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Description of key information

A systemic bioavailability of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters and/or the respective hydrolysis products in humans is considered possible but limited after oral uptake of the substance. The dermal uptake is considered as very limited and the systemic bioavailability of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters in humans after inhalation of aerosols with aerodynamic diameters below 15 μm is considered possible. After absorption, 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters and its hydrolysis products, will be distributed within the organism. 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is mainly hydrolysed to the di- and monoester and the free acid as well as C9-11-alkyl alcohols. The hydrolysis products are mainly excreted vial urine and/or further metabolised to CO2The main route of excretion of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is expected to be by biliary excretion with the faeces.No significant bioaccumulation in adipose tissue is anticipated.

Key value for chemical safety assessment

Additional information

Basic toxicokinetics

 

There are no studies available in which the toxicokinetic behaviour of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters (CAS 94279-36-4) 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, 2017), the assessment of the toxicokinetic behaviour of the substance 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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, 2017).

1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is an ester of three alkyl alcohols (C9-11) and benzene-1,2,4-tricarboxylic acid (trimellitic acid) and meets the definition of an UVCB substance based on the analytical characterization. The substance is a pale yellow organic liquid at room temperature with a molecular weight between 588.86 and 673.02 g/mol and a water solubility < 0.05 mg/L at 20 °C (Henkel, 2011). The log Pow is 10.60 at 55 °C (Croda, 2011) and the vapour pressure is estimated to be < 0.00001 Pa at 20 °C (EPA, 2011).

 

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, 2017).

 

Oral:

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2017). As the molecular weight of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is between 588.86 and 673.02, absorption of the molecule in the gastrointestinal tract is considered limited.

Absorption after oral administration of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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, the substance is favourable for absorption by micellar solubilisation due to the log Pow of 10.6. This mechanism is of importance for highly lipophilic substances (log Pow > 4), with a low water solubility (ECHA, 2017).

After oral ingestion, 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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 di- or monoester and the aromatic acid are 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, 2017). However, for the hydrolysis products, it is anticipated that they are absorbed in the gastro-intestinal tract more easily. 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 hydrolysis products by dissolution into the gastrointestinal fluids. Substances with a molecular weight below 200 g/mol may even pass through aqueous pores (ECHA, 2012), which could be of relevance for the C9 – C11-alcohols.

In an acute oral toxicity study performed with 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters, the limit dose of 2000 mg/kg bw was administered to rats (Croda Europe Ltd., 1991). Neither mortality nor clinical signs of toxicity were observed; thus, it can be assumed that the substance was not well absorbed after oral ingestion and/or of low toxicity.

Also the available repeated dose (Croda Europe Ltd., 2022) and reproduction toxicity studies (OECD 421: Croda Europe Ltd., 2023; OECD 414: Croda Europe Ltd., 2022) did not show effects related to treatment and resulted all in NOAELs of ≥ 1000 mg/kg bw/day (highest dose tested), which also supports the assumption that the substance was either not well absorbed and/or of low toxicity. Available data indicate that esters of trimellitic acid in general are poorly hydrolysed and absorbed across the gastrointestinal tract. As hydrolysis in the gut appears to be an obligatory step for systemic absorption, esters of trimellitic acid exhibit a relatively low toxicity (HPV, 2001).

Overall, a systemic bioavailability of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters and/or the respective hydrolysis products in humans is considered possible but limited 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 g/mol favours dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2017). As the molecular weight of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is 588.86 to 673.02 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, 2017). As 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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 in the range of 1.39E-08 to 6.21E-10 mg/cm²/event (very low) was predicted for 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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, 2017). As the water solubility of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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 g/mol), the high log Pow value and the fact that the substance is not irritating to skin indicate that dermal uptake of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters in humans is as very limited.

 

Inhalation:

1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters has a low vapour pressure < 0.00001 Pa, thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and 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 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, 2017). Lipophilic compounds with a log Pow > 4, that are poorly soluble in water like 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters can be taken up by micellar solubilisation.

Overall, a systemic bioavailability of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters in humans is considered possible after inhalation of aerosols with aerodynamic diameters below 15 μm.

