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EC number: 292-962-5
CAS number: 91031-58-2
The Short Chain Alcohol Esters (SCAE C2-C8) category covers esters
from a fatty acid (C8-C29) and a C2-C8 alcohol (ethanol, isopropanol,
butanol, isobutanol, pentanol, iso-pentanol, hexanol, 2-ethylhexanol or
octanol). This category includes both well-defined mono-constituent
substances as well as related UVCB substances with varying fatty acid
Fatty acid esters are generally produced by chemical reaction of
an alcohol (e.g. isopropanol) with an organic acid (e.g. stearic acid)
in the presence of an acid catalyst (Radzi et al., 2005). The
esterification reaction is started by a transfer of a proton from the
acid catalyst to the acid 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 a carbonyl carbon of 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). Monoesters are the final
product of esterification.
The rationale for grouping the substances in the SCAE C2-C8
category is based on similarities in physicochemical, ecotoxicological
and toxicological properties.
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
In this particular case, the similarity of the SCAE C2-C8 category
members is justified, in accordance with the specifications listed in
Regulation (EC) No. 1907/2006 Annex XI, 1.5
Grouping of substances and read across, based on representative
molecular structure, physico-chemical properties, tox-, ecotoxicological
profiles, supported by a robust set of experimental data and QSAR
calculations. There is no convincing evidence that any one of these
chemicals might lie out of the overall profile of this category,
Grouping of substances into this category is based on:
• Similar/overlapping structural features or functional groups:
All category members are esters of primary alcohols (C2-C8) and fatty
acids (C8-C29), with 13 to 32 carbons in total.
• Common precursors and the likelihood of common breakdown
products via biological
processes: All category members are subject to enzymatic
hydrolysis by pancreatic lipases (Mattson and Volpenhein, 1972; and
references therein). The resulting free fatty acids and alcohols are
absorbed from the intestine into the blood stream. Fatty acids are
either metabolised via the beta-oxidation pathway in order to generate
energy for the cell or reconstituted into glyceride esters and stored in
the fat depots in the body. The alcohols are metabolised primarily in
the liver through a series of oxidative steps, finally yielding carbon
dioxide (Berg et al., 2002).
• Similar physico-chemical properties: The log Kow and log Koc
values of all category members are high (log Kow > 4, log Koc > 3),
increasing with the size of the molecule. The substances are poorly
soluble in water and have low vapour pressure.
• Common properties for environmental fate & eco-toxicological:
Based on experimental data , all substances are readily biodegradable
and do not show toxic effects up to the limit of water solubility.
• Common levels and mode of human health related effects:All
available experimental data indicate that the members of the SCAE C2-C18
category are not acutely toxic, are not irritating to the skin or to the
eyes and do not have sensitizing properties. Repeated dose toxicity was
shown to be low for all substances. None of the substances showed
mutagenic effects, and toxicity to reproduction was low throughout the
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 SCAE C2-C8.
Table 1: Members of the SCAE C2-C8 Category
Alcohol Carbon No.
Fatty acid Carbon No.
ethyl linoleate or ethyl octadeca-9,12-dienoate
Fatty acids, essential, ethyl esters
14 - 22
16 - 24
Fatty acids, C16-18, isopropyl esters
16 - 18
19 - 21
Fatty acids, lanolin, isopropyl esters
10 - 29
13 - 32
Fatty acids, tall-oil, butyl esters
Fatty acids, C16-18, Bu esters
20 - 22
Fatty acids, C16-18 and C18-unsatd., Bu esters
Fatty acids, C16-18 and C18 unsatd. branched and linear, butyl esters
Fatty acids, C16-18, iso-Bu esters
Fatty acids, C16-18 and C18-unsatd., iso-Bu esters
Fatty acids, C8-10, 3-methylbutyl esters
8 - 10
13 - 15
Dodecanoic acid, hexyl ester
Dodecanoic acid, isooctyl ester
Fatty acids, C8-10, 2-ethylhexyl esters
Fatty acids, C8-16, 2-ethylhexyl esters
12 - 14
Hexadecanoic acid, 2-ethylhexyl ester
2-Ethyl hexyl Stearate
Fatty acids, coco, 2-ethylhexyl esters
12 - 18
20 - 26
Fatty acids, C16-18, 2-ethylhexyl esters
24 - 26
Fatty acids, C16-18 and C18-unsatd., 2-ethylhexyl esters
In order to avoid the need to test every substance for every
endpoint, the category concept is applied for the assessment of
environmental fate and 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).
