Hexanedioic acid, di-C16-18 (even numbered) alkyl esters

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Basic toxicokinetics

There were no studies available in which the toxicokinetic behaviour of Hexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9) 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, 2014c), assessment of the toxicokinetic behaviour of the substanceHexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9)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, 2014c) and taking into account further available information on structurally similar substances and hydrolysis products.

The substanceHexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9)is an organic liquid with a molecular weight range of 594.99 to 707.02 g/mol and the vapour pressure is ≤ 0.011 Pa at 20°C. The measured water solubility was < 50 µg/L at 20 °C and the log Pow > 7.7.

 

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, 2014c).

 

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, 2014c). As the molecular weight range ofHexanedioic acid, di-C16-18 (even numbered)-alkyl estersis 594.99 to 707.02 g/mol, absorption of the molecule in the gastrointestinal tract is considered to be 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); likeHexanedioic acid, di-C16-18 (even numbered)-alkyl esterswith a log Pow >7.7 and a water solubility of <50 µg/L.

In an acute oral toxicity study with the source substanceBis(tridecyl) adipate (CAS 16958-92-2), a LD50 value of >15000 mg/kg bw was derived (key, AOT, 1978).Mild clinical signs were observed, but no mortality occurred.Additionally, in a subchronic repeated dose toxicity study with the read across substanceBis(2-ethylhexyl) adipate (CAS 103-23-1)performed in the rat via the oral route, NOAEL values of 630/2187 (m/f) mg/kg bw/day were derived. As systemic effects were observed (reduced body weight gain) the target substance is systemically available. The effect levels were > 1000 mg/kg bw/day (rat), indicating a low level of toxicity.

Dicarboxylic acid esters are expected to have the same metabolic fate as aliphatic acid esters. Aliphatic acid esters are rapidly hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012; Lehninger, 1970). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different locations in the organism: after oral ingestion, diesters undergo stepwise enzymatic hydrolysis in the gastro-intestinal fluids. 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 takes place.

After oral ingestion, all dicarboxylic esters used within this analogue approach are expected to undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). 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 respective alcohol as well as the dicarboxylic acid is formed. 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, and hence the predictions based upon the physico-chemical characteristics of the parent substance do no longer apply (ECHA, 2012). However, the hydrolysis products are expected to be absorbed in the gastro-intestinal tract. The alcohol components of the target and source substances cover a wide range of carbon chain length (C6-C20, MW: 130.23 g/mol for 2-ethylhexanol to 298.56 g/mol for arachidyl alcohol). In case of alcohols with long carbon chains (e.g. C20) and thus relatively low water solubility, absorption will most likely take place by micellar solubilisation (Ramirez et al., 2001). Small and water soluble hydrolysis products will dissolve into the gastrointestinal fluids (ECHA, 2012).

Overall, systemic bioavailability ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersin humans is considered to be limited after oral uptake of the substance, due to its high molecular weight. The respective hydrolysis products of the target substance are expected to be absorbed in the gastrointestinal tract and the absorption rate of the hydrolysis products is expected to be high. The systemic effects observed following oral exposure to rats and mice indicate the target substance or its hydrolysis products are systemically available.

 

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, 2014c). As the molecular weight ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersranges from 594.99 to 707.02 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, 2014c). AsHexanedioic acid, di-C16-18 (even numbered)-alkyl estersis not predicted to be skin irritating in humans, enhanced penetration of the substance due to local skin damage can be excluded. 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, 2014c). No skin irritation or skin sensitisation potential was observed in a skin sensitisation study performed with the target substance (key, 2017).

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, 2014c). With a log Pow >7.7 and a water solubility <50 µg/L, dermal uptake ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersis likely to be low.

In support of this, data available 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).

Overall, based on the available information and using a worst-case approach, the dermal absorption potential of the target substance is predicted to be low - moderate.

