Dodecyl nonan-1-oate

Endpoint summary

Description of key information

The target substance Lauryl nonanoate (CAS 17671-26-0) is expected to be hydrolysed within the gastrointestinal tract and the hydrolysis products are predicted to be readily absorbed via the oral route. Potential for absorption via inhalation and dermal route is predicted to be low. The ester bonds will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and fatty alcohol, which facilitates the absorption. The fatty acid will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; the absorbed alcohol is readily distributed throughout the organism and can be re-esterified to form endogenous triglycerides. The major metabolic pathway for linear fatty acids is the beta-oxidation pathway for energy generation. The excretion will mainly be as CO2 in expired air; with a smaller fraction excreted as conjugated molecules in the urine. Fatty alcohol can likewise be metabolised and incorporated into physiological pathways. 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

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of the target substance Lauryl nonanoate (CAS 17671-26-0) was 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 the Chapter R.7c Guidance document (ECHA, 2017) and taking into account further available information from a source substance. There are no studies available in which the toxicokinetic behaviour of Lauryl nonanoate (CAS 17671-26-0) was investigated.

Lauryl nonanoate (lauryl nonanoate) is a mono-constituent substance with a linear C12-alcohol moiety and linear C9 acid moiety. The substance has a molecular weight of 326.6 g/mol. It is a liquid with melting point of 15.2°C, and a water solubility of 2.43 µg/L at 20 °C (pH 6.3). The log Pow was calculated to be 8.4 - 9.21 and the vapour pressure was calculated to be 3.4E-5 Pa at 20 °C.

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. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2017).

The physical state and molecular weight of the substance favour uptake, while the log Pow and water solubility is in a range that indicate poor absorption from the GI-tract following oral ingestion. Micellar solubilisation may have an effect on the overall absorption rate of the substance.

The indications that the target substance Lauryl nonanoate has low oral absorption are supported by the available data on source substances (CAS 95912-86-0, CAS 2306-88-9, CAS 135800-37, and 22393-85-7), covering acute and repeated dose oral toxicity.

In a study in which mice were administered a single dose of 5000 mg/kg bw (CAS 95912-86-0, Fatty acids, C8-10, C12-18-alkyl esters), there was no mortality and no effect on the body weight. No adverse clinical signs were noted (key study, 1991).

In a study in which rats were administered a single dose of 1000 and 5000 mg/kg bw (CAS 2306-88-9, octyl octanoate), there was no mortality and no effect on the body weight. No adverse clinical signs were noted (supporting study, 1981).

No mortality, no effects on body weight, and no clinical signs were noted in a study on rats administered 2000 mg/kg bw of Fatty acids, C8-12, 2-ethylhexyl esters (CAS 135800-37-2) (supporting study, 1989).

In a 28-day repeated dose toxicity study performed with the source substance Fatty acids, C8-12, 2-ethylhexyl esters (CAS 135800-37-2), as well as in a combined repeated dose toxicity and reproduction/developmental toxicity study performed using the source substance Tetradecyl oleate (CAS 22393-85-7), no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day (WoE, 1991 and 2014).

The potential of a substance to be absorbed in the GI-tract may be influenced by several parameters, like: chemical changes taking place in GI-fluids, as a result of metabolism by GI-flora, by enzymes released into the GI-tract or by hydrolysis. These changes will alter the physico-chemical characteristics of the substance and hence predictions based on the physico-chemical characteristics of the parent substance may in some cases no longer apply or should be adjusted (ECHA, 2017).

In general, alkyl esters are readily hydrolysed in the GI-tract, blood and liver to the corresponding alcohol and fatty acid by the ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine catalysed by pancreatic lipase is lower for alkyl esters than for triglycerides, which are the natural substrates of this enzyme. The speed of hydrolysis of esters of primary n-alcohols containing from 1 to 18 carbon atoms with fatty acids containing from 2 to 18 carbon atoms was found to depend on both, the chain length of either the alcohol or acid. With respect to fatty acid moiety, esters of C12 and C4 were hydrolysed at the most rapid rate. With respect to alcohol moiety C7 was hydrolysed most rapidly (Mattson and Volpenhein, 1969).