There are no studies available in which the toxicokinetic
behaviour of Fatty acids, C16-18, isopropyl esters (CAS No. 91031-58-2)
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, 2008), assessment of the toxicokinetic
behaviour of the substance Fatty acids, C14-18, isopropyl 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, 2008) and
taking into account further available information on the SCAE C2-8
The substance Fatty acids, C16-18, isopropyl esters consists of
esters of isopropyl alcohol and fatty acids with a chain length of
C16-18 and meets the definition of an UVCB substance.
The substance Fatty acids, C16-18, isopropyl esters is liquid at
room temperature and has a molecular weight in the range of 270.46 to
326.57 g/mol. Its water solubility is < 0.05 mg/L at 20 °C (Frischmann,
2012) and the log Pow for the single substances (C16 and C18) were
calculated to be 6.18 and 9.14 at 20°C, respectively (Ozolins, 2011).
The vapour pressure is calculated to be < 0.011 Pa at 20 °C (different
data sources, calculated and extrapolated values, see IUCLID chapter
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, 2008).
The smaller the molecule, the more easily it will be taken up. In
general, molecular weights below 500 are favourable for oral absorption
(ECHA, 2008). As the molecular weight of Fatty acids, C16-18, isopropyl
esters is in the range of 270.46 and 326.57 g/mol, absorption of the
molecule in the gastrointestinal tract is in general anticipated.
Absorption after oral administration is also expected when the
“Lipinski Rule of Five” (Lipinski et al. (2001), refined by Ghose et al.
(1999)) is applied to the substance Fatty acids, C14-18, isopropyl
esters, as all rules are fulfilled except for the log Pow, which is
above the given range of -0.4 to 5.6.
The log Pow in the range of 6.18 to 9.14 at 20°C suggests that
Fatty acids, C16-18, isopropyl esters 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).
After oral ingestion, esters of short-chain (C2-8) alcohols and
fatty acids undergo stepwise chemical changes in the gastro-intestinal
fluids as a result of enzymatic hydrolysis. The respective alcohol as
well as the fatty acid is formed, even though it was shown in-vitro that
the hydrolysis rate of methyl oleate was lower when compared with the
hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and
Volpenhein, 1972). 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, 2008). However, also for both
cleavage products, it is anticipated that they are absorbed in the
gastro-intestinal tract. The highly lipophilic fatty acid is absorbed by
micellar solubilisation (Ramirez et al., 2001), whereas the alcohol,
being a highly water-soluble substance, is readily dissolved into the
gastrointestinal fluids and absorbed from the gastrointestinal tract
Exemplarily, experimental data of the structurally similar Ethyl
oleate (CAS No. 111-62-6) confirmed this assumption: The absorption,
distribution, and excretion of 14C-labelled Ethyl oleate was studied in
Sprague Dawley rats after a single, oral dose of 1.7 or 3.4 g/kg bw. It
was shown that the test material was well (approximately 70–90%)
absorbed (Bookstaff et al., 2003).
Overall, a systemic bioavailability of Fatty acids, C16-18,
isopropyl esters 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, 2008). As the molecular weight
of Fatty acids, C16-18, isopropyl esters is in the range of 270.46 to
326.57 g/mol, dermal absorption of the substance cannot be excluded.
If the substance is a skin irritant or corrosive, damage to the
skin surface may enhance penetration (ECHA, 2008). As Fatty acids,
C16-18, isopropyl esters 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 in the range
of 2.07E-05 to 5.58E-05 mg/cm²/event (very low) was predicted for Fatty
acids, C16-18, isopropyl 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,
2008). As the water solubility of Fatty acids, C16-18, isopropyl esters
is less than 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 Fatty acids, C16-18, isopropyl esters in humans is
considered as very limited.
