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Description of key information

Key value for chemical safety assessment

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 Fatty acids, C14-18 and C16-18-unsatd., esters with 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 Fatty acids, C14-18 and C16-18-unsatd., esters with 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 Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol consist of more than 60% diesters of propylene glycol with fatty acids with the following carbon chain lengths distribution: C14: <10%; C16: 0-20%; C18: <10%; C18:1: 20-85%; C18:2: 0-60%; C18:3: 0-35%. On the basis of the analytical characterization, Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol meets the definition of a UVCB substance. Representative diesters are shown in Figure 1 (see attached document).

Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol is a liquid at 20°C and has a molecular weight range of 286.46-609.02 g/mol and a water solubility of < 0.15 mg/L (Fischermann, 2012). The calculated log Pow value is >10 (Müller, 2011) and the vapour pressure is calculated to be <1E-10 (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 Fatty acids, C14-18 and C16-18-unsatd., esters with 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 C14-C18 and C16-18-unsatd.

The low water solubility and the high log Pow value of the parent 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 molecular weight, esters of the substance in the lower molecular weight range (286.46 g/mol) as well as the breakdown products propylene glycol (76.09 g/mol) and C14-C18 fatty acids (228.37 - 284.48 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 structurally related category members Decanoic acid, mixed diesters with octanoic acid and propylene glycol, Ethane-1,2-diyl palmitate and Fatty acids, C18 and C18 unsatd. Epoxidised, ester with ethylene glycol consistently showed no signs of systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Product Safety Labs 1991; Henkel, 1988; 1989). Furthermore, available data of category members on subchronic oral toxicity showed no adverse systemic effects resulting in NOAELs of 1000 mg/kg bw/day (Henkel, 1993, 1991; Atlas Chemical Industries, 1967). The lack of short- and long-term systemic toxicity of the structurally related category members cannot be equated with a lack of absorption or with absorption but rather with a low toxic potential of the Glycol Esters and the breakdown products themselves.

Dermal

There are no data available on dermal absorption or on acute dermal toxicity of Fatty acids, C14-18 and C16-18-unsatd., esters with 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 < 0.15 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. Furthermore, QSAR calculation using EPIwebv4.1 confirmed this assumption, resulting in a low Dermal Flux of 1.88E-2 mg/cm2 per h exemplarily calculated for a C18-unsatd., 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; Butylene glycol dicaprylate / dicaprate and Octanoic acid ester with 1,2-propanediol, mono- and di– showed no systemic toxicity resulting in LD50 values greater than 2000 mg/kg bw (Henkel, 1989; Hüls AG, 1992a,b).

Moreover, irritation studies with structurally related category members showed no irritating or sensitizing effects or signs of systemic toxicity in respective studies (Gattefosse, 1976; Safepharm Laboratories Ltd., 1989, Henkel, 1991; Hüls AG, 1992; Henkel, 1989).

Overall, taking into account the physico-chemical properties of Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol, the QSAR calculation and available toxicological data on structurally related category members, the dermal absorption potential of the substance is anticipated to be low.

Inhalation

Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol has a very low calculated vapour pressure of <1E-10 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 structurally related category member Decanoic acid, mixed diesters with octanoic acid and propylene glycol in rats and guinea pigs did not show any mortality or systemic toxicity after inhalative exposure (Re, 1978a,b). Therefore, inhalative absorption is considered to be not higher than through the intestinal epithelium.

Based on the physicochemical properties of Decanoic acid, mixed diesters with octanoic acid and propylene glycol and data on acute inhalation toxicity of the category member Decanoic acid, mixed esters with octanoic acid and propylene glycol (CAS 68583-51-7) 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 Fatty acids, C14-18 and C16-18-unsatd., esters with 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 C14 -C18 and C16-C18-unsatd. 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 Fatty acids, C14-18 and C16-18-unsatd., esters with 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 C14-18 and C16-18 unsatd. will be distributed in the organism.

 

Metabolism

Metabolism of Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. propylene glycol mono stearate), free fatty acids (C14-18, C16-18 unsatd.) and propylene glycol.

In vitro studies with propylene glycol distearate (PGDS) demonstrated hydrolysis of the ester (Research Center, 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 Decanoic acid, mixed diesters with octanoic acid and propylene glycol, as well.

In addition, simulation of intestinal metabolism of the representative diester propylene distearate, using the OECD QSAR ToolBox v.2.3.0, resulted in 134 intestinal metabolites including free fatty acids and several propylene glycol monoester (e.g. propylene glycol monostearate) 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. 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 for propylene glycol distearate resulted in 31 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, an Ames-tests with Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol (Henkel, 1991), an in-vitro chromosomal aberration test with C8-C10-1,3-Butandiolester (Hüls AG, 1997), an in-vitro mammalian gene mutation assay with Fatty acids, C16-18, esters with ethylene glycol (NOTOX B.V., 2010) and a micronucleus assay in-vivo with Fatty acids, C18 and C18 unsatd. epoxidized, ester with ethylene glycol (Henkel, 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 (Research Center, 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).

 

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 (2008). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Heymann, E. (1980): Carboxylesterases and amidases. In: Jakoby, W.B., Bend, J.R. & Caldwell, J., eds., Enzymatic Basis of Detoxication, 2nd Ed., New York: Academic Press, pp. 291-323.Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

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

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

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

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

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