Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0) 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, 2014), assessment of the toxicokinetic behaviour of the substance Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol 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, 2014).

The substance Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (CAS 162353-70-0) mainly consists of mixed esters (mono-, di- or tri-component) of fatty acid dimers of predominantly octadecenoic acid (C18 unsaturated) and octadecenoic acid with propylidynemethanol and meets the definition of an UVCB substance based on the analytical characterisation.

The substance Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is liquid at room temperature and has a molecular weight ranging from 610.99 and 1209.97 g/mol and a water solubility <0.025 mg/L at 20 °C (Schwarzkopf, 2016). The log Pow is >10 (QSAR, KOWWIN v1.68) and the vapour pressure is <0.0001 Pa at 20 °C (SPARC v4.6 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

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 are favourable for oral absorption (ECHA, 2014). As the molecular weight of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is between 610.99 and 1209.97 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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol 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, in an acute oral toxicity study according to OECD guideline 423 with the structural analogue substance Fatty acids, C18-unsatd., dimers, mixed esters with oleic acid and trimethylolpropane (CAS 147256-33-5), no mortality and no clinical signs of toxicity were observed at the limit dose of 2000 mg/kg bw (Sanders, 2012). Thus, indicating that 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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol with a log Pow >10 and a water solubility <0.025 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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol represents a much more complex structure than TMP-triheptanoate alone. Hence, potential hydrolysis products probably do not play a prominent role in the toxicokinetic behaviour of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol, nevertheless they will be discussed briefly here.

In general, the physico-chemical characteristics of the hydrolysis 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, 2014). For the expected hydrolysis product TMP (CAS 77-99-6), it is anticipated that it can theoretically be absorbed in the gastro-intestinal tract by dissolution into the gastrointestinal fluids (ECHA, 2014).The second hydrolysis product, Fatty acids, C18 unsatd., dimers (CAS 61788-89-4) 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).

In support of this, a toxicokinetic study with dimeric fatty acids is available, in which low absorption rates were measured in rats (Hsieh and Perkins, 1976). Upon oral administration only ca. 0.4% of the 14C-labeled dimeric fatty acid methyl esters given by gastric intubation were absorbed within 12 h. Ca. 1% of the labeled material was excreted via urine and ca. 2% as CO2. Ca. 80% of the radioactivity was recovered in the gastrointestinal tract and the feces. About 0.115% of the administered test material was incorporated in the liver and metabolized to different lipid classes. Upon dermal application, only a small portion of the dose was absorbed, which was eliminated primarily in the urine, with smaller amounts eliminated in the feces, and as 14CO2, in the breath.

Overall, a systemic bioavailability of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol and/or the respective hydrolysis products in humans is considered possible but limited after oral uptake of the substance due to its high molecular weight and expected low hydrolysis rate

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, 2014). As the molecular weight of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is between 610.99 and 1209.97 g/mol, dermal absorption of the molecule can be regarded as negligible.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2014). As Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is not expected to be skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded.

Based on a QSAR for dermal absorption a calculated value in the range of 0.063 to 3.02 µg/cm²/h (low to medium) was predicted for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol (DERMWIN v.2.02, 2012, EPI Suite).Based on this value the substance has a low to medium 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, 2014). The log Pow is >10, but as the water solubility of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is less than 0.025 mg/L, dermal uptake is likely to be very low.

In support of this, available data for several fatty acids indicate that the skin penetration both in vivo (rat) and in vitro (rats and human) decreases with increasing chain length. Thus, after 24 h exposure approximately 0.14% and 0.04% of C16 and C18 soap solutions are absorbed through human epidermis applied in vitro at 217.95 µg C16/cm² and 230.77 µg C18/cm². When applied at concentrations of 22.27 µg C16/cm² and 24.53 µg C18/cm², approximately 0.3% of both C16 and C18 soap solutions is absorbed through rat skin after 6 h exposure in vivo (see IUCLID section 7.1.2, Howes, 1975).

Overall, the calculated low dermal absorption potential, the low water solubility, the molecular weight (>100), and the fact that the substance is expected to be not irritating to skin implies that dermal uptake of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol in humans is considered as very limited.

Inhalation

Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol has a low vapour pressure ≤ <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 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, 2014). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol can be taken up by micellar solubilisation.

In an acute inhalation toxicity study with the structural analogue substance Fatty acids, C18-unsaturated dimers, 2-ethylhexyl esters (CAS 68334-05-4) performed according to OECD TG 436 (acute toxic class method, limit test), no clinical signs of toxicity were observed and a LC50 value greater than 5.3 mg/L was found for rats. Thus, indicating that absorption after inhalation is not likely and/or the acute toxicity of the substance is low.

Overall, a systemic bioavailability of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol 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 >10 implies that Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol may have the potential to accumulate in adipose tissue (ECHA, 2014).

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 gastrointestinal tract, the hydrolysis products TMP, and Fatty acids, C18 unsatd., dimers are mainly produced. The log Pow of the first hydrolysis 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 the extracellular concentration particularly in fatty tissues (ECHA, 2014).

Distribution of the parent substance is not expected as only very limited absorption is expected. Only the potential hydrolysis products of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol after chemical changes as a result of enzymatic hydrolysis, namely TMP and Fatty acids, C18 unsatd., dimers, might be distributed within the body.

TMP, a rather small (MW = 134.20 g/mol) substance of high 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 hydrolysis 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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol 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, 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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol will be metabolised.

Nevertheless possible hydrolysis products should be discussed here. The first possible hydrolysis product, TMP, is expected to be metabolized by oxidation and excreted via the urine.

The second hydrolysis product Fatty acids, C18 unsatd., dimers, is expected to be 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 acetyl-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 byβ- orω-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, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol that have become systemically available, might be hydrolysed and the hydrolysis products can be further metabolized. However, due to its high molecular weight, absorption of Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol is not likely and thus, no extensive metabolism is expected but rather direct elimination.

Excretion

Very low absorption is expected for Fatty acids, C18-unsatd., dimers, reaction products with fatty acids, C14-18 and C16-18-unsatd. and propylidynemethanol via the gastrointestinal tract, thus the main portion of the ingested substance is considered to be excreted unchanged in the feces.Absorbed hydrolysis products undergo rapid metabolisation and are excreted either as expired CO2 or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic and aromatic fatty acids.

Categories Display