Fatty acids, C16-18, isopropyl esters have a low vapour pressure
of < 0.011 Pa at 20 °C thus being of very 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 not significant.
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 100μm
have the potential to be inhaled. Particles with aerodynamic diameters
below 50μm may reach the thoracic region and those
below 15μm the alveolar region of the respiratory
tract (ECHA, 2008). Lipophilic compounds with a log Pow > 4, that are
poorly soluble in water (1 mg/L or less) like Fatty acids, C16-18,
isopropyl esters can be taken up by micellar solubilisation.
Overall, a systemic bioavailability of Fatty acids, C16-18,
isopropyl esters in humans is considered likely after inhalation of
aerosols with aerodynamic diameters below 15μm.
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 Fatty acids,
C16-18, isopropyl esters may have the potential to accumulate in adipose
tissue (ECHA, 2008).
However, as further described in the section metabolism below,
esters of alcohols and fatty acids undergo esterase-catalysed
hydrolysis, leading to the cleavage products isopropyl alcohol and
C16-18 fatty acids.
The log Pow of the first cleavage product isopropyl alcohol is
0.05, indicating a high solubility in water (HSDB). Consequently, there
is no potential for isopropyl alcohol to accumulate in adipose tissue.
The second cleavage product, the fatty acid (C16-18), can be stored as
triglycerides in adipose tissue depots or be incorporated into cell
membranes. At the same time, fatty acids are also required as a source
of energy. Thus, stored fatty acids underlie a continuous turnover as
they are permanently metabolized and excreted. Bioaccumulation of fatty
acids only takes place, if their intake exceeds the caloric requirements
of the organism.
Overall, the available information indicates that no significant
bioaccumulation 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
Fatty acids, C16-18, isopropyl esters undergo chemical changes as
a result of enzymatic hydrolysis, leading to the cleavage products
isopropyl alcohol and fatty acid (C16-18).
Isopropyl alcohol, a small, water-soluble substance (log Pow =
0.05), will be distributed in aqueous compartments of the organism.
Fatty acids are also distributed in the organism and can be taken up by
different tissues. They can be stored as triglycerides in adipose tissue
depots or they can be incorporated into cell membranes (Masoro, 1977).
Overall, the available information indicates that the cleavage
products, isopropyl alcohol and the fatty acid (C16-18) will be
distributed in the organism.
Esters of fatty acids are hydrolysed to the corresponding alcohol
(isopropyl alcohol) and fatty acid by esterases (Fukami and Yokoi,
2012). Depending on the route of exposure, esterase-catalysed hydrolysis
takes place at different places in the organism: After oral ingestion,
esters of alcohols and fatty acids undergo 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 first cleavage product, isopropyl alcohol, is oxidized by the
non-specific alcohol dehydrogenase (ADH) to acetone, which is either
excreted directly or further metabolized, depending on the substance
level in the organism. It can be oxidized to hydroxyl-acetone, which is
then further metabolized. A minor metabolic pathway was found leading toβ-isopropyl-glucuronide,
which is excreted in the urine (glucuronidation) (EFSA, 2010; IARC,
1987; Wiley online library, 2012).
The second cleavage product, the fatty acid (C16-18), is stepwise
degraded byβ-oxidation based on enzymatic removal of
C2 units in the matrix of the mitochondria in most vertebrate tissues.
The C2 units are cleaved as acyl-CoA, the entry molecule for the citric
acid cycle. The omega- and alpha-oxidation, alternative pathways for
oxidation, can be found in the liver and the brain, respectively (CIR,
For Fatty acids, C16-18, isopropyl esters, the main route of
excretion is expected to be by expired air as CO2 after metabolic
degradation. The second route of excretion is expected to be by biliary
excretion with the faeces. For the cleavage products, the main route is
renal excretion via the urine due to the low molecular weight and the
high water solubility. A large proportion of isopropyl alcohol is
excreted unchanged via exhalation and urinary excretion. Acetone, the
metabolism product of isopropyl alcohol after enzymatic oxidation, is
also excreted via exhaled air (IARC, 1987).
