Fatty acids, C16-18 and C18-unsatd., esters with propylene glycol

Endpoint summary

Description of key information

The target substance is expected to be absorbed through the gastrointestinal tract tract after oral administration only to a minor amount.

Similarly, dermal and inhalation absorption are considered to be low. The esters will be hydrolysed in the gastrointestinal tract to the respective fatty acids moieties (mainly C18) and propylene glycol which facilitates the absorption. The fatty acids will most likely be re-esterified to triglycerides after absorption; while the absorbed propylene glycol will be metabolised primary in the liver by alcohol dehydrogenase to lactic acid and pyruvic acid. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion will mainly be as CO₂ in expired air; with a smaller fraction excreted in the urine. No bioaccumulation will take place, as excess triglycerides are stored and used as the energy need rises.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of the target substance has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 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, 2014), assessment of the toxicokinetic behaviour of the target 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 according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2014) and taking into account further available information on glycol esters.

On the basis of the analytical characterization, the target substance meets the definition of an UVCB substance.

The target substance is a liquid at 20 °C and has a water solubility < 10 mg/L (Younis, 2015). The log Pow value is 8.5 (Schwarzkopf, 2015) and the vapour pressure ≤ 0.1 Pa (Kintrup, 2015). However, based on a weight-of-evidence approach including available data for the source substances and QSAR analysis for the target substance (Werth, 2014), a water solubility of < 0.05 mg/L and a vapour pressure <1E-9 are considered appropriate (for further details, please refer to chapter 1.3 of the CSR). 

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, 2014).

 

Oral

When assessing the potential of the target substance 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 the corresponding fatty acids, mostly C18:1.

The low water solubility (< 0.05 mg/L) and the high log Pow value >8 of the parent compound indicate that 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 molecular weight, the breakdown products propylene glycol (76.09 g/mol) and oleic acid (282.5 g/mol) are generally favourable for absorption. 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).

Moreover, studies on acute oral toxicity of the structural analogue substances Ethylene distearate (CAS 627-83-8), Decanoic acid, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) and Fatty acids, C18 and C18 unsatd. epoxidised, ester with ethylene glycol (CAS 15166-88-0) consistently showed no signs of systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Wnorowski, 1991, Potokar, 1988, 1989). Furthermore, available data on subchronic oral toxicity showed no adverse systemic effects resulting in NOAELs of ≥ 1000 mg/kg bw/day for both analogue substances (CAS 68583-51-7 and CAS 15166-88-0) (Pittermann, 1993, 1991). The lack of short- and long-term systemic toxicity of the structurally related analogue substances cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of Glycol Esters and the breakdown products themselves.

 

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of the target substance. 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 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Furthermore, uptake into the stratum corneum itself may be slow.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2014):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

Considering the water solubility (< 0.00005 mg/cm³) and the calculated Kp value of 3.2E+4 cm/hr (Dermwin v2.02, EpiSuite 4.1), a dermal flux of 2.86E-9 mg/cm²/h is estimated which confirms the assumption that only a low dermal absorption may occur.

In addition, available data on acute dermal toxicity of the analogue substance Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (CAS 151661-88-0) and Octanoic acid ester with 1,2-propanediol, mono- and di (CAS 31565-12-5) showed no systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Potokar, 1989; Mürmann, 1992).

Moreover, irritation studies with structurally related substances showed no irritating or sensitizing effects or signs of systemic toxicity in respective studies (Wnorowski, 1991; Guest, 1989; Coguet, 1976. Müller, 1982 and Kästner, 1989).

Overall, taking into account the physico-chemical properties of the target substance, the QSAR calculation and available toxicological data on structurally related analogue substances, the dermal absorption potential of the substance is anticipated to be low.

 

Inhalation

The target substance has a very low calculated vapour pressure of <1E-9 Pa thus being of low volatility (Werth, 2014). 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, 2014).

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.

Based on the physico-chemical properties of the target substance, 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 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, 2014).

As the parent compound the target substance 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 oleic acid 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, 2001). 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, 1994).

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 the target substance indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected. The breakdown products of hydrolysis, propylene glycol and the respective fatty acids will be distributed in the organism.

 

Metabolism

Metabolism of the target substance initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. propylene glycol mono oleate), free fatty acids (mainly C18 mono-unsatd.) 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 and 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 Propylene glycol dioleate, 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. 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 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. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1970; Stryer, 1994).

Available genotoxicity data from structural related analogue substances do not show any genotoxic properties. In particular, an Ames-tests with Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol (CAS 84988-75-0; Banduhn, 1991), an in-vitro chromosomal aberration test with C8-C10-1,3-Butandiolester (CAS 853947-59-8; Dechert, 1997) and an in-vitro mammalian gene mutation assay with Fatty acids, C16-18, esters with ethylene glycol (CAS 91031-31-1; Verspeek-Rip, 2010) were consistently negative and therefore no indication of a genotoxic reactivity of structurally related glycol esters under the test conditions is indicated.

 

Excretion

Based on the metabolism described above, the target 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 14CO2excretion 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, 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.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010). Toxicological Profile for Ethylene 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 (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

International Programme on Chemical Safety (IPCS) (2001). Ethylene Glycol. Poisons Information Monograph. PIM 227.

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

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.

Miller, O.N., Bazzano, G. (1965). Propanediol metabolism and its relation to lactic acid -metabolism. Annals of the New York Academy of Sciences 119:957-973.

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

Werth, C. 2014. EPIsuite 4.11 calculation with 9-Octadecenoic acid (Z)-, 1-methyl-1,2-ethanediyl ester.Dr. Knoell Consult GmbH, Report No. 20140626-Wer-1. 2014-06-26