Fatty acids, C16-18 (even numbered), esters with 1,2-propanediol

Endpoint summary

Description of key information

The target substance Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) is expected to be readily absorbed through the gastrointestinal tract tract after oral administration. In contrast, 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 C16 and C18) and propylene glycol which facilitates the absorption. The fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons, while the absorbed propylene glycol will enter the carbohydrate cycle. 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 CO₂in 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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) 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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) 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 structural analogue substances.

The substance Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) is a multi-constituent substance specified by mainly C16 and C18 linear fatty acids esterified with 1,2-propanediol resulting in mono- and diesters which meets the definition of an UVCB substance.

Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) is a solid at 20°C which has a molecular weight ranging from 314.51 – 609.04 g/mol and a water solubility of < 0.1 mg/L. The calculated log Pow value is > 6.69 (KOWWIN v1.68) (Werth, 2014) and the vapour pressure is calculated to be < 2.64E-006 Pa at 20 °C (SPARC v4.6) (Nagel, 2014).

 

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

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Shen, 1986; ECHA, 2014).

When assessing the potential of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) 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, 1968; National technical information service, 1973). 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 C16 and C18.

The low water solubility (< 0.1 mg/L) and the high log Pow value >6.69 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 hexadecanoic or octadecanoic acid (256.4 or 284.5 g/mol, respectively) 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; National technical information service, 1973). The highly lipophilic fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

Moreover, a study on acute oral toxicity of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) resulted in a LD50 value greater than 5000 mg/kg bw (Potokar, 1989). In addition, Propylene Glycol Stearate (Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) falls into the specification given for Propylene Glycol Stearate according to the product specification provided) did not induce adverse effects in an acute oral toxicity study and hence, a LD50 > 5000 mg/kg bw was derived (CIR, 1983). Furthermore, available data on subacute oral toxicity of the analogue substance Fatty acids, C6-12, esters with propylene glycol (CAS 85883-73-4) showed no adverse systemic effects resulting in a NOAEL ≥ 2500 mg/kg bw/day (Padgett, 2006). The lack of systemic toxicity of the structurally related analogue substances cannot be equated with a lack of 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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3). 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 < 1 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 thus limit absorption across the skin. Furthermore, uptake into the stratum corneum itself may be slow. In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake vie the skin is possible (ECHA, 2014).

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

The Kp was calculated for the 4 main constituents of the substance (please refer to Table 1). QSAR calculations confirmed this assumption, as low dermal flux rates ranging from 2.5E-4 - 2.2E-9 mg/cm2 per h were calculated indicating only low dermal absorption potential for the components of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1; Werth, 2014).

Table 1: Dermal absorption values for the components of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) (calculated with Dermwin v 2.02, Epiweb 4.1)

Component	Structural formula	Flux (mg/cm2/h)
Hexadecanoic acid, monoester	C19 H38 O3	2.5E-4
Hexadecanoic acid, diester	C35 H68 O4	1.7E-8
Octadecanoic acid, monoester	C21 H42 O	9.2E-5
Octadecanoic acid, diester	C39 H76 O4	2.2E-9

 

In addition, available data on acute dermal toxicity of the analogue substance Octanoic acid ester with 1,2-propanediol, mono- and di (CAS 31565-12-5) and Propylene Glycol Stearate (Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) falls into the specification given for Propylene Glycol Stearate according to the product specification provided) showed no systemic toxicity resulting in an overall dermal LD50 value greater than 2000 mg/kg bw (Mürmann, 1992, CIR, 1983).

Moreover, the irritation studies with the structurally related substances Decanoic acid, mixed diesters with octanoic acid and propylene (CAS 68583-51-7) and Propylene Glycol Stearate (Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) falls into the specification given for Propylene Glycol Stearate according to the product specification provided) showed no or only mild irritating effects (Guest, 1989, CIR, 1983).

Overall, taking into account the physico-chemical properties of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3), the QSAR calculations and available toxicological data on structural analogue substances, the dermal absorption potential of the substance is anticipated to be low.

 

Inhalation

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).

Inhalation of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) is considered as negligible as the test substance is used only as pellets or pastilles with intentional diameters of 3-4 mm and a width of 2 mm. Thus, the contained particles are far above the inhalable size. Moreover, the test substance has a very low calculated vapour pressure of <2.64E-06 Pa 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.

Based on the physical state and the physico-chemical properties of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3), absorption via the lung is expected as negligible.

 

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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) will be hydrolysed prior to 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 the respective fatty acid moieties 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). After absorption, propylene glycol will enter the blood circulating system through which it will be distributed within the body. In fasted animals, propylene glycol was shown to disappear rapidly from the blood most probably due to entry in the carbohydrate cycle (National technical information service, 1973). 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 accumulate 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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) 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 within the organism.

Metabolism

Metabolism of Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. propylene glycol monostearate and -palmitate), the fatty acids moieties (mainly C16 and C18.) 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 Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3), as well.

Following hydrolysis, absorption and distribution of the alcohol component, propylene glycol will enter the carbohydrate cycle (National technical information service, 1973). 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 the test substance and structural related analogue substances do not show any genotoxic properties. In particular, an Ames-tests with Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) (Spruth, 2015), 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 is indicated.

 

Excretion

Based on the metabolism described above, Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3) and its breakdown products will be metabolised in the body to a high extent. In-vivo studies with propylene glycol distearate (PGDS) 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). A similar observation was made for propylene glycol, which was excreted in substantial amounts as 14CO2 during the first 24 h after administration of radioactive label (National technical information service, 1973).

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 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.

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.

Cosmetic Ingredient Review (CIR) (1983). Final Report on the Safety Assessment of propylene Glcol Stearate and Propylene Glycol Stearate Self-Emulsifying. Journal of The American College of Toxicology. 2(5):101-124

ECHA (2014). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 2.0, November 2014

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 Volpenhein R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lip Res 9:79-84.

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

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.

National technical information service (1973). Evaluation of the Health Aspects of Propylene Glycol and Propylene Glycole Monostearate as Food Ingredient. Fed of America Societies for Experimental Biology, Bethesda, MD. Contract No.FDA 72 - 85

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

Werth, C. (2014). Octadecanoic acid, monoester with 1,2-propanediol (CAS 1323-39-3) and Palmitic acid, monoester with propane-1,2-diol (CAS 29013-28-3). EPIsuite 4.11 calculation with Octadecanoic acid and Palmatic acid, mono- and diester.Dr. Knoell Consult GmbH. Report Number: 20141031-Wer-1.