Isooctadecyl pivalate

Endpoint summary

Description of key information

The absorption rate of the target substance Isooctadecyl pivalate is expected to be high via the oral, inhalation and dermal route. The ester will be hydrolysed in the gastrointestinal tract and mucus membranes to the respective fatty acid and fatty alcohols, which facilitates the absorption. Absorbed ester will be hydrolysed mainly in the liver. The fatty alcohols are mainly oxidised to the corresponding fatty acid, which will be re-esterified to triglycerides after absorption and transported via chylomicrons. The fatty acid, pivalic acid, is readily absorbed and rapidly forms a thioester with coenzyme-A. The major metabolic pathway for linear and branched fatty acids is the beta-oxidation pathway for energy generation, while alternatives are the omega-pathway or direct conjugation to more polar products. The excretion will mainly be as CO₂ in expired air; with a smaller fraction excreted as conjugated molecules in the urine. No bioaccumulation will take place, as excess triglycerides are stored and used as the energy need rises. Pivalic acid will form pivaloylcarnitine via several metabolism steps, and be excreted completely via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Isooctadecyl pivalate (CAS 58958-60-4) was investigated.

In accordance with Annex VIII, Column 1, 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, 2014), an assessment of the toxicokinetic behaviour of the target substanceIsooctadecyl pivalatewas 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 the Chapter R.7c Guidance document (ECHA, 2014) and taking into account further available information from source substances. The target substance is a UVCB with a main branched C18iso-alcohol moiety and a highly branched C5-acid moiety.

Physico-chemical properties

Isooctadecyl pivalate has the molecular weight range of 354.61 – 382.66 g/mol. It is a liquid at 20 °C with a water solubility of 0.0117 mg/L at 19 °C. The log Pow was estimated to be > 10 and the vapour pressure was calculated to be < 0.0001 Pa 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

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 can 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) as these would otherwise be poorly absorbed. Solids must be dissolved before absorption; the degree depends on the water solubility (Aungst and Shen, 1986; ECHA, 2014).

Some of the physico-chemical characteristics (log Pow and water solubility) of the substance are in a range that indicate poor absorption from the gastrointestinal (GI-) tract following oral ingestion, while the molecular weight and physical state favours uptake. Micellular solubilisation is likely to occur; although it is unclear to what degree it will affect the total absorption rate of the substance.

The indications that the target substance Isooctadecyl pivalate has relatively low oral absorption and/or low acute toxicity due to its physico-chemical characteristics are supported by the available data on acute oral toxicity. In a study in which male NMRI EOPS mice were administered a single dose of 5000 mg/kg bw of the target substance, there was no mortality observed. From 30 minutes until 1 hour after administration an unspecified number of the mice had closed eyes, were lethargic and had irregular breathing which was likely an unspecific response due to the unusually high dose volume applied. No clinical signs of toxicity were observed during the rest of the 6-day observation period (Dufour, 1993).

In the available subchronic (13-week) oral toxicity study, rats were administered 0, 1.0, 2.0 and 4.0 mL/kg bw (equivalent to 0, 865, 1730 and 3460 mg/kg bw/day, based on a density of 0.865 g/mL) of undiluted Isooctadecyl pivalate, once daily via gavage. No toxicologically relevant effects were observed. An increase in liver weight in the high-dose animals and a slight increase in the frequency and severity of hepatic cytoplasmic vacuolation (females), compared with the control group, was observed. The liver effects were mainly attributed to the increased metabolic load caused by exposure to a fatty ester. The NOAEL was 3460 mg/kg bw/day for male and female rats.

The potential of a substance to be absorbed in the GI-tract may be influenced by several parameters, like: chemical changes taking place in GI-fluids, as a result of metabolism by GI-flora, by enzymes released into the GI-tract or by hydrolysis. These changes will alter the physico-chemical characteristics of the substance and hence predictions based on the physico-chemical characteristics of the parent substance may in some cases no longer apply (ECHA, 2014). In general, alkyl esters are readily hydrolysed in the GI-tract, blood and liver to the corresponding alcohol and fatty acid by the ubiquitous carboxylesterases. There are indications that the hydrolysis rate in the intestine catalysed by pancreatic lipase is lower for alkyl esters than for triglycerides, which are the natural substrates of this enzyme. The hydrolysis rate of linear esters increases with increasing chain length of either the alcohol or acid. Branching reduces the ester hydrolysis rate, compared with linear esters (Mattson and Volpenhein, 1969, 1972; WHO, 1999). It is therefore unclear what percentage of the ester will be hydrolysed.

