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EC number: 304-780-6
CAS number: 94279-36-4
for grouping of substances and read-across
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).
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.
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
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.
category members including CAS and molecular weight (range):
Carbon number in alcohol
(former CAS No. 67989-23-5) (b)
1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters
546.78 - 630.94
1,2,4-Benzenetricarboxylic acid, tri-C9-11-alkyl esters
588.86 - 673.02
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.
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.
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.
of substances into this category is based on:
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
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
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.
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).
Environmental fate and ecotoxicological properties:
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).
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.
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
effects on intrauterine development.
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.
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.
detailed justification for the grouping of chemicals and read-across is
provided in the technical dossier (see IUCLID Section 13).
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.
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.
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
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).
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).
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.
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.
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,
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).
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
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.
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).
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).
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.
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.
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.
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
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.
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.
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.
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.
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.
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).
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.
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.
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).
the available information indicates that no significant bioaccumulation
in adipose tissue is anticipated.
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).
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.
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.
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.
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.
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.
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).
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.
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
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).
biliary excretion of the substance and its metabolites is the most
relevant route of excretion.
detailed reference list is provided in the technical dossier (see
IUCLID, section 13) and within the CSR.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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