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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C18-unsaturated, trimers, hydrogenated has been investigated. In accordance with Annex VIII, Column 1, Section 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, 2012), assessment of the toxicokinetic behaviour of the substance 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 physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2012) and taking into account further available information from the analogue substances Fatty acids, C18-unsatd., dimers (CAS 61788-89-4) and Fatty acids, C18-unsatd., dimers, hydrogenated (CAS 68783-41-5). Available information on the toxicokinetic behaviour of (long-chain) fatty acids is also considered for assessment.

The substance Fatty acids, C18-unsaturated, trimers, hydrogenated is a UVCB composed of trimers of saturated long-chain fatty acids. The substance is derived from catalytically di- and trimerised long-chain fatty acids; dimers and trimers are separated by distillation and unsaturated alkyl chains are hydrogenated as specifically required.

The substance has a molecular weight in the range of ca. 845-850 g/mol. The substance is a viscous liquid at room temperature and atmospheric pressure (Tarran, 2013), with calculated water solubility < 0.001 mg/L at 25 °C (Zhang, 2013), log Pow > 6 (Tarran, 2013) and a calculated vapour pressure of < 0.001 Pa at 25°C (Zhang, 2013).

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

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) which would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2012).

The physicochemical characteristics (high log Pow and low water solubility) of the substance and the high molecular weight are in a range which do not anticipate absorption from the gastrointestinal tract subsequent to oral ingestion. The available acute oral toxicity studies from the analogue substances Fatty acids, C18-unsatd., dimers and Fatty acids, C18-unsatd., dimers, hydrogenated do not provide evidence for or against absorption, since no mortality or any other indication of systemic toxicity occurred (Thouin, 1986; Rijnders, 1988).

However, as indicated above, being a highly lipophilic and poorly water soluble substance, some degree of absorption may occur by micellar solubilisation followed by transport via the lymphatic system. For the analogue substance Fatty acids, C18-unsatd., dimers this appears to be true, as indicated in a 13-week feeding study in rats in which aggregation of macrophages, some of which were pigmented, were seen on microscopic examination of the mesenteric lymph nodes and the spleen. The incidence and amount of pigmented macrophages was dose-dependent (Spurgeon and Hepburn, 1993).

In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. Among common fatty acids, stearic acid (C18:0) is the most poorly absorbed. Thus, the absorption of palmitic (16:0), stearic (18:0), oleic (18:1) and linoleic (18:2) acid from vegetable oils has been shown to be 75, 62, 92 and 94%, respectively, in studies with human infants (Jensen et al., 1986; IOM, 2005). Increasing chain length is suggested to slightly decrease digestibility (Bernard and Carlier, 1991; CIR, 1987; Clayton and Clayton, 1982; Opdyke, 1979).

Long-chain saturated fatty acids in the intestinal lumen are less readily solubilised into mixed micelles than are unsaturated fatty acids. Due to the alkaline conditions of the intestine, they can form insoluble soaps with divalent cations (such as calcium) and be excreted. After being absorbed, long-chain saturated fatty acids are esterified along with other fatty acids into triglycerides and released in chylomicrons. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids 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 likewise taken up by muscle and oxidized for energy or they are released into the systemic circulation and returned to the liver (CIR, 2001; IOM, 2005).

As a result of the di-/trimerisation reaction, cyclic isomers of fatty acids may be present in Fatty acids, C18-unsaturated, trimers, hydrogenated. With respect to oral absorption, studies on cyclic monomers of fatty acids have shown that they are well absorbed and may become incorporated in different tissues (Boatella-Riera et al., 2000; Iwaoka and Perkins, 1978).

Dimeric and oligomeric fatty acids appear to be less absorbed than monomeric 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.

Heated refined soybean oil, heated Primor colza oil and triglycerides containing 9-(2'-Propyl benzene) nonanoic acid or 9-(2'-Propyl cyclohex-4'-en-1'-yl) nonanoic acid were administered to thoracic-cannulated rats (ca. 3 mL/kg bw, single dose) and the lymph was continuously collected for 48 h. Approximately 4% of the total polymerised fatty acids, 53% of the total monomeric oxidised fatty acids and 96% of the total cyclic monomers of fatty acids were absorbed as determined by analysis of the recovered lymphatic fatty acids (Combe et al., 1981).

Methyl esters of the oxidation products obtained from heat-abused randomised labelled corn oil were fed to thoracic duct-cannulated rats (1 g, single administration). The lymph was collected and the lipids were analysed by thin-layer chromatography (TLC) and radioassayed. A maximum absorption of the methyl esters of the non-volatile oxidation products did not occur until 21 to 48 h after it had been fed, and only 31.2% was absorbed within 48 h after its administration (Perkins et al., 1970). Details on the composition of the non-volatile oxidation products, as to the proportion of mono- and polymeric fatty acids, were not given.