Inhalation

Hexanedioic acid, di-C16-18 (even numbered)-alkyl estershas a vapour pressure below 0.011 Pa at 20 °C, i.e. a 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 100μm have the potential to be inhaled. Particles with aerodynamic diameters below 50μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract (ECHA, 2014c). Lipophilic compounds with a log Pow >4, that are poorly soluble in water (1 mg/L or less) likeHexanedioic acid, di-C16-18 (even numbered)alkyl esterscan be taken up by micellar solubilisation.

In support of this, an acute inhalation toxicity study was performed with the source substanceBis(tridecyl) adipate (CAS 16958-92-2), resulting in a LC50 value of >3.2 mg/L. There was no mortality and no clinical signs were observed. No adverse effects were observed on body weight (gain), or during gross pathology.

Overall, the systemic bioavailability ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersin humans is expected to be low.

 

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 > 7.7 implies thatHexanedioic acid, di-C16-18 (even numbered)-alkyl estersmay have the potential to accumulate in adipose tissue (ECHA, 2014c).

Absorption is a prerequisite for accumulation within the body. Due to its MW and high log Pow, absorption is expected to be minimal forHexanedioic acid, di-C16-18 (even numbered)-alkyl esters, therefore accumulation is not favoured as well. In case of esterase-catalysed hydrolysis, the hydrolysis products (fatty acids C16-20) and adipic acid are produced.

The first hydrolysis product of the analogue substance Bis(2-ethylhexyl) adipate (CAS 103-23-1), 2-ethylhexanol is known to be metabolized and excreted rapidly, meaning that no accumulation is expected (Deisinger, 1994). The second hydrolysis product, the fatty acid, 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. Furthermore, hydrolysis products with high water solubility, like adipic acid, do not have the potential to accumulate in adipose tissue due to their low log Pow and are thus widely distributed within the body and rapidly eliminated via renal excretion. The available information indicates that dimeric fatty acids are poorly absorbed depending on the chain length and that the absorbed fraction follows the same pattern of metabolism and excretion as the monomeric acids. In conclusion, no significant bioaccumulation in adipose tissue is expected.

Overall, the available information indicates that no significant bioaccumulation of the parent substanceHexanedioic acid, di-C16-18 (even numbered)-alkyl esters or its hydrolysis productsin adipose tissue is anticipated.

 

Distribution

Distribution within the body through the circulatory system depends primarily 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, 2014c).

Distribution ofHexanedioic acid, di-C16-18 (even numbered)-alkyl estersis not expected as only very limited absorption will occur. The hydrolysis products ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersare expected to be distributed widely within the body. Furthermore, hydrolysis products with high water solubility, like adipic acid, do not have the potential to accumulate in adipose tissue due to their low log Pow and are thus widely distributed within the body and rapidly eliminated via renal excretion.

 

Metabolism

Dicarboxylic acid esters are expected to be rapidly hydrolysed to the corresponding alcohol and fatty acid by esterases (Fukami and Yokoi, 2012; Lehninger, 1970). Alcohol metabolism proceeds by oxidation to the corresponding carboxylic acids, followed by a stepwise elimination of C2-units in the mitochondrialβ-oxidation process (OECD SIDS, 2006). Depending on the carbon chain length dicarboxylic acids are either predominantly excreted unchanged via urine or metabolised via peroxisomal and mitochondrialβ-oxidation (Passi et al., 1983). The products ofβ-oxidation of odd-chain dicarboxylic acids are acetyl-CoA and malonyl-CoA, which cannot be oxidized further, are used in lipogenesis. Moreover even-chain dicarboxylic acids produce acetyl-CoA and succinyl-CoA, which is a gluconeogenesis precursor (Grego and Mingrone, 1994). Further oxidation of the C2-untis (acetyl-CoA) via the citric acid cycle leads to the formation of H2O and CO2(Lehninger, 1970; Stryer, 1994).