Based on the generic information on hydrolysis of alkyl esters, the target substance Lauryl nonanoate is expected to be enzymatically hydrolysed to the C9 fatty acid and the C12 fatty alcohol.

Free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are (re-)esterified with glycerol to triglycerides. In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. As for fatty acids, the rate of absorption of alcohols is likely to decrease with increasing chain length (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974).

In conclusion, the physico-chemical properties and molecular weight of Lauryl nonanoate suggest that some oral absorption is likely to occur. However, the substance is anticipated to undergo enzymatic hydrolysis in the GI-tract and therefore absorption of the ester hydrolysis products is also relevant. The absorption rate of the hydrolysis products is expected to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow 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 will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2017).

The molecular weight of Lauryl nonanoate of 326.6 g/mol favours dermal absorption. However, other physico-chemical properties (low water solubility, log Pow >9 ) indicate a limited dermal absorption, as the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis is considered to be slow as well (ECHA, 2017).

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

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

Using a water solubility of 2.43 µg/L and a log Pow of 9.21 Dermwin v2.02 calculated the Kp to be 30.4 cm/h. The dermal flux was calculated to be 0.00055 mg/cm²h, indicating a low dermal absorption potential.

An acute dermal toxicity study was performed with the source substance Decyl oleate (CAS 3687-46-5), in which rats were exposed to 2000 mg/kg bw for 24 hours under occlusive conditions (key study, 2010). No mortality occurred and no toxicologically relevant systemic effects were observed. Erythema (score 1) was noted during Day 3-7 in 4/10 animals, while scales or scabs were observed in 8/10 animals for up to 9 days during Day 7-15.

In a summary of an acute dermal toxicity study in which rabbits were exposed to 2000 mg/kg bw tetradecyl myristate (CAS 3234-85-3) for 24 hours, no mortality was reported (supporting study, 1982). No treatment -related clinical signs were observed. The maximum skin irritation scores reported were well-defined erythema (score 2) and very slight edema (score 1). Based on the results from the source substances, the target substance is not expected to be acutely toxic via the dermal route.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017).

The available skin irritation data on the source substances Fatty acids, C8-10, C12-18-alkyl esters) (CAS 95912-86-0) and 2-ethylhexyl laurate (CAS 135800-37-2), show only mild skin irritating effects in the rabbit (key study, 1991; supporting study, 1990). In the acute dermal toxicity studies reversible skin irritation was observed (key study, 2010; supporting study, 1982).

In a LLNA assay conducted according to OECD guideline 442B in mice with the target substance Lauryl nonanoate (CAS 17671-26-0) no skin irritation was found upon three daily topical applications of 25 µL of the undiluted test substance.

Therefore, no increase in the penetration rate of the substance due to skin damage is expected, however some dermal uptake was indicated by the skin sensitising potential detected in the LLNA assay.

Overall, based on the available information and using a worst-case approach, the dermal absorption potential of Lauryl nonanoate is predicted to be low to moderate.

Inhalation

Lauryl nonanoate is a liquid with a very low vapour pressure (3.4E-5 Pa at 20 °C), and therefore inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases or mists is limited due to the low volatility. The substance is not used in spray applications. Under normal use and handling conditions, the substance is contained in containers. Inhalation exposure and thus availability for respiratory absorption of the substance is therefore not likely.

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 discussed under oral absorption, Lauryl nonanoate may undergo enzymatic hydrolysis in the GI-tract prior to absorption. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). The distribution and accumulation of the hydrolysis products is considered the most relevant.