In a digestibility study, rats were fed olive oil, olive oil heated at 180 °C for 150 h and 1:1 unheated/heated mixtures 12 and 20% in basal fat-free diet for 14 days. Analysis of faecal lipids indicated high digestibility of nonpolar fatty acid monomers (94.8% on average). Oxidised fatty acid monomers from heated olive oil had an apparent average absorption of 76.7%. Nonpolar dimers had the lowest average digestibility (10.9%), while oxidised dimers and polymers showed higher apparent absorbability, ranging from 22.7% to 49.6% (Márquez-Ruiz et al., 1992).

In a lymph cannulation study, rats were given 14C-labelled dimeric acid methyl esters via gastric intubation. After 12 h only 0.4% of the radioactivity was recovered in the lymph (Hsieh and Perkins, 1976).

Other studies investigating the systemic distribution and excretion of 14C-labelled dimeric fatty acid methyl esters provide further evidence for a low level of oral absorption of dimeric fatty acids, as described further below.

In conclusion, the available data indicate that the rate of oral absorption of Fatty acids, C18-unsaturated, trimers, hydrogenated is low.

Inhalation

The substance Fatty acids, C18-unsaturated, trimers, hydrogenated is a viscous liquid with low vapour pressure and it is not intended for use in spraying/brushing processes. Thus, exposure of humans via inhalation is unlikely.

As for oral absorption, the molecular weight and physicochemical properties of the substance are in a range suggestive of low absorption across the respiratory tract epithelium. Absorption by micellar solubilisation may occur, but this mechanism is more relevant for oral absorption due to the requirement of the emulsifying bile salts.

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, 2012).

The physicochemical characteristics (log Pow > 6 and water solubility < 0.001 mg/L) of the substance and the molecular weight (ca. 845-850 g/mol) are in a range suggestive of low absorption through the skin.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

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

The Kp is thus estimated to be ca. 2.6E-04 cm/h. Considering the water solubility (1E-06 mg/cm³), the dermal flux is estimated to be ca. 2.6E-10 mg/cm²/h.

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, 2012).

Based on the available experimental data, the substance is considered to be not acutely toxic by the dermal route and not skin irritating; the data on skin sensitisation are inconclusive. The data thus suggest a low level of dermal uptake.

In support of this, available information 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 about 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. At 22.27 µg C16/cm² and 24.53 µg C18/cm², about 0.3% of both C16 and C18 soap solutions is absorbed through rat skin after 6 h exposure in vivo (Howes, 1975).

In conclusion, the available data indicate that the dermal absorption rate of Fatty acids, C18-unsaturated, trimers, hydrogenated is very low.

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, 2012).

The high molecular weight of the substance does not anticipate a wide distribution in the organism. Due to its lipophilicity, the substance is may distribute in fatty tissue. The results of the 13-week feeding study with Fatty acids, C18-unsatd., dimers indicate that, following absorption from the intestine, the absorbed fraction of substance is distributed via the lymphatic system (Spurgeon and Hepburn, 1993).

Absorbed fatty acids are distributed all over the organism and can be absorbed by different tissues. Proposed uptake mechanisms range from passive diffusion to facilitated diffusion or a combination of both (Abumrad et al., 1984; Harris et al., 1980). Fatty acids can be stored as triglycerides (98% occurring in adipose tissue depots), be incorporated into cell membranes or they are oxidised via the β-oxidation and tricarboxylic acid cycle pathways of catabolism (Masoro, 1977; CIR 1987, 2001; IOM, 2005).

In studies with rats orally given methyl esters of uniformly labelled cyclic fatty acid monomers, low levels of radioactivity were recovered from the gastrointestinal tract (ca. 1.62%), liver (ca. 0.97%), epidydimal (ca. 0.38%) and perirenal fat (ca. 0.58%) at 48 h post-administration (Iwaoka and Perkins, 1978).

The fraction of orally bioavailable dimeric fatty acids appears to follow the same pattern of distribution. In rats fed 14C-labelled dimeric acid methyl esters via gastric intubation, about 0.115% of the administered test material was incorporated in the liver and metabolised to different lipid classes. Only ca. 0.04-0.05% was incorporated in epidydimal and perirenal fat, respectively. In comparison, rats given 14C-labelled methyl oleate showed that ca. 0.4, 3.7 and 6% of the administered dose was incorporated in the liver, epidydimal and perirenal fat, respectively. In average, ca. 34% were expired as 14CO2 and ca. 0.9% excreted via urine (Hsieh and Perkins, 1976).

In another study, methyl esters of 14C-labelled dimeric fatty acids prepared from uniformly labelled methyl oleate by the method of Paschke et al. (1964) were orally given to rats by gavage. At 48 h post-administration, rats were killed and selected organs were removed for analysis. A low level of incorporation was observed in the liver (ca. 5.5%) and the adipose tissues analysed (epididymal and perirenal fat: ca. 1.4 and 1.7%, respectively) (Perkins and Taubold, 1978).

As mentioned above, 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 metabolised and excreted. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

Cyclic isomers of fatty acids appear to be metabolised into polar metabolites, which cannot be further degraded by β- or ω-oxidation and which are rapidly excreted via urine (Iwaoka and Perkins, 1976). Therefore, no significant accumulation is expected.

