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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of diisodecyl azelate (CAS 28472-97-1) 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 diisodecyl azelate 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).

Diisodecyl azelate is a diester of isodecanol and azelaic acid (nonanedioic acid).

Diisodecyl azelate is liquid at room temperature and has a molecular weight of 468.75 g/mol and a water solubility of < 0.05 mg/L at 20 °C. The log Pow is calculated to be 11.55 (Erler, 2013) and the vapour pressure is estimated to be <0.0001 Pa at 20 °C (Dr. Knoell Consult GmbH, 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 Diisodecyl azelate is 468.75 g/mol, absorption of the molecule in the gastrointestinal tract is in general anticipated.

Absorption after oral administration of diisodecyl azelate is also expected when the “Lipinski Rule of Five” (Lipinski et al., 2001; Ghose et al., 1999) is applied. Except for the log Pow and the total number of atoms that are above the given range, all rules are fulfilled.

The log Pow of 11.55 suggests that diisodecyl azelate is favourable for 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).

The results of an acute oral study performed with diisodecyl azelate did not reveal any clinical signs of toxicology at 2000 mg/kg bw (Bien, 1993). This indicates that the substance is of low toxicity and/or badly absorbed after oral administration.

After oral ingestion, diisodecyl azelate undergoes stepwise hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the dicarboxylic acid is formed. 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). However, also for both cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract. In case of long carbon chains and thus rather low water solubility by micellar solubilisation (Ramirez et al., 2001), and for small and water soluble cleavage products by dissolution into the gastrointestinal fluids (ECHA, 2012).

Overall, a systemic bioavailability of diisodecyl azelate and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

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 diisodecyl azelate is 468.75 g/mol, dermal absorption of the molecule cannot be excluded.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As diisodecyl azelate 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 of 0.00001 mg/cm²/event (very low) was predicted for diisodecyl azelate (Danish EPA, 2010). Based on this value the substance has a 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). As the water solubility of diisodecyl azelate 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), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of diisodecyl azelate in humans is considered as very limited.

Inhalation:

Diisodecyl azelate has a low vapour pressure of 9.71E-10 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, 2012). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water (1 mg/L or less) like diisodecyl azelate can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of diisodecyl azelate in humans is considered likely 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 diisodecyl azelate may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, esters of alcohols and dicarboxylic acids undergo esterase-catalysed hydrolysis, leading to the cleavage products isodecanol and azelaic acid.

The first cleavage product, isodecanol, is moderately soluble in water.

The second cleavage product, azelaic acid, has a log Pow value of 1.57 and is soluble in water (HSDB, 2011). Consequently, accumulation in adipose tissue is not likely.

This assumption is supported by results from studies performed with the structurally similar substance Bis(2-ethylhexyl) adipate (CAS 103-23-1) indicating no potential for bioaccumulation (Elcombe, 1981; Takahashi et al., 1981).

Overall, the available information indicates that no significant bioaccumulation of the parent substance in adipose tissue is anticipated (Mostert, 2010).

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).

Diisodecyl azelate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products isodecanol and azelaic acid. Isodecanol, a rather small (MW = 158.28 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. Azelaic acid will be distributed in aqueous compartments, too.

As described in the following chapter, the distribution of Bis(2-ethylhexyl) adipate (DEHA, CAS 103-23-1), a structurally similar substance, was assessed in rats treated with the radioactive labelled substance. Relatively high levels of radioactivity appeared in the liver, kidney, blood, muscle and adipose tissue apart from the stomach and intestine. All other tissues contained very little residual radioactivity. In liver, kidney, testicle and muscle, the amount of residual radioactivity reached a maximum in the first 6 - 12 h and reduced to less than 50% at 24 h. In other tissues the radioactivity declined with time after 6 h. The blood contained about 1% of the radioactivity after 6-12 h and then decreased to undetectable levels by the end of 2 days. It was also evident that total radioactivity in the tissues examined was about 10% after 24 h of dosing and it decreased to about 2% and 0.5% after 48 h and 96 h, respectively. From these results, it can be concluded that the elimination of radioactivity from tissues and organs is very rapid and there is no specific organ affinity under these experimental conditions (Takahashi et al., 1981).