Based on the generic information on hydrolysis of alkyl esters, the target Isooctadecyl pivalate is expected to be enzymatically hydrolysed to the highly branchedpivalic acidand branched fatty alcohol.

In general, free fatty acids and alcohols are readily absorbed by the intestinal mucosa. Within the epithelial cells, fatty acids are mainly (re-)esterified with glycerol to triglycerides. Branching is likely to reduce the absorption rate, depending on the chain length and degree of branching (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964; OECD, 2006; Sieber, 1974). For pivalic acid, the absorption rate is most likely high due to the short C-chain. The fraction of ester that is hydrolysed to the corresponding fattyacidand alcohol is more likely to be absorbed from the GI-tract than the parent substance. With increasing chain-length the fatty acids are increasingly absorbed via the lymphatic route, and will be metabolised in the liver (Ramirez et al., 2001).

The target substance is predicted to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products rather than the parent substance is likely. The absorption rate of the hydrolysis products is expected to be high.

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. 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 the 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, 2014).

The target substance Isooctadecyl pivalate has a molecular weight range of 354.61 – 382.66 g/mol, which indicates a potential for dermal absorption. In contrast, the substance has very low water solubility and therefore a low dermal absorption potential might be assumed (ECHA, 2014). The log Pow is > 10, which means that the uptake into the stratum corneum is predicted to be slow and the rate of transfer between the stratum corneum and the epidermis will be slow (ECHA, 2014).

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. The available acute data on the target substance showed very mild skin irritating effects in the rabbit (Dufour, 1993). No skin irritating effects were noted in the skin sensitisation studies performed in the guinea pig using 3 source substances (Clouzeau, 1991; Potokar, 1984; Sanders, 2002). Furthermore, no alerts for the C16iso- and C20iso component of the target substance were predicted in the OECD QSAR Toolbox 3.3 using the ‘Protein binding alerts for skin sensitisation’ in the OASIS v1.3 database (Nordheim, 2016). Therefore, no enhanced penetration of the substance due to skin damage is expected.

As carboxylesterases have been shown to be present in the skin, hydrolysis of the ester may take place in the skin, although at a lower rate than via the oral route due to the lower amount of enzymes in the skin. For the fraction of ester that is absorbed into the skin, the ester bond will be hydrolysed and the hydrolysis products may enter the blood circulation.

Taking all the available information into account, the dermal absorption potential is considered to be moderate.

Inhalation

Isooctadecyl pivalate is a liquid with low vapour pressure (0.0117 Pa at 19 °C), and therefore very low volatility. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of particles will depend on the aerodynamic particle size (ECHA, 2014). The substance may also be available for inhalatory absorption after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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. Particles deposited in the nasopharyngeal/ thoracic region will mainly be cleared from the airways by the mucocilliary mechanism and swallowed.

It is not clear to which extent the ester and the hydrolysis products will be absorbed in the respiratory tract. For absorption of the hydrolysis products, enzymatic hydrolysis in the airways would be required, and the presence of esterases and lipases in the mucus lining fluid of the respiratory tract would be important. Due to the physiological function of enzymes in the GI-tract for nutrient absorption, esterase and lipase activity in the lung is expected to be lower in comparison to the gastrointestinal tract. Therefore, hydrolysis comparable to that in the gastrointestinal tract and subsequent absorption in the respiratory tract is considered to happen at a lower rate. The log Pow and water solubility indicate that the parent substance may be absorbed across the respiratory tract epithelium by micellar solubilisation to a certain extent. However, low water solubility (<0.05 mg/L) does restrict the diffusion/dissolving into the mucus lining before reaching the epithelium, and it is not clear which percentage of the inhaled aerosol could be absorbed as the ester. 

An acute inhalation toxicity study was performed with the read-across (source) substance isopropyl laurate (CAS 10233-13-3), in which rats were exposed nose-only to > 5.3 mg/L (analytical concentration) of an aerosol for 4 hours (Van Huygevoort, 2010). No mortality occurred and no toxicologically relevant effects were observed. Therefore, the target substance is not expected to be acutely toxic by the inhalation route, but no firm conclusion can be drawn on respiratory absorption. Furthermore, the effects observed in the oral and dermal repeated dose toxicity studies with the target substance indicate it may cause effects via the inhalation route as well.

