Reaction mass of octadecyl heptanoate and octadecyl octanoate

Endpoint summary

Description of key information

The target substance Reaction mass of octadecyl heptanoate and octadecyl octanoate (List No. 915-334-0) is expected to undergo limited absorption via the oral and inhalation route, and absorbed via the dermal route to a large extent. The esters will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and fatty alcohols. This facilitates the oral absorption and will most likely lead to an overall high oral absorption rate. Absorbed esters will be hydrolysed mainly in the liver. The fatty acids will most likely be re-esterified to triglycerides after absorption and transported via chylomicrons; while the absorbed alcohols are mainly oxidised to the corresponding fatty acid and then to a triglyceride, as described above. The major metabolic pathway for linear 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 as conjugated molecules 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 Reaction mass of octadecyl heptanoate and octadecyl octanoate (List No. 915-334-0) was investigated.

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, 2014), an assessment of the toxicokinetic behaviour of the target substance Reaction mass of octadecyl heptanoate and octadecyl octanoate (List No. 915-334-0) 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 physic-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2014) and taking into account further available information from a source substance. The substance Reaction mass of octadecyl heptanoate and octadecyl octanoate (List No. 915-334-0) is a multiconstituent with a linear C18-alcohol moiety and linear C7/C8 acid moieties.

Reaction mass of octadecyl heptanoate and octadecyl octanoate has a molecular weight range of 382.66 – 396.69 g/mol. It is a solid at 20 °C with melting point 24 – 26 °C, and a water solubility of < 0.7 mg/L at 24 °C. Depending on the individual components of the substance, the log Pow was estimated to be > 10 (11.18 – 11.67) and the vapour pressure was calculated to be < 0.0001 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, 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. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2014).

The physico-chemical characteristics (log Pow, water solubility and physical state) of the substance are in a range that indicate poor absorption from the gastrointestinal tract following oral ingestion, while the molecular weight favours uptake. It is unclear to what degree micellar solubilisation will affect the absorption rate of the substance.

The indications that the target substance Reaction mass of octadecyl heptanoate and octadecyl octanoate has relatively low oral absorption and/or low acute toxicity are supported by the available data on acute and repeated dose oral toxicity. In a study in which female mice were administered a single dose of 5000 mg/kg bw of the target substance, there was no mortality and no adverse clinical signs were noted (Planchette, 1986). No mortality, no effects on body weight, and no lesions were noted at necropsy in a study on rats administered 16 mL target substance/kg bw (equivalent to 15.4 mg/kg bw of Reaction mass of octadecyl heptanoate and octadecyl octanoate) (Cuthbert, 1977). 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 (Rosiello, 2014). This indicates that Reaction mass of octadecyl heptanoate and octadecyl octanoate also has a low potential for oral toxicity.

 

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 (ECHA, 2014).

In general, alkyl esters are readily hydrolysed in the gastrointestinal 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 hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching reduces the ester hydrolysis rate, compared with linear esters (Mattson and Volpenhein, 1969, 1972; WHO, 1999).

Based on the generic information on hydrolysis of alkyl esters, the target Reaction mass of octadecyl heptanoate and octadecyl octanoate is expected to be enzymatically hydrolysed to the C7/C8 fatty acids and the linear C18 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 physicochemical properties and molecular weight of Reaction mass of octadecyl heptanoate and octadecyl octanoate suggest that medium-low oral absorption will 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, 2014).

The substance Reaction mass of octadecyl heptanoate and octadecyl octanoate has a molecular weight range of 382.66 – 396.69 g/mol, which indicates a potential for dermal absorption. In contrast, the substance has very low water solubility and therefore a low dermal absorption potential (ECHA, 2014). The log Pow is > 6, which means that the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (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 (2012), using the Epi Suite software:

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

The Kp was calculated for the two main constituents of the substance; a C18 alcohol- and C7 fatty acid or C8 fatty acid component. This gave a Kp of 300 cm/h and 530 cm/h for the ester with a C7- and C8 component, respectively. Considering the water solubility (0.0007 mg/cm³, Pass, 2014), the dermal flux is estimated to be ca. 0.225 mg/cm²/h and 0.434 mg/cm²/h for the ester with a C7- and C8-component, respectively. The most conservative value is then 0.434 mg/cm²/h, indicating a high dermal absorption potential.

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, 2014).