Overall, the available information indicates that diisodecyl azelate and its cleavage products, isodecanol and azelaic acid, will be distributed within the organism.

Metabolism

Dicarboxylic acid esters are expected have the same metabolic fate as fatty acid esters. Esters of fatty acids are hydrolysed to the corresponding alcohol and carboxylic acid by esterases (Fukami and Yokoi, 2012; Lehninger, 1970). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of alcohols and dicarboxylic acids likewise undergo stepwise enzymatic hydrolysis already in the gastro-intestinal fluids. 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.

In the first step of hydrolysis, the monoester is produced that is further hydrolysed to the alcohol and the dicarboxylic acid. The first cleavage product, isodecanol, is mainly oxidized to the corresponding acid which is either glucuronidated or to a small extent further oxidized leading to various products (HSDB, 2011; Mostert, 2010). The second cleavage product, azelaic acid, is partly metabolized by beta-oxidation. After 8 hr, 6% of the radioactivity from a tracer dose of [14C]azelaic acid to rats was recovered as 14CO2. Successive cleavage by beta-oxidation results in the formation of pimelic and glutaric acids and subsequently malonyl-CoA and acetyl-CoA. Thus, azelaic acid is incorporated into fatty acid biosynthesis and the citric acid cycle (HSDB, 2011).

Experimental data of the structurally similar Bis(2-ethylhexyl) adipate (DEHA, CAS 103-23-1) are regarded exemplarily. The elimination, distribution and metabolism were assessed in rats according to a protocol similar to OECD Guideline 417 (Takahashi et al., 1981).14C-DEHA in DMSO was administered to male Wistar rats by oral gavage. 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 less extent. Thus, cleavage of parent substance was shown in vivo within 6 hours into adipic acid (20-30% in urine, 1% in blood, 2-3% in liver) and MEHA to a lesser 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 vitro, DEHA was hydrolysed to MEHA and adipic acid by tissue preparations from liver, pancreas and small intestine. When testing MEHA, the monoester was more rapidly hydrolysed to adipic acid than DEHA by these preparations, and the intestinal preparation was the most active one among them (Takahashi et al., 1981).

In another in vivo study in rats and mice, 2-ethylhexanoic acid (EHA), 2-ethyl-5-hydroxyhexanoic acid and 2-ethylhexan-1,6-dioic acid and their glucuronides were found in urine after administration of DEHA. In monkey, however, large amounts of MEHA-glucuronide and 2-ethylhexanol glucuronide were excreted and only a very small proportion of the dose was converted to EHA and other downstream metabolites (Elcombe, 1981).

Overall, Bis(2-ethylhexyl) azelate is hydrolyzed and the cleavage products are metabolized by beta oxidation and/or glucuronidation.

Excretion

For diisodecyl azelate and its cleavage products, the main routes of excretion are expected to be via expired air as CO2 after metabolic degradation (beta oxidation) and by renal excretion via the urine (Mostert, 2010). Azelaic acid is extensively and rapidly excreted via the urine; approximately 60% of an oral-dose is excreted unchanged in the urine within 12 hours (HSDB, 2011).

Experimental data of the structurally similar DEHA (CAS 103-23-1) are available. In monkeys, large amounts of MEHA-glucuronide and 2-ethylhexanol glucuronide were detected in urine (Elcombe, 1986). In in vivo and in vitro studies with DEHA, adipic acid was found as main metabolite in a short time and its excretion reached 20-30% of the administered dose within 6 h. In rats, excretion within 24 h amounted to 86% of the administered dose and almost all the dose was excreted in 48 h. The greater part of the excretion was recovered in breath and urine; excretion in faeces was small (Takahashi et al., 1981).

           

Thus, renal excretion after glucuronidation and exhalation as CO2 are the most relevant routes of excretion of the substance itself or its metabolites.

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