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Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (CAS 90193-76-3) 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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters 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).

1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is an ester of two alkyl alcohols (C16-18) and 1,2-benzenedicarboxylic acid and meets the definition of an UVCB substance based on the analytical characterization.

1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is an organic solid at room temperature with a molecular weight >600 g/mol and a water solubility < 0.05 mg/L at 20 °C (Frischmann, 2012). The log Pow is 17.4 (Dr. Knoell Consult GmbH, 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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is >600 g/mol, absorption of the molecule in the gastrointestinal tract is considered limited.

Absorption after oral administration of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is not expected to be high either when the “Lipinski Rule of Five” (Lipinski et al., 2001; refined by Ghose et al., 1999) is applied. The log Pow, the total number of atoms and the molecular weight are above the given ranges.

If at all, 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is favourable for absorption by micellar solubilisation due to the high log Pow of >10. This mechanism is of importance for highly lipophilic substances (log Pow > 4), with a low water solubility (ECHA, 2012).

After oral ingestion, 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters can undergo stepwise hydrolysis of the ester bonds by gastrointestinal enzymes (Lehninger, 1970; Mattson and Volpenhein, 1972). The respective alcohol as well as the monoester and the aromatic acid are 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, for the cleavage products, it is anticipated that they are absorbed in the gastro-intestinal tract due to their lower molecular weights. 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. Substances with a molecular weight below 200 may even pass through aqueous pores (ECHA, 2012).

No data are available for acute oral toxicity of 1,2-Benzenedicarboxylic acid, di-C16-18-alkyl esters. However, in acute oral toxicity studies with a structurally similar substance, rats were administered 1,2-Benzenedicarboxylic acid, mixed cetyl and stearyl esters (CAS# 68442-70-6) by gavage. The LD50 for this substance was reported to be > 5000 mg/kg bw (Gloxhuber 1971, Potokar 1981) taking into account the rule of 5 by Lipinski, bioavailability of 1,2-Benzenedicarboxylic acid, di-C16-18-alkyl esters after oral administration is considered to be non-toxic.

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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is >600 g/mol, dermal absorption of the molecule will be low.

If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is not skin irritating, 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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (Dermwin v.2.01, EPI Suite). Based on this value the substance has a very 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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is < 0.05 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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters in humans is considered as very limited.

Inhalation:

1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is a solid. As the vapour pressure of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is very low (< 0.0001 Pa at 20 °C), the volatility is also low. Therefore, the potential for exposure and subsequent absorption via inhalation during normal use and handling is considered to be negligible. 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 like 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters can be taken up by micellar solubilisation.

No data are available for acute inhalation toxicity of 1,2-Benzenedicarboxylic acid, di-C16-18-alkyl esters. However, there are data available for particle size distribution of the solid substance, indicating that the particle size is > 200 µm in diameter for > 99.9% of the substance (Peter Greven Fett-Chemie, 2009). Thus the substance does not consist of inhalable-, or alveolar available particles and therefore bioavailability via the inhalative route is considered to be negligible for hazard assessment.

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 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, esters of alcohols an acids undergo esterase-catalysed hydrolysis, leading to the cleavage products C16-C18 alkyl alcohol and 1,2-Benzenedicarboxylic acid and the monoesters, respectively.

The first cleavage product, the C16-18 alkyl alcohol is only slightly water-soluble (HSDB, 2011). However, fatty alcohols have limited potential for retention or bioaccumulation as they are efficiently metabolised (OECD SIDS, 2006). The second cleavage product, 1,2-Benzenedicarboxylic acid, has a log Pow of 1.415 and is thus water-soluble. It can be easily converted into the respective anhydride, but as the environment in the body is aqueous, the free acid will predominantly be present (OECD SIDS, 2002). The intermediate products, the monoesters, are less water soluble than the free acid, but no accumulation is expected either, because further metabolism is assumed as described in the metabolism section below. Consequently, there is no potential for accumulation in adipose tissue.

Overall, the available information indicates that no significant bioaccumulation 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 extracellular concentration particularly in fatty tissues (ECHA, 2012).

1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters undergoes chemical changes as a result of enzymatic hydrolysis. Aliphatic fatty alcohols, like C16-18 alkyl alcohol, are widely distributed within the body and efficiently eliminated (OECD SIDS, 2006). 1,2-benzenedicarboxylic acid or rather the corresponding ester are expected to be distributed within the organism as well.

Overall, the available information indicates that 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters and its cleavage products, will be distributed within the organism.

Metabolism

In general, esters of fatty acids are hydrolysed to the corresponding alcohol and Phthalic 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 aromatic dicarboxylic acids 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.

The ester bonds are stepwise cleaved to the alcohol and the acid. During the first step of alcohol metabolism of the biotransformation the alcohols are oxidised to the corresponding carboxylic acids, followed by a stepwise elimination of C2-units in the mitochondrial beta-oxidation process (OECD SIDS, 2006). 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is an aromatic diester; thus, during hydrolysis also the monoester can be formed. Further metabolization by beta-oxidation, the degradation pathway of fatty acids, might be possible after cleavage of the aromatic ring.

Overall, 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is mainly hydrolyzed to the corresponding free acid as well as C16-18 alkyl alcohols. The cleavage products are mainly excreted via urine and/or further metabolized to CO2.

Excretion

The main route of excretion of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters is expected to be by biliary excretion with the faeces, either unchanged, as monoester or as the free dicarboxylic acid. A further route of excretion is expected to be by expired air as CO2 after metabolic degradation (beta-oxidation) of C16-18 alkyl alcohols. Due to the lower molecular weights and the higher water solubility, compared to the parent substance, the cleavage products can also be excreted via the urine.  

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