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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

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Basic toxicokinetics

There are only few studies available in which the toxicokinetic behaviour of polyglycerol esters has been investigated. No toxicokinetic studies are available for the substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS No. 63705-03-3).

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.There are no studies evaluating the toxicokinetic properties of the substance available.

The substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is a UVCB based on analytical characterization . It is a yellowish-brown liquid. It is poorly water soluble (< 0.15 mg/L, Frischmann, 2012) with a molecular weight range of 358.56 – 891.48g/mol, a log Pow range of 4.3->10 (Hopp, 2011) and a vapour pressure of < 0.0001 Pa at 20 °C (Hinze, 2012).



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, 2012).



The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favorable for oral absorption (ECHA, 2012). As the molecular weight range of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is 358-891 g/mol, an absorption of the molecule in the gastrointestinal tract is expected to be partially low.

Absorption after oral administration is also not expected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate which fails to fulfill partially three rules (more than 10 hydrogen bond acceptors, molecular weight partially > 500 g/mol and log Pow partially > 5).

The log Pow range of 4.3->10 suggests that 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is favourable for absorption by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), who are poorly soluble in water (1 mg/L or less).

Fatty acid esters of aliphatic alcohols are normally degraded to the corresponding fatty acid and the alcohol by enzymatic hydrolysis in the gastrointestinal tract prior to absorption (Michael and Coots, 1971, Laposata et al., 1990). The respective alcohol as well as the fatty acid is formed. In this case, the predicted metabolites are the free fatty acid (C18iso) and glycerol, diglycerol, and triglycerol. However it was shown in-vitro that the hydrolysis rate of methyl oleate was lower when compared with the hydrolysis rate of the triglyceride glycerol trioleate (Mattson and Volpenhein, 1972). The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) are likely to be different from those of the parent substance before absorption into the blood takes place, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, also for both cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract. The highly lipophilic fatty acid is absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the alcohol is readily dissolved into the gastrointestinal fluids and absorbed from the gastrointestinal tract.

Moreover, data from metabolism studies with fatty acid-labelled polyglyerol esters have shown that more than 90% of triglycerol moieties from respective esters were absorbed. Furthermore, it was shown that hydrolysis of the polyglycerol esters occurred to a large extent prior to absorption (Michael and Coots,1971). Therefore, hydrolysis of the parent compound is expected to be high resulting in low systemic exposure to the parent compound, but but absorption of both metabolites, C18 branches fatty glycerol, and polyglycerol diglycerol and triglycerol, from the gastrointestinal tract is expected to be high. The available data on oral toxicity are also considered for assessment of oral absorption.

A study conducted with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is available. In acute oral studies conducted with the the test substance, no sign of systemic toxicity were observed at doses of 2000 mg/kg bw. In repeated dose toxicology conducted with structurally related analogue substances deca-glycerol deca-oleate, no evidence of toxic systemic effects were observe after oral exposure.

These results suggest that test substance is of low systemic toxicity, presumably due to low toxicity potency. Based on these results, no conclusions on the oral absorption potential is possible. 

In summary, the above discussed physico-chemical properties of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate and relevant data from available literature do indicate hydrolysis before absorption of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate

to the respective fatty acids and the alcohol. On the basis of the above mentioned data, oral absorption of the test material and/or the hydrolysis products is predicted.



The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight range of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is 358-891 g/mol, a dermal absorption of the molecule can be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012).

To this regard primary skin irritation studies conducted with 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) showed no sign of skin irritation. As 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is not considered as skin irritating in humans, an enhanced penetration of the substance due to local skin damage is not expected.

Based on QSAR dermal absorption a range values of 3.36E-005 and 5.79E-011 for 1,2,3-Propanetriol, homopolymer, diisooctadecanoate was calculated (Dermwin v2.01, 2013). Based on this value, the substances have a very low potential for dermal absorption.

For substances with a log Pow > 4, the rate of dermal penetration is limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. For substances with a log Pow > 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin, and the uptake into the stratum corneum itself is also slow. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis (ECHA, 2012). As the water solubility of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate is less than 1 mg/L, dermal uptake is likely to be very low.


Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100 g/mol), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate in humans is considered as very low.



1,2,3-Propanetriol, homopolymer, diisooctadecanoate has a low vapour pressure of 0.0001 Pa at 20 °C 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 expected to be significant.

The substance is not acute toxic after inhalation as demonstrated by studies conducted with structural analogue substances Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7), Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS# 85536-35-2), and Glycerides, mixed decanoyl and octanoyl (CAS# 73398-61-5).

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed. In humans, particles with aerodynamic diameters below 100 μm have the potential to be inhaled. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2012). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like 1,2,3-Propanetriol, homopolymer, diisooctadecanoatecan be taken up by micellar solubilisation.