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. This route of absorption and metabolism of a fatty acid was shown in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [1-14C]-radiolabelled octadecanoic acid to rats, 52.5 ± 26% of the radiolabelled carbon was recovered in the lymph. A large majority (68 - 80%) of the recovered radioactive label was incorporated in triglycerides, 13 - 24% in phospholipids and 0.7 - 1% in cholesterol esters. No octadecanoic acid was recovered. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. Fatty acids of carbon chain length ≤ 12 may be transported directly to the liver via the portal vein as the free acid bound to albumin, instead of being re-esterified. This is supported by the Sieber study (1974), in which, following the same protocol as described above, administration of hexanoic acid lead to only 3.3% recovery from lymphatic fluid. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are also taken up by muscle and oxidized to derive energy or they are released into the systemic circulation and returned to the liver, where they are metabolised, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; NTP, 1994; Stryer, 1996; WHO, 2001). There is a continuous turnover of stored fatty acids, as they are constantly metabolised to generate energy and then excreted as CO₂. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism.

Absorbed alcohols are mainly oxidised to the corresponding fatty acid and then follow the same metabolism as described above for fatty acids, to form triglycerides. The absorption and metabolism of a fatty alcohol was assessed in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [1-14C]-radiolabelled octadecanol to rats, 56.6 ± 14% of the radiolabelled carbon was recovered in the lymph. More than half (52-73%) of the recovered radioactive label was incorporated in triglycerides, 6-13% in phospholipids, 2-3% in cholesterol esters and 4-10% in un-metabolised octadecanol. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. The results of administration of hexanol resulted in a recovery of 8.5% in the lymph (Sieber, 1974), indicating that alcohols with shorter-length carbon chains are hydrolysed to the corresponding fatty acid and transported directly to the liver via the portal vein as the free acid bound to albumin. The conversion into the corresponding fatty acids by oxidation and distribution in the form of triglycerides, means that the metabolites of fatty alcohols are also used as an energy source or stored in adipose tissue.

Metabolism

The metabolism of Lauryl nonanoate initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C9 fatty acid and the linear C12 fatty alcohol. The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI-tract and in the liver (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the body. After oral ingestion, esters of alcohols and fatty acids can undergo enzymatic hydrolysis in the GI-tract. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin may enter the systemic circulation directly before entering the liver where hydrolysis will generally take place.

The C12 fatty alcohol of the target substance, as well as the fatty alcohols of the source substances, will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increased chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, bypassing additional metabolism steps (WHO, 1999).

The fatty acids can be further metabolised directly following absorption, following oxidation from an alcohol or following de-esterification of triglycerides. A major metabolic pathway for linear and branched 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. Fatty acids having an odd number are oxidized in the same way as fatty acids having an even number, except that propionyl CoA and acetyl CoA, rather than two molecules of acetyl CoA, are produced in the final round of degradation. The activated three-carbon unit in propionyl CoA enters the citric acid cycle after it has been converted into succinyl CoA (Berg, 2002).

Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂(Lehninger, 1993). Alternative pathways for long-chain fatty acids include the omega-oxidation at high dose levels (WHO, 1999). The fatty acid can also be conjugated (by e.g. glucuronides, sulphates) to more polar products that are excreted in the urine.

The potential metabolites following enzymatic metabolism of the substance were predicted using the QSAR OECD toolbox (OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in vivo (rat), in (rat) liver and in the skin, and by intestinal bacteria in the GI-tract. Forty-two (42) metabolites in vivo and 12 hepatic metabolites were predicted for Lauryl nonanoate. Primarily, the ester bond is broken both specifically in the liver and in general in vivo, and the hydrolysis products may be further metabolised. The resulting liver metabolites are the product of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. Two skin metabolites were predicted: the C12-alcohol and the C9-acid, respectively. The metabolites formed in the skin are expected to enter the blood circulation and eventually meet the same fate as the hepatic metabolites. Seventy-eight (78) metabolites were predicted to result from all kinds of microbiological metabolism of the ester in the GI-tract, including hydrolysis of the ester bond, aldehyde formation and fatty acid chain degradation of the molecule. The results of the OECD Toolbox simulation support the information retrieved in the literature on metabolism.

There is no indication that Lauryl nonanoate is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, and chromosome aberration assay in mammalian cells in vitrousing source substances were negative, with and without metabolic activation (Ames, 1990; Ames, 1996; Ames, 2000; CA, 2010; MLA, 2010). The result of the skin sensitisation study (LLNA) performed with the target substance revealed that lauryl nonanoate is to be classified as skin sensitising Category 1 (H317) according to Regulation (EC) No 1272/2008.

