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EC number: 249-044-4
CAS number: 28472-97-1
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
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
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).
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
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.
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
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.
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
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.
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
Overall, the available information indicates that no significant
bioaccumulation of the parent substance in adipose tissue is anticipated
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.
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
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
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.
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
A detailed reference list is provided in the technical dossier (see
IUCLID, section 13) and within 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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