 2-ethylhexanoic acid, can both be distributed within the body. Data from studies in humans and animals indicate that glycerol is rapidly absorbed in the intestine and the stomach, distributed over the extracellular space (Lin 1977, Tourtelotte 1970) and excreted. The distribution of free 2-ethylhexanoic acid was monitored following intraperitoneal administration to male Balb/C mice and male Wistar rats. In the mouse most of the radioactivity was detected in the kidneys, the liver, and the GI tract 30 minutes after administration. At one hour small amounts were observed in the salivary gland, skin, and olfactory bulb. In the rat the highest levels were found in the blood, liver and kidneys. Small amounts were also observed in the brain (BG Chemie, 2000).

The parent compound propane-1,2,3-triyl 2-ethylhexanoate could be distributed into cells because of its lipophilic properties. An accumulation is, however, unlikely as enzymatic hydrolysis and further metabolism is anticipated.

Metabolism

Metabolism of propane-1,2,3-triyl 2-ethylhexanoate occurs initially via enzymatic hydrolysis resulting in glycerol, glycerol mono- or diester, and 2-ethylhexanoic acid. Glycerol is phosphorylated to alpha-glycerophosphate by glycerol kinase predominantly in the liver (80-90%) and kidneys (10-20%) and incorporated in the standard metabolic pathways to form glucose and glycogen (Lin 1977). Glycerol kinase is also found in intestinal mucosa, brown adipose tissue, lymphatic tissue, lung and pancreas. Glycerol may also be combined with free fatty acids in the liver to form triglycerides (lipogenesis) which are distributed to adipose tissues. The turnover rate is directly proportional to plasma glycerol levels (Bortz, 1972).

2-Ethylhexanoic acid metabolism was found to take place via conjugation with glucuronic acid as well as cytochrome P-450-dependent omega and omega-1 oxidation. The major urinary metabolites identified were the glucuronide of 2-ethylhexanoic acid as well as 2-ethyl-1,6-hexanedioic acid, 6-hydroxy-2-ethylhexanoic acid and their respective glucuronides. With increasing single dose, the fraction of glucuronidated 2-ethylhexanoic acid increased while the percentage of cytochrome P-450 dependent, more highly oxidised metabolites decreased (BG Chemie, 2000).

Excretion

Glycerol is fully metabolised and incorporated in standard metabolic pathways to form glucose and glycogen. Thus, low levels of glycerol may be excreted via urine whereas the rest is fully metabolised to CO2 via glycolysis and citric acid cycle.

In all available studies with 2-ethylhexanoic acid, irrespective of the route of administration employed, the radioactivity was predominantly excreted in the urine and faeces within 24 h, with half-lives of elimination ranging from 4.2 to 6.8 h.

References

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.

BG Chemie (2000) Toxicological evaluation No. 275, 2-Ethylhexanoic acid 06/00.

Bortz, W. (1972) Glycerol turnover and oxidation in man, The Journal of Clinical Investigation 51: 1537-1546 (34)

Danish (Q)SAR Database (2019). http://qsardb.food.dtu.dk/db/index.html; RN: 149-57-5; last accessed: 2019-04-01

ECHA (2017). Chapter R.7c: Endpoint specific guidance, ECHA-17-G-11-EN, version 3.0, June 2017, European Chemicals Agency

EPA (Environmental Protection Agency, 1986) 2-Ethyl hexanoic acid, final test rule, Federal Register, 51, 40318-40330.

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

Lin, E.C.C. (1977) Glycerol utilization and its regulation in mammals, Ann. Rev. Biochem. 46: 765-95 (52)

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.

Tourtellotte, M. D. et al. (1970) Cerebral dehydration action of glycerol, Clinical Pharmacology and Therapeutics 13(2): 159-171, (68)

Yuasa, H. (2003) Saturable absorption of glycerol in the rat intestine. Biological & Pharmaceutical Bulletin 26(11), 1633-6.