Excretion

The linear C12-fatty acid derived from the oxidation of the corresponding alcohol as well as the C9-fatty acid resulting from hydrolysis of the ester will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions, like incorporation into cell membranes (Lehninger, 1993). Therefore, the fatty acid metabolites are not expected to be excreted to a significant degree via the urine or faeces but to be excreted via exhaled air as CO₂or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid) support this principle. The absorption, distribution, and excretion of ¹⁴C-labelled ethyl oleate was studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw (Bookstaff et al., 2003). At sacrifice (72 hours post-dose), mesenteric fat was the tissue with the highest concentration of radioactivity. The other organs and tissues had very low concentrations of test material-derived radioactivity. The main route of excretion of radioactivity in the groups was via the expired air as CO₂. 12 hours after dosing, 40-70% of the administered dose was excreted in expired air (consistent with beta-oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine.

The alcohol component may be conjugated with e.g. glutathione to form a more water-soluble molecule and excreted via the urine, bypassing further metabolism steps (WHO, 1999). The fraction of Lauryl nonanoate that is not absorbed in the GI-tract will be excreted via the faeces.

References

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.

Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002. Section 22.3, Certain Fatty Acids Require Additional Steps for Degradation.

Bookstaff et al. (2003). The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans. Regul Toxicol Pharm 37: 133-148.

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

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metab Pharmacokinet 27(5): 466-477

Greenberger et al. (1966). Absorption of medium and long chain triglycerides: factors influencing their hydrolysis and transport. J Clin Invest. 45(2):217-27.

IOM (2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Institute of the National Academies. The National Academies Press. http://www.nap.edu/openbook.php?record_id=10490&page=R1

Johnson, R.C. et al. (1990). Medium-chain-triglyceride lipid emulsion: metabolism and tissue distribution. Am J Clin Nutr 52(3):502-8.

Johnson W. Jr; Cosmetic Ingredient Review Expert Panel. (2001). Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate. Int J Toxicol. 2001;20 Suppl 4:61-94.

Lehninger, A.L., Nelson, D.L. and Cox, M.M. (1993). Principles of Biochemistry. Second Edition. Worth Publishers, Inc., New York, USA. ISBN 0-87901-500-4.

Mattson, F.H. and Volpenhein, R.A. (1962). Rearrangement of glyceride fatty acids during digestion and absorption. J Biol Chem. 237:53-5.

Mattson, F.H. and Volpenhein, R.A. (1964). The digestion and absorption of triglycerides. J Biol Chem. 239:2772-7.

Mattson, F.H. and Volpenhein, R.A. (1969). Relative rates of hydrolysis by rat pancreatic lipase of esters of C2 - C18 fatty acids with C1 – C18 primary n-alcohols. J Lipid Res Vol(10): 271-276.

National Toxicology Program (NTP) (1994) Comparative toxicology studies of Corn Oil, Safflower Oil, and Tricaprylin (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as vehicles for gavage. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr426.pdf (2011-12-19). Report No.: C62215. Owner company: U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health.

OECD (2006). Long Chain Alcohols. SIDS Initial Assessment Report For SIAM 22. Paris, France, 18-21 April 2006. TOME 1: SIAR. http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=7A14361C-4676-4339-A915-2CFD51F12483

OECD (2016). (Q)SAR Toolbox v3.4 Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 25 April 2017. http://toolbox.oasis-lmc.org/?section=overview

Sieber, S.M., Cohn, V.H., and Wynn, W.T. (1974). The entry of foreign compounds into the thoracic duct lymph of the rat.Xenobiotica 4(5), 265.

Stryer, L. (1996). Biochemie. 4. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer 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

WHO (1999). Evaluation of certain food additives and contaminants. Forty-ninth report of the joint FAO/WHO Expert Committee on Food Additives. WHO Technical Report Series 884. ISBN 92 4 120884 8.

WHO (2001). Safety Evaluation of Certain Food Additives and Contaminants: Aliphatic Acyclic Diols, Triols, and Related Substances. WHO Food Additives Series No. 48.