Decanoic acid, mixed diesters with octanoic acid and propylene glycol

Endpoint summary

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.

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Decanoic acid, mixed diesters with octanoic acid and propylene 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, 2008), assessment of the toxicokinetic behaviour of the substance Decanoic acid, mixed diesters with octanoic acid and propylene 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, 2008) and taking into account further available information on the Glycol Ester category.

The substance Decanoic acid, mixed diesters with octanoic acid and propylene glycol consist of C6: < 10%; C8: 10-85%; C10: 10-85%; C12: < 10%; diester: > 80% and therefore meets the definition of a UVCB substance based on the analytical characterization. Two representative diesters are shown in Figure 1 (see attached document).

Decanoic acid, mixed diesters with octanoic acid and propylene glycol is a light yellow liquid at 20°C and has a molecular weight range of 328.49 - 384.59 g/mol and a water solubility of < 0.05 mg/L at 20°C (Fischermann, 2012). The experimental log Pow is 5.21 (Bargallo, 2011) and the vapour pressure is calculated to be 1.24E-6 to 0.000155 Pa (Nagel, 2011).

 

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, 2008).

Oral

When assessing the potential of Decanoic acid, mixed diesters with octanoic acid and propylene glycol 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 expressed GI enzymes (Long, 1958; Lehninger, 1970; Mattson and Volpenhein, 1972). Thus, due to the hydrolysis 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 propylene glycol and fatty acids ranging from C6 to C12.

The low water solubility and the high log Pow value of the compound indicate that the absorption 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 log Pow > 4 and low water solubility (Aungst and Shen, 1986). Regarding the molecular weight of the intact compound (328.49 - 384.59 g/mol) as well as of the breakdown products propylene glycol (76.09 g/mol) and C6-C12 fatty acids (116.16 - 298.9 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). Matulka (2009) described that the absorption of medium chain triglycerides (MCT) differs from those of long chain triglycerides (LCT). MCFA are most often transported directly to the liver through the portal vein and do not necessarily form micelles in the gastrointestinal tract like LCT. Moreover, MCFA do not re-esterify into MCT across the intestinal mucosa. MCFA are transported into the hepatocytes through a carnitine-independent mechanism. The alcohol component propylene glycol is highly water-soluble and has a low molecular weight and can therefore dissolve into GI fluids. Thus, propylene glycol will be readily absorbed through the GI tract (ATSDR, 1997).

Several studies on acute oral toxicity of Decanoic acid, mixed diesters with octanoic acid and propylene glycol consistently showed no signs of systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Potokar, 1988; Blackwell, 1989; Blackwell, 1988; Consultox Laboratories Ltd., 1972; Masson, 1985). Furthermore, available data of the substance on subchronic oral toxicity showed no adverse systemic effects resulting in a NOAEL of 1000 mg/kg bw/day (Pittermann, 1993). The lack of short- and long-term systemic toxicity of the substance cannot be equated with a lack of absorption or with 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 Decanoic acid, mixed diesters with octanoic acid and propylene glycol. On the basis of the following considerations, the dermal absorption of the substance is considered to be low.

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Thus, with a water solubility < 0.05 mg/L, dermal uptake of the substance is likely to be low. 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 EPIwebv4.1 confirmed this assumption, resulting in a low Dermal Flux of 1.45E-4 mg/cm² per h (for a C8 diester) to 4.62E-5 mg/cm² per h (for a C10 diester).

In addition, available data on acute dermal toxicity of three substances of the Glycol Ester category (Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0); Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8) and Octanoic acid ester with 1,2-propanediol, mono- and di- (CAS 31565-12-5, Potokar, 1989; Mürmann, 1992a,b)) showed no systemic toxicity.

Moreover, irritation studies with the substance or structurally related category members showed no irritating or sensitizing effects or signs of systemic toxicity in respective studies (Guest, 1989, 1988; Kästner, 1988; Masson, 1985; Consultox Laboratories Ltd., 1972; Kästner, 1989; Mürmann, 1992a,b).

Overall, taking into account the physico-chemical properties of Decanoic acid, mixed diesters with octanoic acid and propylene glycol, the QSAR calculation and available toxicological data on the substance and several structurally related category members, the dermal absorption potential of the substance is anticipated to be low.

 

Inhalation

Decanoic acid, mixed diesters with octanoic acid and propylene glycol has a very low calculated vapour pressure of 1.24E-6 to 0.000155 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 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, 2008).

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 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.

In addition, acute inhalation studies with the substance in rats and guinea pigs did not show any mortality or systemic toxicity after inhalative exposure (Re, 1978a,b). Therefore, inhalative absorption of Decanoic acid, mixed diesters with octanoic acid and propylene glycol is considered to be not higher than through the intestinal epithelium.

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, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2008).

As the parent compound Decanoic acid, mixed diesters with octanoic acid and propylene glycol will be hydrolysed before absorption as discussed above, the distribution of the intact substance is not relevant but rather the distribution of the breakdown products of hydrolysis. The absorbed products of hydrolysis, propylene glycol and fatty acids with carbon chain length from C6-C12 can be distributed within the body.

The alcohol propylene glycol has a low molecular weight and high water solubility. Based on the physico-chemical properties, propylene glycol will be distributed within the body (ICPS, 1997). Substances with high water solubility like propylene 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, 1996).

Therefore, the intact parent compound is not assumed to be accumulated 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 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 Decanoic acid, mixed diesters with octanoic acid and propylene glycol indicate that no significant bioaccumulation of the parent substance in adipose tissue is expected. The breakdown products of hydrolysis, propylene glycol and fatty acids from carbon chain lengths C6-C12 will be distributed in the organism.

 

Metabolism

Metabolism of Decanoic acid, mixed diesters with octanoic acid and propylene glycol initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. propylene glycol mono decanoate), free fatty acids (C6-C10) and propylene glycol.

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; 1972). 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 Decanoic acid, mixed diesters with octanoic acid and propylene glycol, as well.

In addition, simulation of intestinal metabolism of the substance, using the OECD QSAR ToolBox v.2.3.0, resulted in 106 intestinal metabolites including free fatty acids and several propylene glycol monoester (e.g. propylene glycol monodecanoate) supporting the metabolism pathway, as well.

Following hydrolysis, absorption and distribution of the alcohol component, propylene glycol will be metabolised primary in the liver by alcohol dehydrogenase to lactic acid and pyruvic acid which are endogenous substances naturally occurring in mammals (Miller & Bazzano, 1965). 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. 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 beta-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, 1996).

Available genotoxicity data from the substance and all other category members do not show any genotoxic properties. In particular, Ames-tests with Decanoic acid, mixed diesters with octanoic acid and propylene glycol (Banduhn, 1991; Ebert, 1995), an in-vitro chromosomal aberration test with Butylene glycol dicaprylate / dicaprate (CAS 853947-59-8; Dechert, 1997), an in-vitro mammalian gene mutation assay with Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1; Verspeek-Rip, 2010) and a micronucleus assay in-vivo with Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0; Banduhn, 1990) were consistently negative and therefore no indication of a genotoxic reactivity of any member of the Glycol Esters category under the test conditions is indicated.

 

Excretion

Based on the metabolism described above, the substance and its breakdown products will be metabolised in the body to a high extent. In-vivo studies with propylene glycol distearate showed, that 94% of the labeled PGDS was recovered from 14CO2 excretion and only ~ 0.4% of the total dose of PGDS were excreted in the urine after 72 h supporting this notion as well (Long et al., 1958).

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, 1996). 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 CO2 or 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).

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