This hypothesis is supported by experimental toxicokinetics data from the structurally analogue substance Bis(2-ethylhexyl) adipate (DEHA, CAS 103-23-1). In this study the elimination, distribution and metabolism of DEHA were assessed in rats according to a protocol similar to OECD Guideline 417 (Takahashi et al., 1981). Adipic acid was found as main metabolite in urine in a short time and its excretion reached 20-30% of the administered dose within 6 h. In blood it was found at 1% and in liver at 2-3%; mono-(2-ethylhexyl) adipate (MEHA) was the second metabolite found, but to a very low extent. Thus, hydrolysis of parent substance was shown in vivo within 6 hours into adipic acid (20-30% of administered dose in urine, 1% of administered dose in blood, 2-3% of administered dose in liver) and MEHA to a lower extent. From these results, it is clear that orally ingested DEHA is rapidly hydrolyzed to MEHA and adipic acid which is the main intermediate metabolite. In addition, DEHA was hydrolyzed to MEHA and adipic acid in vitro by tissue preparations from liver, pancreas and small intestine. When testing MEHA, the monoester was more rapidly hydrolyzed to adipic acid than DEHA by these preparations, and the intestinal preparation was the most active one among them (Takahashi et al., 1981).

Overall, the part ofHexanedioic acid, di-C16-18 (even numbered)-alkyl estersthat is systemically available may be hydrolysed and the hydrolysis products are metabolized by beta oxidation and/or glucuronidation. However, due to its high molecular weight, absorption of the parent substance is likely to be limited.

 

Excretion

The main route of excretion ofHexanedioic acid, di-C16-18 (even numbered)alkyl estersis expected to be excretion of the unabsorbed fraction via the feces. The second route of excretion is expected to be by expired air as CO2after metabolic degradation (β-oxidation). The metabolism of 2-ethylhexanol was studied in rats (Deisinger, 1994). Following oral exposure, 2-ethylhexanol was absorbed effectively by the gastrointestinal tract. The major portion of the dose was excreted within 24 h, primarily in the urine. Smaller amounts of the dose were excreted in the feces primarily within 24 h. A mean of 11% of the dose was recovered as14CO2, but only a fraction of a percent of the dose was recovered from the breath as [14C] volatile organics. Following dermal exposure, only a small portion of the dose was absorbed, which was eliminated primarily in the urine, with smaller amounts eliminated in the feces, and as14CO2, in the breath. Furthermore, hydrolysis products with high water solubility, like adipic acid, do not have the potential to accumulate in adipose tissue due to their low log Pow and are thus widely distributed within the body and rapidly eliminated via renal excretion.

The potential hydrolysis products might also be excreted via the urine unchanged (Deisinger, 1994).

Reference list:

Deisinger, P.J. (1994). Metabolism of 2-ethylhexanol administered orally and dermally to the female Fischer 344 rat. XENOBIOTICA, 1994, VOL. 24, NO. 5 , 429-440.

ECHA (2016): Guidance on information requirements and chemical safety assessment - Chapter R.7a. European Chemicals Agency, Helsinki.

ECHA (2014) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance

Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

Grego, A.V. and Mingrone, G. (1995). Dicarboxylic acids, an alternate fuel substrate in parenteral nutrition: an update. Clinical nutrition 14(3):143-8.

Howes, D. (1975). The percutaneous absorption of some anionic surfactants. J. Soc. Cosmet. Chem. 26:47-63.

Lehninger, A.L. (1970). Biochemistry. Worth Publishers, Inc.

Mattson F.H. and Volpenhein R.A., 1972: Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of rat pancreatic juice. Journal of Lipid Research 13, 325-328

Passi, S. et al. (1983). Metabolism of straight saturated medium chain length (C9 to C12) dicarboxylic acids. Journal of Lipid Research 24(9):1140-7.

Ramirez et al. (2001). Absorption and distribution of dietary fatty acids from different sources. Early Human Development 65 Suppl.: S95–S101.

Stryer, L. (1994): Biochemie. 2nd revised reprint, Heidelberg; Berlin; Oxford: Spektrum Akad. Verlag.

Takahashi T. et al., 1981: Elimination, distribution and metabolism of di(2-ethylhexyl)adipate (DEHA) in rats. Toxcology 22: 223-233