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Additional information

Justification for grouping of substances and read-across

The Polyfunctional acid ester (PFAE) aromatic category covers fatty alcohol esters of Benzene-1,2,4-tricarboxylic acid. The category contains both mono constituent and UVCB substances with fatty alcohol carbon chain lengths from C8-C13 (linear and iso-alcohols) building tri-esters with Benzene-1,2,4-tricarboxylic acid in variable proportions. A further surrogate substance of similar structure is included, namely a triester of Benzene-1,2,4-tricarboxylic acid with a C8 alcohol, but the alcohol moiety is branched (2-ethylhexyl).

Esters are generally produced by chemical reaction of an alcohol (e.g. Triisodecanol) with an organic acid (e.g. Benzene-1,2,4-tricarboxylic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the alcohol to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to the carbonyl carbon of the acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al., 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Tri-esters are the final products of esterification.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substances listed below are allocated to the category of PFAE aromatic.

 

List of category members including CAS and molecular weight (range):

CAS

Chemical Name

Molecular weight

Carbon number in alcohol

Acid

Substance type

3319-31-1 (c)

Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate

546.78

C8branched

Benzene-1,2,4-tricarboxylic acid

M

90218-76-1

(former CAS No. 67989-23-5) (b)

1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters

546.78 - 630.94

C8; C10

Benzene-1,2,4-tricarboxylic acid

UVCB

36631-30-8

Triisodecyl benzene-1,2,4-tricarboxylate

630.94

C10iso

Benzene-1,2,4-tricarboxylic acid

M

94279-36-4 (a)

1,2,4-Benzenetricarboxylic acid, tri-C9-11-alkyl esters

588.86 - 673.02

C9; C11

Benzene-1,2,4-tricarboxylic acid

UVCB

72361-35-4

Triisotridecyl benzene-1,2,4-tricarboxylate

757.18

C13iso

Benzene-1,2,4-tricarboxylic acid

UVCB

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Category specific similarities/trends:

Grouping of substances into this category is based on:

(1) common functional groups: all members of the respective category are esters of three mono-functional fatty alcohols with 1,2,4-benzene tricarboxylic acid. The fatty alcohol moiety comprises chain lengths from C8-C13 inlcuding linear and iso-chains (branched in case of the surrogate substance) and the acid moiety is 1,2,4-benzene tricarboxylic acid (trimellitic acid) and common in for all category members resulting in tri-esters; and

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: all members of the category result from esterification of an alcohol with the aromatic tricarboxylic acid. Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the alcohol and the tricarboxylic acid moieties are simultaneously precursors and breakdown products of the category members. Taken into account the high MW, the high log Pow and the limited water solubility absorption of the substance is possible but limited for any category member. For the purpose of grouping of substances, stepwise enzymatic hydrolysis via di- and mono-ester in the gastrointestinal tract and/or liver after absorption is identified as the biological process, by which the breakdown of the category members result in structurally similar chemicals. However, available data on a category member indicate that the substance will only be partly absorbed. If absorbed, trimellitic acid might be enzymatically degraded via β-oxidation, the degradation pathway of fatty acids following hydrolysis and cleavage of the aromatic ring. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids. The fatty alcohol is, in general, likewise enzymatically oxidized to the corresponding carboxylic acid, which can be further degraded by β-oxidation (refer to Toxicokinetics for details); and

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities in regard to physicochemical, environmental fate, ecotoxicological and toxicological properties. In case of the surrogate substance, the applicability of the read-across principle does not include all endpoints, as the short-chain branched alcohol moiety is known to affect the toxicological behaviour of the substance at the endpoint toxicity to reproduction/ developmental toxicity. Therefore a read across to the surrogate substance at this endpoint is considered unsuitable. A detailed justification is provided in the endpoint summary toxicity to reproduction.

 

 a) Physicochemical properties:

The molecular weight of the category members ranges from 546.78 to 757.18 g/mol. All category members are non-volatile liquids at room temperature with vapour pressures < 0.001 Pa. The octanol/water partition coefficients of the category members are > 10 and the water solubility is very low (< 0.05 mg/L; surrogate substance: 0.13 mg/L).

b) Environmental fate and ecotoxicological properties:

Considering the low water solubility (< 0.05 mg/L) and the potential for adsorption to organic soil and sediment particles (log Koc > 5), the main compartments for environmental distribution are expected to be the soil and sediment. Nevertheless, persistency in these compartments is not expected since all members of the category are enhanced ultimate biodegradable and are thus expected to be eliminated in sewage treatment plants to a high extent. Release to surface waters, and thereby exposure of sediment, is very unlikely. Thus, the soil is expected to be the major compartment of concern. Nevertheless, the category members are expected to be metabolised by soil microorganisms. Evaporation into air and the transport through the atmosphere to other environmental compartments is not expected since the category members are not volatile based on the low vapour pressure (< 0.001 Pa).