The available information indicates that dimeric (and consequently higher oligomerised) 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.

Metabolism

The β-oxidation of fatty acids takes place in most vertebrate tissues using an enzyme complex for a series of oxidation and hydration reactions which result in the cleavage of acetate groups as acetyl CoA. The alkyl chain length is reduced by 2 carbon atoms in each β-oxidation cycle, thus releasing acetic acid. Another carboxyl group remains on the shortened alkyl chain for further β-oxidation. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerisation reaction is required. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation) (CIR, 1987). Thus iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates (Lippel, 1973) and to be metabolised to a large extent by ω-oxidation (CIR, 1983).

The 14CO2 expired by rats orally given dimers probably arises from β- or ω-oxidation of the dimeric fatty acid, followed by oxidation of the resulting Acetyl-CoA into water and CO2 during the tricarboxylic acid cycle (Hsieh and Perkins, 1976).

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).

Excretion

In general, fatty acids are entirely catabolised by oxidative processes resulting in carbon dioxide and water as the principal excretion products. Small amounts of ketone bodies arising from the oxidation of fatty acids are excreted via the urine (IOM, 2005).

Metabolised fatty acids are mainly excreted via expired CO2. The turnover of 14C-labelled surfactants of increasing chain length (soap solutions of fatty acid sodium salts) was tested in rats after intraperitoneal and subcutaneous application. Decanoic acid (C10:0), dodecanoic acid (C12:0), tetradecanoic acid (C14:0), hexadecanoic acid (C16:0) and octadecanoic acid (C18:0) were given in a single dose (ca. 1.09, 1.18, 1.36, 1.55 and 1.64 mg/kg bw, respectively) to groups of 6 rats per test substance, 3 animals treated i. p., the other 3 by injection. Total urine, faeces and expired air were collected for 6 h and analysed radiometrically. At 6 h post-application, all animals were sacrificed and prepared for14C-determination in the carcass. The turnover of the 14C-surfactants in the rat showed that there was no significant difference in the rate or route of excretion of 14C given by intraperitoneal or subcutaneous administration. The main route of excretion was as 14CO2 in the expired air at 6 h after administration. The remaining material was incorporated in the body. Longer fatty acid chains are more readily incorporated than shorter chains. At ca. 1.55 and 1.64 mg/kg bw, 71% of the C16:0 and 56% of the C18:0 was incorporated and 21% and 38% was excreted as 14CO2, respectively (Howes, 1975).

Studies with rats orally given methyl esters of uniformly labelled cyclic fatty acid monomers indicated that, after 48 h, ca. 40% of the total radioactivity is found in the urine (ca. 60% thereof being excreted within the first 12 h). About 14% of the total radioactivity was expired as 14CO2 48 h post-administration, with a peak expiration at 4-6 h. (Iwaoka and Perkins, 1978).

Methyl esters of the oxidation products obtained from heat-abused randomised labelled corn oil were fed to thoracic duct-cannulated rats (1 g, single administration). 18.7% of the dose was metabolised within 48 h after its administration. Approximately 7.6% of the radioactivity was found in the carcass, 1% in the liver, 5.9% in the gastrointestinal tract, 4.5% in the urine, and 62.8% in the faeces (Perkins et al., 1970).

Rats fed 14C-labelled dimeric acid methyl esters via gastric intubation excreted ca. 1% of the labelled material via urine and ca. 2% as CO2. Ca. 80% of the radioactivity was recovered in the gastrointestinal tract and the faeces (Hsieh and Perkins, 1976).

In another metabolic study, methyl esters of 14C-labelled dimeric fatty acids prepared from uniformly labelled methyl oleate by the method of Paschke et al. (1964) were orally given to rats by gavage. Animals were placed in metabolic cages for 48 h and urine, faeces and expired CO2 were collected. In average, ca. 85% of the recovered radioactivity was found in the gastrointestinal tract and faeces, ca. 1% in urine and ca. 5% in the expired CO2. Based on the study results, the authors concluded that the absorption of noncyclic dimers via the gastrointestinal tract appears to be limited to ca. 10%, which is then metabolised (Perkins and Taubold, 1978).

Taken together, the available data allow the recognition of trends in toxicokinetic behaviour of mono- and oligomeric fatty acids, which are likely to apply to Fatty acids, C18-unsaturated, trimers, hydrogenated and the analogue substances used for read-across. Hence, after oral exposure unsaturated monomeric C16-C18 fatty acids are more readily absorbed than saturated fatty acids such as octadecanoic and isooctadecanoic acid (but still less absorbed than fatty acids of shorter chain length). Cyclic fatty acids which may be found in mono- and dimeric acid mixtures are also absorbed to a similar extent as the corresponding linear fatty acids. Very low absorption is expected for dimeric and trimeric fatty acids via the gastrointestinal tract, thus much of the ingested substance is excreted in the faeces. Absorbed fatty acids undergo rapid metabolisation and excretion either in the expired CO2 or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic fatty acids.

 

References

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