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Assessment of the Toxicokinetic Behaviour of Fatty acids, vegetable-oil, esters with dipropylene glycol (CAS 95009-41-9)

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, vegetable-oil, esters with dipropylene glycol has been investigated.

Therefore, 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, 2012), assessment of the toxicokinetic behaviour of the substance Fatty acids, vegetable-oil, esters with dipropylene glycol 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, 2012) and taking into account further available information on the analogue substances Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) and Octanoic acid ester with 1,2-propanediol, mono- and di- (CAS 31565-12-5).

The substance Fatty acids, vegetable-oil, esters with dipropylene glycol represents a UVCB substance specified by mainly C8 and C10 fatty acids esterified with dipropylene glycol isomers, based on analytical characterization.

Fatty acids, vegetable-oil, esters with dipropylene glycol is a liquid at 20°C and has a molecular weight range of 386.6 – 442.7 g/mol and a water solubility of < 0.01 mg/L at 20°C (Affolter, 2014). The calculated log Pow ranges between 6.85 (for a fatty acid chain length of C8) and 8.82 (for a fatty acid chain length of C10) depending on the chain length of the fatty acid (Müller, 2014). The vapour pressure is calculated to be < 0.0001 Pa at 20 °C (Nagel, 2014).

 

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) and the water solubility. The log Pow provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

Oral

When assessing the potential of Fatty acids, vegetable-oil, esters with dipropylene glycol to be absorbed in the gastrointestinal (GI) tract, it has to be considered that fatty acid esters will undergo hydrolysis by ubiquitous expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Thus, the predictions based upon 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 moiety, di- and propylene glycol and fatty acids ranging from C8 to C10.

The low water solubility and the high log Pow of the parent compound indicate that absorption in the gastrointestinal tract may be limited by the inability to dissolve into GI fluids. However, micellular solubilisation by bile salts may enhance absorption, a mechanism which is especially of importance for highly lipophilic substances with a log Pow > 4 and low water solubility (Aungst and Shen, 1986). Regarding the molecular weight of the intact compound (386.6 – 442.7 g/mol) as well as of the breakdown products dipropylene glycol (134.2 g/mol), propylene glycol (76.1 g/mol) and C8-C10 fatty acids (144.2 – 172.3 g/mol) absorption is generally favoured.

Fatty acids with carbon chain lengths from C6 to C12 are typically classified as medium chain fatty acids (MCFA). MCFA are most often transported directly to the liver through the portal vein and do not necessarily form micelles in the gastrointestinal tract like long chain triglycerides (LCT). Moreover, MCFA do not re-esterify into medium chain triglycerides (MCT) across the intestinal mucosa. MCFA are transported into the hepatocytes through a carnitine-independent mechanism. The alcohol components including dipropylene glycol and propylene glycol are highly water-soluble and have a low molecular weight and can therefore dissolve into GI fluids followed by readily absorption in the GI tract (ATSDR, 1997; OECD SIDS).

Based on the available data on acute toxicity following oral ingestion, Fatty acids, vegetable-oil, esters with dipropylene glycol showed no signs of systemic toxicity resulting in a LD50 > 2000 mg/kg bw (Richeux, 2014). Furthermore, available data on the analogue substance Decanoic acids, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) did not indicate subchronic oral toxicity based on a NOAEL ≥ 1000 mg/kg bw/day (Pittermann, 1993). The lack of short- and long-term systemic toxicity of the target and source substances cannot be equated with a lack of absorption but rather with a low toxic potential of the test substance and the breakdown products themselves.

 

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Fatty acids, vegetable-oil, esters with dipropylene glycol. Nevertheless, on the basis of the following considerations, the dermal absorption of the substance is considered to be low.

To pass from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a water solubility < 0. 01 mg/L, dermal uptake of the substance is likely to be low (ECHA, 2012). In addition, for substances having an octanol/water partition coefficient 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 may be high. Furthermore, QSAR calculation using EPIweb v4.1 confirmed this assumption, resulting in a low Dermal Flux of 1.65 x 10-5mg/cm2/h (for a C8 diester) to 2.18 x 10-6mg/cm2/h (for a C10 diester) (Müller, 2014).

In addition, available data on acute dermal toxicity of Octanoic acid ester with 1,2-propanediol, mono- and di- (CAS 31565-12-5, Mürman, 1992) showed no systemic toxicity.

Moreover, experimental data on irritation and sensitization did not reveal irritating (Colas, 2014) or sensitizing effects (Richeux, 2014).

Overall, taking into account the physico-chemical properties of Fatty acids, vegetable-oil, esters with dipropylene glycol, QSAR calculations and available toxicological data on the substance, the dermal absorption potential of the substance is anticipated to be low.

 

Inhalation

Fatty acids, vegetable-oil, esters with dipropylene glycol has a very low calculated vapour pressure of < 0.0001 Pa thus being of low volatility (Nagel, 2011). 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 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2012).

As discussed above, absorption after oral administration of the substance is driven by enzymatic hydrolysis of the ester bond to the respective metabolites and subsequent absorption of the breakdown products. Therefore, for effective absorption in the respiratory tract enzymatic hydrolysis in the airways would be required first. The presence of esterases and lipases in the mucus lining fluid of the respiratory tract would therefore be essential. However, due to the physiological function in the context of nutrient absorption, esterase and lipase activity in the lung is expected to be much lower in comparison to the gastrointestinal tract. Thus, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to be less effective.

Based on the physicochemical properties of the substance and data on acute inhalation toxicity the absorption via the lung is expected to be not higher than after oral absorption.