All members of the category did not show any effects on aquatic organisms in the available acute and chronic tests representing the category members up to the limit of water solubility and effects on terrestrial organisms is negligible. Moreover, due to the low water solubility, complete environmental biodegradation in a short time period and low absorption potential in biota due to the high molecular weight of the substances (which significantly reduces the absorption due to steric hindrance to cross biological membranes of the PFAE aromatic category members), a relevant uptake and bioaccumulation in aquatic organisms is not expected. Furthermore, absorbed molecules of the category members will be metabolized and the metabolites will be excreted.

c) Toxicological properties:

The toxicological properties show that all category members have similar toxicokinetic behaviour (partial hydrolysis of the ester bond before absorption followed by absorption and metabolism of the breakdown products) and that the constant pattern consists in a lack of potency change of properties across the category, explained by the common metabolic fate of all trimellitate esters independently of the fatty alcohol chain length. Thus, considering all available evidence and expert judgement, no category member showed acute oral, dermal or inhalation toxicity, no skin irritation, eye irritation or sensitizing properties, and are of low toxicity after repeated oral exposure and not mutagenic or clastogenic and have shown no indication for reproduction toxicity or effects on intrauterine development.

Effects on male fertility (change in sperm parameters) seen in a disregarded study with the surrogate substance (CAS 3319-31-1) is presumably due to the branching of the short-chain alcohol moiety (2-ethylhexanyl) and not considered relevant for the category members.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

 

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, 2012), 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, 2012) and taking into account further available information on the PFAE aromatic category.

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 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters 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 (Frischmann, 2011). The log Pow is 10.60 at 55 °C (Villa, 2011) and the vapour pressure is estimated to be < 1E-10 Pa at 20 °C (Nagel, 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, 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, 2012c). 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 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 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters 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, 2012).

After oral ingestion, the members of the PFAE aromatic category 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 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. 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).

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 (Dreher, 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.

One toxicokinetic study is available performed with the structurally similar substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1) according to a protocol similar to the OECD guideline 417. Groups of 4 rats were treated with 100 mg/kg bw (corresponding to approx. 16-18 µCi radioactivity per rat) of the substance and absorption, distribution, metabolism and excretion were examined.

As a result of hydrolysis, the di- and monoester as well as 2-ethylhexanol, and consequently the tricarboxylic acid, were produced. Absorption of the monoester, 2-ethylhexanol and the free acid was observed. However, only a small part of the substance was absorbed from the gastro intestinal tract after hydrolysis (Enriquez, 1984).

Consistently, available data indicate that esters of trimellitates 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 trimellitates 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 cleavage 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 favours dermal absorption, above 500 the molecule may be too large (ECHA, 2012c). 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, 2012). 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 a value 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, 2012). 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), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters in humans is considered as very limited.

Inhalation:

1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters has a low vapour pressure < 1E-10 Pa 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 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 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 > 6 implies that 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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 and fatty acids undergo esterase-catalysed hydrolysis, leading to the cleavage products C9-11 alkyl alcohol and benzene-1,2,4-tricarboxylic acid and the mono- or diester, respectively.

The first cleavage product, the C9-11 alkyl alcohol, is slightly to moderately 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, 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 either, because further metabolism is assumed as described in the metabolism section below. Consequently, there is no potential for accumulation in adipose tissue.

This is supported by results obtained with the structurally similar substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1). The substance and its cleavage products were distributed within the body and only 0.6% remained in the liver and adipose tissue. Only the radioactively labelled alcohol residue could be detected, but as the free acid is water soluble no accumulation is expected. Thus, there is a very low potential for bioaccumulation (Enriquez, 1984).

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).

1,2,4-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 rather the mono- or diester will be distributed within the organism as well.

Data from the structurally similar subtstance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1) indicate distribution within the body, whereby most of the radioactivity (of 0.6% that remained in the body) was found in liver and adipose tissues. In comparison to the average concentration of radioactivity found in the carcass, concentrations of radioactivity in adipose tissue and liver were 3- and 5-fold increased, respectively.

Overall, the available information indicates that 1,2,4-Benzene tricarboxylic acid, tri-C9-11-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 (C9-11 alkyl 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 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 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). 1,2,4-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 beta-oxidation, the degradation pathway of fatty acids, might be possible after cleavage of the aromatic ring.

Consistently, examination of the metabolism of the structurally similar substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1) revealed no evidence for phase I metabolism as the origin of exhaled CO2 was exclusively the alcohol (2-ethylhexanol). In urine, only the monoester, the alcohol and its metabolites (e.g. 2-ethyl hexanoic acid and heptanone) were found – the free acid could not be detected because only the alcohol was labelled. Additionally, unidentified polar metabolites were present in the faeces that accounted for not more than 5%. Thus, the main metabolic pathway was hydrolytic cleavage of one to three ester bonds followed by oxidation of the alcohol and production of CO2 by beta oxidation (Enriquez, 1984).

Overall, 1,2,4-Benzene tricarboxylic acid, tri-C9-11-alkyl esters is mainly hydrolyzed to the di- and monoester and the free acid as well as C9-11-alkyl alcohols. The cleavage products are mainly excreted vial urine and/or further metabolized 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 (beta-oxidation) of C9-11 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.               

The structurally similar substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (CAS 3319-31-1) was mainly excreted via the faeces (75%), thereof 85.6% unchanged, 6.8% as diester and 1.1% as monoester. The second route of excretion was via urine as metabolites (16%). Additional 1.9% was excreted via expired air as CO2 after metabolic degradation of 2-ethylhexanol (Enriquez, 1984).

Thus, biliary excretion of the substance and its metabolites is the most relevant route of excretion.

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