Isooctadecanoic acid, monoester with propane-1,2-diol

Endpoint summary

Description of key information

Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) is expected to be readily absorbed via the oral route, and partly absorbed via the dermal route. The ester will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and propylene glycol, which facilitates the absorption. The fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons: The alcohol component is highly water-soluble and has low molecular weight and can therefore dissolve into GI fluids. Thus, this alcohol will be readily absorbed through the GI tract. The main route of excretion is expected to be by expired air as CO2 after stepwise metabolic degradation. No bioaccumulation is expected to take place, as excess triglycerides are stored and used as the energy need rises.

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.

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.

The substance Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) is a multi-constituent substance specified by mainly C18 linear fatty acids esterified with 1,2-propanediol (>90% monoester C18iso, <5% diester C18iso, <5% other). The definition of an UVCB substance is met, as several different branching options in the isooctadecanoic acid are possible.

Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) is a liquid at 20°C which has a molecular weight of 342.56 g/mol and a water solubility of < 0.02 mg/L. The calculated log Pow value is >7 (KOWWIN v1.1.4, 2017) and the vapour pressure is calculated to be 7.23E-007 Pa at 20 °C (SPARC v4.6, 2017).

 

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, 2017).

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, 2017).

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 labelled 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 Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0), as well.

When assessing the potential of Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) to be absorbed in the 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; National technical information service, 1973). Therefore, due to the hydrolysis the predictions based on the physico-chemical characteristics of the intact parent substance as well as the physico-chemical characteristics of the breakdown products of the ester will be relevant. The hydrolysis products are the alcohol propylene glycol and the corresponding fatty acids, mostly C18.

The low water solubility (< 0.1 mg/L) and the high log Pow value >7 of the parent compound indicate that absorption may be limited by the inability to dissolve into GI fluids. However, mi-cellular solubilisation by bile salts may enhance absorption (Aungst and Shen, 1986). The alcohol component propylene glycol is highly water-soluble and has a low molecular weight (76.09 g/mol) 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 C18-fatty acids are absorbed by micellar solubilisation. Within the epithelial cells, fatty acids are (re)-esterified with glycerol to triglycerides.

In an acute oral toxicity study in rats the LD50 value of Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) was found to be greater than 2000 mg/kg bw.

The repeated dose toxicity potential of the target substance isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) was assessed by applying read across of data from two source substances. In a sub-chronic (90-day) oral repeated dose studies in rats with stearic acid, monoester with propane-1,2-diol / 2-hydroxypropyl stearate (CAS 1323-39-3) the NOAEL was found to be greater than 5000 mg/kg bw/day. In a sub-chronic (90-day) oral repeated dose studies in rats with Decanoic acids, mixed diesters with octanoic acid and propylene glycol (CAS 68583-51-7) the NOAEL was found to be greater than 1000 mg/kg bw/day.

The lack of systemic toxicity of the structurally related source substances cannot be equated with a lack of absorption but indicates a low toxic potential of glycol esters and the breakdown products themselves.

Dermal

There are no data available on the dermal absorption or on acute dermal toxicity of Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0). An acute dermal toxicity study with an source substance, 1,2-Propandiol-mono/di-dodecanoat (CAS 37321-62-3) the LD50 value in male and female rats was found to be greater than 2000 mg/kg bw.

On the basis of the following considerations, the dermal absorption of the substance Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) 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.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2012):

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

QSAR calculation confirmed this assumption, as a low dermal flux rate of 9.5E-5 mg/cm2 per h was calculated indicating only low dermal absorption potential for Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) (please refer to Table 1, Dermwin v2.02, EpiSuite 4.1; 2017).

Table 1: Dermal absorption value for Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) was calculated using Dermwin v 2.02, Epiweb 4.1 by entering the CAS number and using a Kow of 7:

Component	Structural formula	Molecular weight	estimated water concentration [mg/cm³)	Kp [cm/h]	Flux [mg/cm²h]
Isooctadecanoic acid, monoester with propane-1,2-diol	C21 H42 O3	342.57	2.34e-005	0.841	0.000162

 

In a in vivo rabbit skin irritation study with Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) only mild skin irritating effects were found.

Overall, taking into account the physico-chemical properties of Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0), the QSAR calculations and available toxicological data on structural analogue substances, the dermal absorption potential of the substance is expected to be low.

Inhalation

Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) is a liquid with a very low calculated vapour pressure of 7.23E-007 Pa at 20 °C and therefore a low volatility. Therefore, under normal use and handling conditions, inhalation exposure and the availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited (ECHA, 2017).

Systemic bioavailability in humans is generally considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm (ECHA 2017). Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) is is used in cosmetics as skin-conditioning agent-emollient; surfactant-emulsifying agent (CIR, 2015). The cosmetic ingredient review panel noted that 95%–99% of droplets/particles from sprays with propylene glycol esters would not be respirable to any appreciable amount.

In conclusion, based on a worst-case approach the absorption potential via the inhalation route is expected to be as high as via the oral route. However, the exposure potential is 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, 2017).

As the parent compound Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) will be hydrolysed prior to absorption (as discussed above); the distribution of the intact substance is less relevant than the distribution of the breakdown products following hydrolysis. The absorbed hydrolysis products, 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 enter the blood circulation and 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). 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. The 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 Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) 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 Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) initially occurs via stepwise enzymatic hydrolysis of the ester resulting in the corresponding monoesters (e.g. propylene glycol monostearate), the fatty acids moieties (mainly C18.) and propylene glycol.

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 esterified 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 source substances do not show any genotoxic properties. In particular, Ames tests with the source substances Octadecanoic acid, monoester with 1,2-propanediol / Palmitic acid, monoester with 1,2-propanediol (CAS 1323-39-3 / 29013-28-3), Stearic acid, monoester with propane-1,2-diol (CAS 1323-39-3), and Fatty acids, C14-18 and C16-18-unsatd., esters with propylene glycol -0) were negative for bacterial mutation potential. Furthermore in vitro tests in mammalian cells including a mammalian cell gene mutation assay in mouse lymphoma L5178Y cells and a mammalian chromosome aberration test in primary human lymphocytes with the target substance Isooctadecanoic acid, monoester with propane-1,2-diol indicated no mutagenic or clastogenic potential. Therefore, no indication of a genotoxic reactivity is indicated for the target and source substances.

 

Excretion

Based on the metabolism described above, Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0) 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 labelled PGDS was recovered from14CO2excretion and only ~ 0.4% of the total dose of PGDS was excreted in the urine after 72 h (Long et al., 1958). A similar observation was made for propylene glycol, which was excreted in substantial amounts as14CO2during 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

ATSDR Agency for Toxic Substances and Disease Registry (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) 2015: Safety Assessment of Propylene Glycol Esters as Used in Cosmetics, Final Amended Report, 15 Jan 2014

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017.

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

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.

US EPA (2012). Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA. Downloaded from: http://www.epa.gov/oppt/exposure/pubs/episuite.htm

Werth, C. (2014). Isooctadecanoic acid, monoester with propane-1,2-diol (CAS 68171-38-0). EPIsuite 4.11 calculation with Octadecanoic acid and Palmatic acid, mono- and diester. Dr. Knoell Consult GmbH. Report Number: 20141031-Wer-1.