 

Accumulation

Highly lipophilic substances in general to tend 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 > 6 indicates that 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters may have the potential to accumulate in adipose tissue (ECHA, 2017).

However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo esterase-catalysed hydrolysis, leading to the hydrolysis products 1-C9-11 alkyl alcohol and benzene-1,2,4-tricarboxylic acid and the mono- or diesters, respectively. The first hydrolysis product, the C9-11 alkyl alcohol, is slightly to moderately water-soluble (HSDB, 2011). However, fatty alcohols generally have limited potential for retention or bioaccumulation as they are efficiently metabolised (OECD SIDS, 2006). The second hydrolysis product, benzene-1,2,4-tricarboxylic acid, has a log Pow of 0.95 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 mono- and di-ester are less water soluble than the free acid, but no accumulation is expected 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, 2017).

1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters undergoes chemical changes as a result of enzymatic hydrolysis. Aliphatic fatty alcohols, like C9-11 alkyl alcohol, are widely distributed within the body and efficiently eliminated (OECD SIDS, 2006). Benzene-1,2,4-tricarboxylic acid or its mono- or diesters will be distributed within the organism as well.

Overall, the available information indicates that 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters, and its hydrolysis products, will be distributed within the organism.

 

Metabolism

In general, esters of fatty acids are hydrolysed to the corresponding alcohol (C9-11 alkyl alcohol) and fatty acid (benzene-1,2,4-tricarboxylic 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 tricarboxylic 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 hydrolysed to the alcohol and the acid. During the first step of alcohol metabolism, the alcohols are oxidised to the corresponding carboxylic acids, followed by a stepwise elimination of C2-units in the mitochondrial β-oxidation process (OECD SIDS, 2006). 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is an aromatic triester; thus, during hydrolysis also the di- and monoester can be formed. Further metabolization by β-oxidation might be possible after additional hydrolysis steps.

There is no indication that 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is activated to reactive intermediates under the relevant test conditions. The experimental studies performed with the registered substance on genotoxicity (Ames test, gene mutation in mammalian cells in vitro, and micronucleus test in vitro) were negative, with and without metabolic activation. Overall, 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is mainly hydrolysed to the di- and monoester and the free acid as well as C9-11-alkyl alcohols. The hydrolysis products are mainly excreted vial urine and/or further metabolised to CO2.

 

Excretion

The main route of excretion of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is expected to be by biliary excretion with the faeces, either unchanged, as mono- or diester or as the free tricarboxylic acid. A further route of excretion is expected to be by expired air as CO2 after metabolic degradation (β-oxidation) of C9-11 alkyl alcohols. Due to the lower molecular weights and the higher water solubility, compared to the parent substance, the hydrolysis products can also be excreted via the urine.

 

References cited in this assessment:

ECHA (2017). 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.

Ghose et al. (1999). A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. J. Comb. Chem. 1 (1): 55-68.

High Production Volume (HPV, 2001) Chemical Challenge Program; Test Plan for Trimellitate Category;http://www.epa.gov/hpv/pubs/summaries/trime/c13468tp.pdf.

HSDB (2011). Hazardous Substances Data Bank, Toxnet Home, National Library of Medicine; http: //toxnet. nlm.nih. gov/cgi-bin/sis/htmlgen?HSDB

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

Lipinski et al. (2001). Experimental and computational approaches to estimate solubility and permeability indrug discovery and development settings. Adv. Drug Del. Rev. 46: 3-26.

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. J Lip Res 13, 325-328.

OECD SIDS (2002): SIDS Initial Assessment Report for 15th SIAM (Boston, USA, 22-25 October 2002): Trimellitic anhydride and trimellitic acidhttp: //www.inchem.org/documents/sids/sids/TLANA. pdf

OECD SIDS (2006): SIDS Initial Assessment Profile: Long Chain Alcohols (C6-22 primary aliphatic alcohols):http://webnet.oecd.org/hpv/UI/handler.axd?id=03441f78-d135-4cab-b832-edfb1d0d677e

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