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Endpoint summary

Description of key information

Based on the available information, the physicochemical properties and molecular weight of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers suggest limited systemic absorption via oral, dermal and inhalation absorption. However, the substance is expected to undergo enzymatic hydrolysis in the gastrointestional tract and absorption of the ester hydrolysis products (polyglycerols and fatty acids) is relevant. The absorption rate of the hydrolysis products is considered to be low to moderate, as the C-chain lengths of the fatty acid and the alcohol are both rather long and the absorption potential decreases with increasing C-chain length.

No significant bioaccumulation of the parent substance or its hydrolysis products in adipose tissue is expected. The distribution of the parent compound within the body is assumed to be low, but the cleavage products, polyglycerols and fatty acids, will be distributed in the organism more extensively. Polyglycerols are assumed to be excreted almost in the urine. The fatty acid components will be metabolised in the body for energy generation, and on the basis of the extensive metabolism, the primary route of excretion will be exhalation in the form of CO2. Thus, fatty acids are not expected to be excreted to any significant amount via the urine or faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

No toxicokinetic studies are available for the substance Fatty acids, C16-18 (even numbered), esters with glycerol oligomers.

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, 2017), assessment of the toxicokinetic behavior of the registration substance Fatty acids, C16-18 (even numbered), esters with glycerol oligomers was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics.

Fatty acids, C16-18 (even numbered), esters with glycerol oligomers is a UVCB based on analytical characterization. It is a white solid with poor water solubility (91.9 µg/L at 20°C and pH 6.3, Schwarzkop, 2019) and a molecular weight range of 166.17 – 1113.72 g/mol, a log Pow range of -8.05 – 20.38 (QSAR, EPI Suite v4.11, Kowwin v1.68) and a vapour pressure of < 0.00001 Pa at 20 °C (QSAR, SPARC v4.6)

 

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

 

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favorable for oral absorption (ECHA, 2017). As the molecular weight of the registration substance is 166.17 – 1113.72 g/mol, absorption of the molecule in the gastrointestinal tract is expected to be low.

The log Pow range of -8.04 – 20.38 suggests that it is favorable for absorption perhaps by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), which 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 (C16 -18) and glycerol, diglycerol, triglycerol, tetragylcerol and pentaglycerol. This assumption was confirmed by an in-vitro hydrolysis test with the structural analogue Oleic acid, monoester with oxybis(propanediol) (CAS 49553-76-6), which was conducted according to EFSA Note for Guidance for Food Contact Materials Annex 1 to Chapter III ”Measurement of hydrolysis of plastics monomers and additives in digestive fluid simulants (30/07/2008)” (Jensen, 2013). After incubation with the intestinal fluid, the remaining content of Oleic acid, monoester with oxybis(propanediol) was extracted and measured by gas chromatography. The in vitro experiment demonstrated that approximately 94% of the total Oleic acid, monoester with oxybis(propanediol) was hydrolysed by intestinal fluid simulant within 4 hours at 37°C (Jensen 2013). 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, 2017). However, also for both cleavage products, it is anticipated that they are absorbed in the gastrointestinal 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 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.

 

An acute oral toxicity study in rats with the source substance 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) is available and no signs of systemic toxicity were observed at doses of 5000 mg/kg bw (BASF, 1988) . In the repeated dose toxicity study conducted with structurally related analogue substances deca glycerol deca oleate, no evidence of toxic systemic effects were observed after oral exposure (King, 1971). These results suggest that the registration substance will also be of low systemic toxicity after both acute and repeated oral exposure, presumably due to low toxicity potency.

In conclusion, based on the available information, the physico-chemical properties and molecular weight of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers suggest limited oral absorption. However, the substance is expected to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products is relevant. The absorption rate of the hydrolysis products is considered to be low to moderate, as the C-chain lengths of the fatty acid and the alcohol are both rather long and the absorption potential decreases with increasing C-chain length. 

 

Dermal

 

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, 2017). As the molecular weight range of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers is 166.17 – 1113.72 g/mol, dermal absorption of the molecule can be concluded to be low/negligible.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). To this regard primary skin irritation studies conducted with a structural related analogue 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS 63705-03-3) showed no sign of skin irritation. By analogy to 1,2,3-Propanetriol , homopolymer diisooctadecanoate, the registration substance is not expected to be a skin irritant and to damage skin. Thus, an enhanced penetration of the compound due to local skin damage is not expected.

The dermal absorption potential – the permeability constant (Kp) – of the registration substance was calculated (Dermwin v2.01, 2013). The Kp value range was determined to be equal or less than 2.39E-01 cm/h, which suggests low to very low dermal absorption potential.

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, 2017). As the water solubility of the registration substance 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 expected to be irritating to skin implies that dermal uptake of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers in humans is considered as very low.

 

Inhalation

 

Fatty acids, C16-18 (even numbered), esters with glycerol oligomers has a negligible vapour pressure of < 0.00001 Pa at 20 °C. Therefore, it is off negligible volatility. 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.

 

Accumulation

 

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 assumed that substances with high log Pow values have long biological half-lives. The high log Pow of Fatty acids, C16-18 (even numbered), esters with glycerol oligomers indicates an increased affinity of the compound to adipose tissue; accordingly accumulation in adipose tissue cannot be excluded (ECHA, 2017). 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 oleic acid.

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

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, 2017).

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 polyglycerol and fatty acids.

Glycerol and polyglycerol digylcerol and triglycerol, a rather small (MW range = 92-240 g/mol) substance 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, diglycerol and fatty acids, will be distributed in the organism.

 

Metabolism

 

Fatty acids, C16-18 (even numbered), esters with glycerol oligomers are hydrolysed to the corresponding alcohols (glycerol, diglycerol, triglycerol etc.) 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). An in vitro experiment conducted with the structural analogue Oleic acid, monoester with oxybis(propanediol) (CAS 49553-76-6) demonstrated that approximately 94% of the total Oleic acid, monoester with oxybis(propanediol) was hydrolysed by intestinal fluid simulant within 4 hours at 37°C. The main isomer of Oleic acid, monoester with oxybis(propanediol) was fully hydrolysed within 1 hour, indicating rapid hydrolysis. The other positional isomers of the test item were shown to have a lower rate of hydrolysis (Jensen, 2013). Based on these results and due to the structural similarity, the registration substance is also considered to be hydrolysed in intestinal fluid, resulting in the formation of the corresponding free fatty acids as well as the respective polyol polyglycerols (glycerol, diglycerol, and triglycerol).

After hydrolysis, the fatty acids resulting from cleavage of the ester 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 the citric 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 other cleavage products (polyol polyglycerols) are assumed to be rapidly excreted and metabolism via cleavage of the ether bond to glycerol will not occur as for the related triglycerol (Michael and Coots, 1971).

 

 Excretion

 

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

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.