Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane

Endpoint summary

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of the substance Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is 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 Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012).

The substance Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane mainly consists of mixed esters (mono-, di- or tri-component) of fatty acid dimers of oleic acid (C18 unsaturated) and oleic acid with trimethylolpropane (TMP) and meets the definition of an UVCB substance based on the analytical characterisation.

The substance Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is liquid at room temperature and has a molecular weight between 624.97 and 1762.8 g/mol and a water solubility < 0.05 mg/L at 20 °C (Frischmann, 2012). The log Pow is > 5.7 (Frischmann, 2009) and the vapour pressure is ≤ 0.48 Pa at 20 °C (Kintrup, 2009).

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, 2012).

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2012). As the molecular weight of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is between 624.97 and 1762.8 g/mol, absorption of the molecule in the gastrointestinal tract is considered limited.

By applying the “Lipinsky Rule of Five” (Lipinski et al., 2001; refined by Ghose et al., 1999), the potential for absorption after oral administration can be assessed. When Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is considered, three of the rules are not fulfilled; the molecular weight, the log Pow as well as the total number of atoms are above the given ranges. Thus, based on this method, oral absorption is not expected to be high either.

Consistently, after treatment with 2000 mg/kg bw, no mortality and no clinical signs of toxicity were observed in an acute oral toxicity study according to OECD guideline 423 (Sanders, 2012). The same result was obtained in another acute oral toxicity study (Potokar, 1989); thus, absorption after oral ingestion is not likely and/or the acute toxicity of the substance is low.

If absorption occurs, the favourable mechanism will be absorption 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) like Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane with a log Pow > 5.7 and a water solubility < 0.05 mg/L.

After oral ingestion, an ester undergoes stepwise hydrolysis of the ester bond by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the corresponding acid is formed. In this case, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place due to the high molecular weight and the complex structure of the molecule.No hydrolysis in a digestive fluid simulant study according to EFSA guidance could be detected for the surrogate substance TMP-triheptanoate, which is a representative subunit of a PFAE mixed and branched (Severac, 2012). The substance Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane represents a much more complex structure than TMP-triheptanoate alone. Hence, potential cleavage products probably do not play a prominent role in the toxicokinetic behaviour of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane, nevertheless they will be discussed briefly here. In general, 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).For the expected cleavage product TMP, it is anticipated that it can theoretically be absorbed in the gastro-intestinal tract by dissolution into the gastrointestinal fluids (ECHA, 2012).The second cleavage product, Fatty acids, C18 unsatd., trimers, seems to be less absorbed than monomeric fatty acids, as indicated by studies carried out to investigate the absorption, distribution and excretion of the polymeric fraction of heated cooking oils of vegetable origin (Combe et al., 1981; Perkins et al., 1970; Márquez-Ruiz et al., 1992 Hsieh and Perkins, 1976).

Overall, a systemic bioavailability of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane and/or the respective cleavage products in humans is considered possible but limited after oral uptake of the substance due to its high molecular weight.

Dermal:

The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012). As the molecular weight of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is between 624.97 and 1762.8 g/mol, dermal absorption of the molecule is not likely.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is not skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR calculated dermal absorption a value in the range of 1.58E-08 to 1.16E-20 mg/cm2/event (very low) was predicted for Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (Dermwin v.2.01, EPI Suite). Based on this value the substance has a very low potential for dermal absorption.

For substances with a log Pow above 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 above 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). The log Pow is > 5.7, but as the water solubility of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane 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 molecular weight (>100), and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane in humans is considered as very limited.

Inhalation:

Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane has a low vapour pressure ≤ 0.48 Pa 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 considered negligible.

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 Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane in humans cannot be excluded after inhalation of aerosols with aerodynamic diameters below 15 μm.

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 generally the case that substances with high log Pow values have long biological half-lives. The high log Pow of > 5 implies that Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane may have the potential to accumulate in adipose tissue (ECHA, 2012).

Absorption is a prerequisite for accumulation within the body. Due to its molecular weight and high log Pow, absorption is expected to be minimal for the registered substance, therefore accumulation is not favoured as well. In the exceptional case of esterase-catalysed hydrolysis in the gastro intestinal tract, the cleavage products TMP, Oleic acid and dimer of fatty acids, C18-unsatd. are mainly produced. The log Pow of the first cleavage product TMP is < 0 indicating a high water solubility (OECD SIDS, 1991). Consequently, there is no potential for TMP to accumulate in adipose tissue.

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. Bioaccumulation of fatty acids only takes place, if their intake exceeds the caloric requirements of the organism.The available information indicates that dimeric fatty acids are poorly absorbed and that the absorbed fraction follows the same pattern of metabolism and excretion as the monomeric acids. Thus, no significant bioaccumulation in adipose tissue is expected.

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

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, 2012).

Distribution of the parent substance is not expected as only very limited absorption will occur. Only the potential cleavage products of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane after chemical changes as a result of enzymatic hydrolysis, namely TMP and the fatty acid, might be distributed within the body.

TMP, a rather small (MW = 134.20 g/mol) substance of moderate water solubility will mainly be distributed in aqueous compartments of the organism and may also be taken up by different tissues (OECD SIDS). 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 only the potential cleavage products and not the parent substance might be distributed in the organism.

Metabolism

Esters of fatty acid dimers are hydrolysed to the corresponding alcohol and dimerized fatty acid by esterases (Fukami and Yokoi, 2012). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and mono-and dimerized fatty acids might theoretically undergo enzymatic hydrolysis in the gastro-intestinal fluids.However, as discussed previously, it is not anticipated that enzymatic hydrolysis of the parent substance is taking place in the gastrointestinal tract due to the high molecular weight and the complex structure of the molecule.

In contrast, substances that 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. Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane esters are of more complex structure than the simple fatty acid esters, therefore, ester bond hydrolysis is expected to occur to a minor extent in the gastrointestinal tract. This has also been shown for the surrogate substance TMP-triheptanoate (Polyol), for which no hydrolysis in a digestive fluid simulant could be detected in a study according to EFSA guidance (Severac, 2012). It is possible that in the gastrointestinal tract these complex structures are not forming lipid droplets with the help of bile acids in the same fashion as common triglycerides and thus the lipase/colipase complex cannot function properly. Taken together, it is highly unlikely that Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane will be metabolised.

Nevertheless possible cleavage products should be discussed here. The first possible cleavage product, TMP, is expected to be metabolized by oxidation.

The second and the third cleavage products, the fatty acid and the fatty acid dimer, 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. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).The cyclic portion of mono- and dimers cannot be degraded by β- or ω-oxidation and is probably hydroxylated or conjugated, which are common detoxification mechanisms of cyclic compounds, leading to polar metabolites readily excreted via urine (Iwaoka and Perkins, 1976). Likewise, after oxidative degradation of aromatic fatty acids, the remaining structure can be excreted in the urine after conjugation with glycine or glutamine in a similar way as in the case of benzoic and phenylacetic acid, respectively (WHO, 2000; Caldwell et al., 1980).

Overall, the part of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane that have become systemically available, might be hydrolysed and the cleavage products can be further metabolized. However, due to its high molecular weight, absorption of Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane is not likely and thus, no extensive metabolism is expected but rather direct elimination.

Excretion

Very low absorption is expected for dimeric and fatty acid esters via the gastrointestinal tract, thus much of the ingested substance is excreted in the faeces. Absorbed fatty acid esters undergo rapid metabolisation and excretion either in the expired CO₂or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic and aromatic fatty acids.

 

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