The available data on the target substances provide very mild or no indications for skin irritating effects in the rabbit (Cuthbert, 1977; Planchette, 1986). Therefore, no penetration of the substance due to skin damage is expected. No indications for local effects were noted in skin sensitisation studies performed in the mouse and the guinea pig, using two source substances (Beerens-Heijnen, 2010; Steiling, 1991).

Overall, based on the available information and using a worst-case approach, the dermal absorption potential of Reaction mass of octadecyl heptanoate and octadecyl octanoate is predicted to be high.

 

Inhalation

Reaction mass of octadecyl heptanoate and octadecyl octanoate is a solid with low vapour pressure (< 0.0001 Pa at 20 °C), and therefore very low volatility. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of particles will depend on the aerodynamic particle size (ECHA, 2014). The substance may also be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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. Particles deposited in the nasopharyngeal/thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed.

Absorption after oral administration of the substance is mainly 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, and the presence of esterases and lipases in the mucus lining fluid of the respiratory tract would be important. Due to the physiological function of enzymes in the GI-tract for nutrient absorption, esterase and lipase activity in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to happen at a lower rate. The molecular weight, log Pow and water solubility indicate that the parent substance may be absorbed across the respiratory tract epithelium by micellar solubilisation to a certain extent. However, low water solubility (<0.7 mg/L) and the solid form does restrict the diffusion/dissolving into the mucus lining before reaching the epithelium, and it is not clear which percentage of the inhaled aerosol could be absorbed as the ester. 

An acute inhalation toxicity study was performed with the read-across (source) substance 2-ethylhexyl oleate (CAS 26399-02-0), in which rats were exposed nose-only to > 5.7 mg/L of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Therefore, the target substance is not expected to be acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption.

Due to the limited information available a worst case approach is made, and absorption via inhalation is assumed to be as high as via the oral route.

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, 2014).

As discussed under oral absorption, Reaction mass of octadecyl heptanoate and octadecyl octanoate will mainly undergo enzymatic hydrolysis in the gastrointestinal 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 unmetabolised 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 Reaction mass of octadecyl heptanoate and octadecyl octanoate initially occurs via enzymatic hydrolysis of the ester resulting in the corresponding linear C7/C8 fatty acids and the linear C18 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 C18 fatty alcohol 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. Further oxidation via the citric acid cycle leads to the formation of H2O and CO2 (Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999). The alpha-oxidation pathway is a major metabolic pathway for branched-chain fatty acids where a methyl substituent at the beta-position blocks certain steps in the beta-oxidation (Mukherji, 2003). Generally, a single carbon unit is cleaved off the branched acid in an additional step before the removal of 2-carbon units continues. 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, sulfates) 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, 2014). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Twelve hepatic metabolites and 10 dermal metabolites were predicted for the esters of C18 alcohol with C7 or C8 fatty acid, respectively. Primarily, the ester bond is broken both in the liver and in the skin and the hydrolysis products may be further metabolised. The resulting liver and skin metabolites are the products 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. For a branched fatty acid, the alpha- and omega pathways are particularly relevant. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 94 metabolites were predicted to result from all kinds of microbiological metabolism of the ester of C18 alcohol and C7 or C8 fatty acid 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 of Reaction mass of octadecyl heptanoate and octadecyl octanoate 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 in vivo micronucleus test in mice) using source substances were negative, with and without metabolic activation (Andersen, 1995; Banduhn, 1989; Grötsch, 1993, Verspeek-Rip, 2010; Wollny, 2000). The results of the skin sensitisation studies performed with source substances were likewise negative (Beerens-Heijnen, 2010; Steiling, 1991).

Excretion

The linear C18 fatty acid from the oxidation of the corresponding alcohol as well as the fatty acids 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 CO2 or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of oleic acid (ethyl oleate)) 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. At sacrifice (72 h 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 h 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 (Bookstaff et al., 2003).

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 Reaction mass of octadecyl heptanoate and octadecyl octanoate 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.

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

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.

Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal of Lipid Research 13: 325-328.

Mukherji M. et al. (2003). The chemical biology of branched-chain lipid metabolism. Progress in Lipid Research 42: 359-376.

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 (2014). (Q)SAR Toolbox v3.3. Developed by Laboratory of Mathematical Chemistry, Bulgaria for the Organisation for Economic Co-operation and Development (OECD). Calculation performed 17 February 2015. 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.