Additionally, as described above, 1,2,3-Propanetriol, homopolymer, diisooctadecanoate can be hydrolysed enzymatically to the respective metabolites, for which absorption would be higher.


Overall, a systemic bioavailability of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate in humans is considered likely after inhalation of aerosols with aerodynamic diameters below 15 μm.



Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, esters of polyglycerol and fatty acids will undergo esterase-catalysed hydrolysis, leading to the cleavage products polyglycerol and fatty acids.

The log Pow of the first cleavage products glycerol, diglycerol and triglycerol is < 0 (Danish QSAR database, 2013; OECD SIDS, 2002), indicating a high solubility in water. Consequently, there is no potential for glycerol and polyglycerols diglycerol and triglycerol to accumulate in adipose tissue. This is confirmed also from Michael and Coots, 1971. The second cleavage product, the fatty acids, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolized and excreted (Henwood et al., 1997). Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.


Overall, the available information indicates that no significant bioaccumulation of the parent substance in adipose tissue is expected.



Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. 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, 2012).

Distribution of the intact parent compound within the body is assumed to be low, as fatty acid esters are normally degraded to the corresponding fatty acid by ubiquitously distributed esterase and by gastrointestinal lipases prior to absorption. Therefore, distribution of the intact compound is not relevant but rather the distribution of the breakdown products of hydrolysis.


Esters of polyglycerol and fatty acids will undergo chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products glycerol and polyglycerols and fatty acids.

Glycerol and polyglycerol digylcerol and triglycerol, rather small (MW range = 92-240 g/mol) substances of high water solubility, and log Pow < 0 (Danish QSAR database, 2013, and OECD SIDS 2002) will be distributed in aqueous compartments of the organism and may also be taken up by different tissues.

The fatty acids are also distributed in the organism and can be taken up by different tissues. They can be stored as triglycerides in adipose tissue depots or they can be incorporated into cell membranes (Masoro 1977).

Overall, the available information indicates that the cleavage products, polyglycerols and fatty acids, will be distributed in the organism.



1,2,3-Propanetriol, homopolymer, diisooctadecanoate are hydrolysed to the corresponding alcohols (glycerol, diglycerol and triglycerol) and fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different sites in the organism: after oral ingestion, esters of polyglycerol and fatty acids will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In contrast, substances which are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place.

In an in vitro enzymatic digestion method using fresh pancreatic juice plus bile described by King et al. 1971 the fatty acid labelled polyglycerol esters were studied thin layer chromatography (TLC) and radioassay procedures were used to determine the distribution of 14C among the products of digestion.

After enzymatic digestion of oleate-labelled polyglycerol ester, 89-92% of the recovered 14C was present as free oleic acid, whereas the remaining 8 and 11% was unhydrolysed or partially hydrolysed starting material. Hydrolysis of the eicosanoate-labelled polyglycerol ester was much slower than the oleate ester and only 21% of the 14C was recovered as free eicosanoic acid (Michael and Coots, 1971)

After hydrolysis cleavage products, fatty acids, are stepwise degraded by beta -oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for thecitric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).

The othercleavage products polyol polyglycerol, are assumed to be rapidly excreted ad metabolism via cleavage of the ether bond to glycerol will not occur as for the related triglycerol (Michael and Coots, 1971).



Polyol polyglycerols are assumed to be to be excreted almost quantitatively in the urine (Michael and Coots, 1971). As the fatty acid component, fatty acid will be metabolised in the body for energy generation and on the basis of the extensive metabolism, the primary route of excretion results to be CO2 exhalation. Thus, fatty acids are not expected to be excreted to any significant amount via the urine or faeces.



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Danish EPA (2010). CAS No. 49553-76-6 Danish (Q)SAR Database Report powered by OASIS Database.


Danish EPA (2013). CAS 627-82-7. Danish (Q)SAR Database Report powered by OASIShttp://

EPA (2011). Dermwin v2.01, Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.10. United States Environmental Protection Agency, Washington, DC, USA. Downloaded from Calculation performed 04 February 2013.


ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.


Fukami and Yokoi (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.


Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.


Laposata EA, Harrison EH, Hedberg EB. 1990. Synthesis and degradation of fatty acid ethyl esters by cultured Hepatoma cells exposed to ethanol. The Journal of Biological Chemistry 265(17):9688-9693


Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

Masoro (1977). Lipids and lipid metabolism. Ann. Rev. Physiol.39: 301-321.


Mattson and Volpenhein (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.


Michael WR, Coots RH. 1971. Metabolism of polyglycerols and polyglycerols esters.Toxicology and Applied Pharmacology 20(3):334-345


Ramirez et al. (2001). Absorption and distribution of dietary fatty acids from different sources. Early Human Development 65 Suppl.: S95–S101.


King W. R., Michael W. R., Coots R.H. (1970). Metabolism of stearoyl propylene glycol hydrogen succinate. Toxicol. Appl. Pharmacol. 17, 519-528