Due to the limited information available a worst case approach is applied, and absorption via inhalation is assumed to be as high as via the oral route.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance; particularly the molecular weight, the lipophilic character and the water solubility. In general the relation is: the smaller the molecule, the wider 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, 2014).

As discussed under oral absorption, Isooctadecyl pivalate will undergo some enzymatic hydrolysis in the gastrointestinal tract prior to absorption. The fraction of ester absorbed unchanged will undergo enzymatic hydrolysis by ubiquitous esterases, primarily in the liver (Fukami and Yokoi, 2012). The distribution and accumulation of the hydrolysis products is considered the most relevant.

After being absorbed, linear and simple branched fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system (Sieber, 1974). Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase 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 also taken up by muscle and oxidized to derive energy or they are released into the systemic circulation and returned to the liver, where they are metabolised, stored or re-enter the circulation (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1993; NTP, 1994; Stryer, 1996; WHO, 2001). Fatty acids of carbon chain length ≤ 12 may be transported directly to the liver via the portal vein as the free acid bound to albumin, instead of being re-esterified. Highly branched, short-chain fatty acids like pivalic acid are expected to be widely distributed, although the distribution is likely to be facilitated via other routes than the chylomicrons. Pivalic acid is used in prodrugs as the inactive byproduct, where the ester bond is hydrolysed to free pivalic acid and the therapeutic agent (Brass, 2002). Pivalic acid is readily absorbed and rapidly forms a thioester with coenzyme-A.

Absorbed alcohols are mainly oxidised to the corresponding fatty acid and then follow the same metabolism as described above for fatty acids, to form triglycerides. The absorption and metabolism of a fatty alcohol was assessed in an in vivo study performed by Sieber (1974). Twenty-four hours after intraduodenal administration of a single dose of [1-¹⁴C]-radiolabelled Octadecanol to rats, 56.6 ± 14% of the radiolabelled carbon was recovered in the lymph. More than half (52-73%) of the recovered radioactive label was incorporated in triglycerides, 6-13% in phospholipids, 2-3% in cholesterol esters and 4-10% in unmetabolised octadecanol. Almost all the radioactivity recovered in the lymph was localized in the chylomicron fraction. The results of administration of hexanol resulted in a recovery of 8.5% in the lymph (Sieber, 1974), indicating that alcohols with shorter-length carbon chains are hydrolysed to the corresponding fatty acid and transported directly to the liver via the portal vein as the free acid bound to albumin. Branched fatty alcohols, including the highly branched alcohols, are also converted into the corresponding fatty acids and distributed via the circulation.

Due to the rapid metabolism of pivalic acid it is not expected to accumulate in any tissues, while the alcohol moiety of the target substance is expected to be metabolised to the corresponding fatty acid. The accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism. The potential ofIsooctadecyl pivalateas well as the hydrolysis products to accumulate is therefore considered to be low.

Substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before transport to the liver where hydrolysis will generally take place.

 Metabolism

The metabolism of Isooctadecyl pivalate initially occurs via a stepwise enzymatic hydrolysis of the ester resulting in the corresponding pivalic acid and C18iso-alcohol. The esterases catalysing the reaction are present in most tissues and organs, with particularly high concentrations in the GI-tract and the liver (Fukami and Yokoi, 2012).

The C18iso-alcohol will mainly be metabolised to the corresponding carboxylic acid via the aldehyde as a transient intermediate (Lehninger, 1993). The stepwise process starts with the oxidation of the alcohol by alcohol dehydrogenase to the corresponding aldehyde, where the rate of oxidation increases with increasing chain-length. Subsequently, the aldehyde is oxidised to carboxylic acid, in a reaction catalysed by aldehyde dehydrogenase. Both the alcohol and the aldehyde may also be conjugated with e.g. glutathione and excreted directly, bypassing further metabolism steps (WHO, 1999). Fatty acids can be metabolised directly following absorption, following oxidation from an alcohol or following de-esterification of triglycerides. The beta-oxidation pathway for energy generation is the major metabolic pathway for linear and an important pathway for simple branched fatty acids. In this multi-step process, the fatty acids are at first esterified into acyl-CoA derivatives and subsequently transported into cells and mitochondria by specific transport systems (IOM, 2005; Lehninger, 1998; Stryer, 1996; WHO 2001). In the next step, the acyl-CoA derivatives are broken down into acetyl-CoA molecules by sequential removal of 2-carbon units from the aliphatic acyl-CoA molecule. Further oxidation via the citric acid cycle leads to the formation of H₂O and CO₂(Lehninger, 1993). Branched-chain acids can be metabolised via the same beta-oxidation pathway as linear, depending on the steric position of the branch, but at lower rates (WHO, 1999).