Experimental data of the structurally similar Ethyl oleate (CAS
No. 111-62-6, ethyl ester of oleic acid) are regarded exemplarily. The
absorption, distribution, and excretion of 14C labelled Ethyl oleate was
studied in Sprague Dawley rats after a single, oral dose of 1.7 or 3.4
g/kg bw. At sacrifice (72 h post-dose), mesenteric fat was the tissue
with the highest concentration of radioactivity. The other organs and
tissues had very low concentrations of test material-derived
radioactivity. The main route of excretion of radioactivity in the
groups was via expired air as CO2. Excretion of 14CO2 was rapid in the
groups, thus 12 h after dosing 40-70% of the administered dose was
excreted in expired air (consistent withβ-oxidation of
fatty acids). The females had a higher percentage of radioactivity
expired as CO2 than the corresponding males. A second route of
elimination of radioactivity was via the faeces. Faecal elimination of
Ethyl oleate appeared to be dose-dependent. At the dose of 1.7 g/kg bw,
7–8% of the administered dose was eliminated in the faeces. At the dose
of 3.4 g/kg bw, approximately 20% of the administered dose was excreted
in the faeces. Renal elimination was minimal, with approximately 2% of
the radioactivity recovered in urine over 72 h post-dose for the groups
(Bookstaff et al., 2003).
*Berg, J.M., Tymoczko, J.L. and Stryer, L., 2002, Biochemistry, 5thedition,
W.H. Freeman and Company
* Bookstaff et al. (2003). The safety of the use of ethyl oleate
in food is supported by metabolism data in rats and clinical safety data
in humans. Regul Toxicol Pharm 37: 133-148.
* CIR (1987). Final report on the safety assessment of oleic acid,
lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am.
Coll. of Toxicol.6 (3): 321-401.
* Danish EPA (2010). CAS No. 68937-84-8 Danish (Q)SAR Database
Report powered by OASIS Database.http://126.96.36.199/index.html
* ECHA (2008). Guidance on information requirements and chemical
safety assessment, Chapter R.7c: Endpoint specific guidance.
* EFSA (2010). Scientific Opinion: Flavouring Group Evaluation 7,
Revision 3 (FGE.07Rev3): Saturated and unsaturated aliphatic secondary
alcohols, ketones and esters of secondary alcohols and saturated linear
or branched-chain carboxylic acids from chemical group 5. EFSA Journal,
8 (12): 1845
* 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.
* Gubicza, L. et al. (2000). Large-scale enzymatic production of
natural flavour esters in organic solvent with continuous water removal.
Journal of Biotechnology 84(2): 193-196
* HSDB – Hazardous Substances Data Bank, Toxnet Home, National
Library of Medicinehttp://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB
* IARC Monographs – Isopropanol
* Lilja, J. et al. (2005). Esterification of propanoic acid with
ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst.
Chemical Engineering Journal, 115(1-2): 1-12
* Lipinski et al. (2001). Experimental and computational
approaches to estimate solubility and permeability in drug discovery and
development settings. Adv. Drug Del. Rev. 46: 3-26.
* Liu, Y. et al. (2006). A comparison of the esterification of
acetic acid with methanol using heterogeneous versus homogeneous acid
catalysis. Journal of Catalysis 242: 278-286
* Masoro (1977). Lipids and lipid metabolism. Ann. Rev.
* 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 the rat pancreatic juice. Journal of lipid research
* Radzi, S.M. et al. (2005). High performance enzymatic synthesis
of oleyl oleate using immobilised lipase from Candida antartica.
Electronic Journal of Biotechnology 8: 292-298
* Ramirez et al. (2001). Absorption and distribution of dietary
fatty acids from different sources. Early Human Development 65 Suppl.:
*Tocher, D.R. (2003):Metabolism and function of lipids and fatty
acids in teleost fish,Reviews of Fisheries Science, 11 (2), 197
* Wiley online library – Isopropanol. The MAK Collection for
Occupational Health and Safety
* Zhao, Z. (2000). Synthesis of butyl propionate using novel
aluminophosphate molecular sieve as catalyst.Journal of Molecular
Catalysis 154(1-2): 131-135.
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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