 

Distribution and accumulation

Distribution of a compound within the body depends on the physicochemical 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 (log Pow > 0), it is likely to distribute into cells and the intracellular concentration may be higher than the extracellular one, particularly in fatty tissues. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. However, distribution of highly water-soluble molecules is limited by their transfer through cell membranes and access to specific organs like the central nervous system and testes is likely to be hindered by the blood-brain barrier and blood-testes barrier (ECHA, 2012).

Due to the low water-solubility, the high log Pow and the relatively small molecular size, distribution of the parent compound within the body especially in cells and fatty tissue is reasonable. However, as Fatty acids, vegetable-oil, esters with dipropylene glycol undergo hydrolysis before absorption in the gastrointestinal tract occurs (as discussed below), distribution of the breakdown products of hydrolysis may be more relevant to consider. Due to the physico-chemical properties, the absorbed products of hydrolysis, namely di- and propylene glycol and the respective fatty acids will be distributed within the body. However, it has to be considered that dipropylene glycol is readily converted into propylene glycol, which itself is further converted to lactic and pyruvic acid. Non-metabolised propylene glycol was shown to be mainly excreted in the urine and hence, distribution of the primary hydrolysis products will predominantly depend on their respective metabolism rate. For tripropylene glycole it was shown that only 10% of the administered dose remained in the tissues whereas the major amount was recovered as CO2or urinary metabolites (OECD SIDS, 1992).

Like all medium and long chain fatty acids, the fatty acids may be re-esterified with glycerol into triacylglycerides (TAG) 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).

Overall, the intact parent compound and the breakdown products di- and propylene glycol are not assumed to be accumulated as hydrolysis takes place before absorption and distribution. However, accumulation of the fatty acids as 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 may also be used for energy generation. Thus, 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.

In summary, the available information on Fatty acids, vegetable-oil, esters with dipropylene glycol indicate that no significant bioaccumulation of the parent substance and the hydrolysis product di- or propylene glycol is expected. The remaining fatty acid moieties will be distributed in the organism.

 

Metabolism

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, 1970; Mattson and Volpenhein, 1972). Therefore, dipropylene glycol diesters are expected to be readily hydrolysed at the ester bond resulting in release of dipropylene glycol and the respective fatty acid.

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 propylene 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 und Volpenheim, 1968). Furthermore, the in-vivo hydrolysis of propylene glycol distearate (PGDS), a structurally related glycol ester, was studied using isotopically labeled PGDS (Long et al., 1958). Oral administration of PGDS showed intestinal hydrolysis into propylene glycol monostearate, propylene glycol and stearic acid, confirming above discussed metabolism of Fatty acids, vegetable-oil, esters with dipropylene glycol, as well.

Following hydrolysis and absoption, the alcohol component dipropylene glycol is readily converted into propylene glycol, which itself is converted to lactic and pyruvic acids. These conclusions are drawn from a metabolism study of tripropylene glycol and propylene glycol (Dow, 1995, as cited in OECD SIDS, 2001).

Following absorption into the intestinal lumen, fatty acids are re-esterified with glycerol to triacylglycerides (TAG) and included into chylomicrons for transportation via the lymphatic system and the blood stream to the liver. Additionally, MCFA may be transported directly to the liver through the portal vein and do not necessarily form micelles in the gastrointestinal tract as discussed above. In the liver, fatty acids can be metabolised in Phase I and II metabolism. Using the OECD QSAR ToolBox 2.3.0, liver metabolism simulation resulted in 40 metabolites.

An important metabolic pathway for fatty acids is the ß-oxidation for energy generation. In this multi-step process, the fatty acids are at first esterificated 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 (see Figure 3 in attached document). Further oxidation via the citric acid cycle leads to the formation of H2O and CO2(Lehninger, 1970; Stryer, 1994).

 

Excretion

Major routes of excretion are the urine and the bile. Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. Substances that are excreted in the bile tend to have higher molecular weights and are amphipathic, hydrophobic or strongly polar. Moreover, elimination via the bile is generally favored for non-absorbed substances following passage of the intestines (ECHA, 2012).

Based on the metabolism described above, the substance and its breakdown products will be metabolised in the body to a high extent. However, due to the molecular weight (> 300 g/mol), the low water solubility (< 0.1 mg/L) and the high log Pow (> 4), biliary excretion of non-hydrolysed parent compound is considered likely.

As discussed above, the parent compound will be hydrolysed resulting in release of dipropylene glycol and the fatty acid moiety. Dipropylene glycol will subsequently be absorbed and converted to propylene glycol, which is further converted to lactic and pyruvic acid. A metabolism study performed with tripropylene glycol showed that 21% of the administered dose was recovered as CO2and 53% as urinary metabolites, including tri-, di and propylene glycol conjugates. Only 10% of the administered dose remained in the tissues. Thus, in regard to the rapid hydrolysis of tri- and dipropylene glycol, a similar elimination process is expected for dirpopylene glycol including expiration via CO2and urinary exretion.

The fatty acid components will be metabolised for energy generation, 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 CO2or stored as described above. As propylene glycol will be highly metabolised as well, the primary route of excretion will be via exhaled air as CO2 (ATSDR, 1997).

References

Agency for Toxic Substances and Disease Registry (ATSDR) (1997): Toxicological Profile for Propylene Glycol. US Department of Health and Human Services. Atlanta, 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 (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

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.

Müller, T. (2014). Fatty acids, vegetable-oil, esters with dipropylene glycol (CAS 95009-41-9). EPIsuite 4.10 calculation with fatty acids, vegetable-oil, esters with dipropylene glycol. Report No. 20140123-Mue-1

OECD SIDS (2001). DIPROPYLENE GLYCOL (MIXED ISOMERS AND DOMINANT ISOMER) CAS N°: 25265-71-8 & 110-98-5). SIDS Initial Assessment Report for 11thSIAM (USA, January 23 - 26, 2001)

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