Pivalic acid will bind to coenzyme A to form pivaloyl-CoA, which cannot be metabolised further in mammalian cells (Brass, 2002). Subsequently, the pivaloyl-moiety can be transferred to carnitine to generate pivaloylcarnitine. Carnitine is an endogenous substance that is involved in the mitochondrial oxidation of long-chain fatty acids. Although the formation of pivaloylcarnitine following absorption of high concentrations of pivalic acid may deplete the carnitine pool in a tissue or tissues, it has been shown that the likelihood of adverse effects from long-term low exposure levels and short-term high exposure levels is negligible. Only patients receiving treatment involving high doses of pivalic acid (as part of a prodrug) may require a carnitine supplement (Brass, 2002).   

The potential metabolites following enzymatic metabolism of the test substance were predicted using the QSAR OECD toolbox (OECD, 2014). This QSAR tool predicts which metabolites of the test substance may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. Five (5) hepatic metabolites and 10 dermal metabolites were predicted for the main components of the substance. Primarily, the ester bond is broken both in the liver and in the skin, after which the hydrolysis products may be metabolised further. The resulting liver and skin metabolites are the products of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). In the case of omega-oxidation, it is followed by further oxidation to the aldehyde, which is then oxidised to the corresponding carboxylic acid. For a branched fatty acid, the alpha- and omega pathways are particularly relevant. The ester bond may also remain intact, in which case a hydroxyl group is added to, or substituted with, a methyl group. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites.  Up to 82 metabolites were predicted to result from all kinds of microbiological metabolism. The high number includes many minor variations in the c-chain length and number of carbonyl- and hydroxyl groups; reflecting the many microbial enzymes identified. Not all of these reactions are expected to take place in the human GI-tract. The results of the OECD Toolbox simulation support the information on metabolism routes retrieved in the literature.

There is no indication that Isooctadecyl pivalate is activated to reactive intermediates under the relevant test conditions. The experimental studies performed on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, chromosome aberration assay in mammalian cells in vitro) using the target and source substances were consistently negative, with and without metabolic activation (Buskens, 2010; Cathalot, 2015; Durward, 2004; Flanders, 2007; Verspeek-Rip, 2010). The result of the skin sensitisation studies performed in guinea pigs using source substances were likewise negative (Clouzeau, 1991; Potokar, 1984; Sanders, 2002).

Excretion

In general, linear fatty acids and fatty acids with simple branching derived directly from the hydrolysis of the ester or from the oxidation of the corresponding alcohol, as well as the fatty acids, will be metabolised for energy generation or stored as lipid in adipose tissue or used for further physiological functions, like incorporation into cell membranes (Lehninger, 1993). Therefore, the fatty acid metabolites derived from the alcohol component C18iso-alcohol are not expected to be excreted to a significant degree via the urine or faeces but to be excreted via exhaled air as CO₂or stored as described above. Experimental data with ethyl oleate (CAS 111-62-6, ethyl ester of Oleic acid (Ethyl oleate)) support this principle. The absorption, distribution, and excretion of 14C-labelled Ethyl oleate was studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw. At sacrifice (72 h post-dose), mesenteric fat was the tissue with the highest concentration of radioactivity. The other organs and tissues had very low concentrations of test material-derived radioactivity. The main route of excretion of radioactivity in the groups was via the expired air as CO₂. 12 h after dosing, 40-70% of the administered dose was excreted in expired air (consistent with beta -oxidation of fatty acids). 7-20% of the radioactivity was eliminated via the faeces, and approximately 2% via the urine (Bookstaff et al., 2003). The alcohol component C18iso-alcohol may also be conjugated with e.g. glutathione to form a more water-soluble molecule and excreted via the urine, bypassing further metabolism steps (WHO, 1999).

Pivalic acid will form pivaloylcarnitine via several metabolism steps, and be excreted completely via the urine. 

The fraction of Isooctadecyl pivalate that is not absorbed in the GI-tract, will be excreted via the faeces.

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