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EC number: 287-827-2 | CAS number: 85586-24-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
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- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
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- Nanomaterial radical formation potential
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- Endpoint summary
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- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
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- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
Description of key information
Key value for chemical safety assessment
Additional information
Justification for grouping of substances and read-across
The polyol esters category comprises of 49 aliphatic esters of polyfunctional alcohols containing two to six reactive hydroxyl groups and one to six fatty acid chains. The category contains mono constituent, multi-constituent and UVCB substances with fatty acid carbon chain lengths ranging from C5 - C28, which are mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9,branched C14 – C22 building mono-, di-, tri-, and tetra esterswith an alcohol (i.e.polyol). Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. pentaerythritol, trimethylolpropane or neopentylglycol) with an organic acid (e.g. oleic 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 alkyl oxonium ion. The 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 a proton to give an ester (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). The final products of esterification of an alcohol and fatty acids are esters ranging from monoesters to hexa-esters. An indication of the general composition is given within the table below (members of the polyol esters category).
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 for human toxicity, 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).
Keeping in line with the existing OECD category for polyol esters, the polyol ester substances regarded here are considered in one single category based primarily on structural and chemical similarities that result in “close commonalities” in physicochemical and toxicological properties (U.S. EPA, 2010) and 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.
In order to facilitate the practicability of dealing with such an extensive category, its members were further arranged into three groups on the basis of the polyol moiety of the category members (pentaerythritol (PE), trimethylolpropane (TMP) or neopentylglycol (NPG)). This grouping may also be considered to follow the assumption that the degree of esterification may be associated with a varying rate of enzymatic hydrolysis of the ester bond. However, as the U.S. EPA states within their screening level hazard characterization, “although multiple linked polyols are in general subject to slower rates of enzymatic hydrolysis due to steric hindrance, it is nevertheless expected that they would be fully metabolized over a period of time and thus polyols can be treated and considered as one analogous category, whereby their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, thus data can be used as read-across from one member to another to address any data gaps” (U.S. EPA, 2010).
The arrangement of polyol esters into three groups enables a clear overview of the similarity of structures and alcohol moiety and this was often used as an aid in finding the structural suitable or similar substance particularly with regard to the environmental effects, in terms of read-across. Nonetheless, all the experimental data confirm that the polyol esters have the same environmental fate and ecotoxicological properties (i.e. low water solubility, low mobility in soil, ready biodegradability, low persistence and low bioaccumulation potential), and no toxicological effects up to the limit of water solubility in aquatic toxicity tests. Similarly all the category members show similar toxicological properties, and thus follow a similar toxicological profile. None of the category members caused acute oral, dermal or inhalation toxicity, or skin or eye irritation, or skin sensitisation. The polyol esters category members are of low toxicity after repeated exposure. They did not show a potential for toxicity to reproduction, fertility and development and no mutagenic or clastogenic potential was observed.
Members of the polyol esters category
[Please note that the substances given in this table were sorted according to alcohol groups (NPG, TMP, and PE), followed by the degree of esterification, then sorted by increasing chain length and finally by their molecular weight]
ID No. |
CAS |
EC name |
Fatty acid chain length |
Type of Alcohol |
Degree of esterifi-cation |
Molecular Formula |
Molecular weight |
1 |
68855-18-5 (a) |
Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol |
C7 |
NPG |
Di |
C19H36O4 |
328.49 |
2 |
31335-74-7 |
2,2-dimethyl-1,3-propanediyl dioctanoate |
C8 |
NPG |
Di |
C21H40O4 |
356.54 |
3 |
85711-80-4 |
1,3-Propoanediol, 2,2-dimethyl-, C5-9 carboxylates |
C5-9 |
NPG |
Di |
C15H28O4 |
272.38 – 384.59 |
4 |
70693-32-2 |
Decanoic acid, mixed esters with neopentyl glycol and octanoic acid |
C8-10 |
NPG |
Di |
C21H40O45 |
356.54 - 412.65 |
5 |
85186-86-3 |
Fatty acids, C8-18 and C18-unsatd., esters with neopentyl glycol |
C8-18 C18:1 |
NPG |
Di |
C21H40O4 |
356.54 - 633.04 |
6 |
85186-95-4 |
Fatty acids, C12-16, esters with neopentyl glycol |
C12-16 |
NPG |
Di |
C29H56O4 |
468.75 - 580.97 |
7 |
91031-85-5 |
Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters |
C12-14 |
NPG |
Di |
C29H56O4 |
468.75 - 524.86 |
8 |
91031-27-5 |
Fatty acids, C6-18, 2,2-dimethyl-1,3-propanediyl esters |
C16, C18:1 |
NPG |
Di |
C37H72O4 |
580.98 - 637.07 |
9 |
42222-50-4 |
2,2-dimethyl-1,3-propanediyl dioleate |
C16-18, C18uns |
NPG |
Di |
C37H72O4 |
580.98 - 633.06 |
10 |
67989-24-6 |
9-Octadecenoic acid (Z)-, ester with 2,2-dimethyl-1,3-propanediol |
C18:1 |
NPG |
Di |
C41H76O4 |
633.04 |
11 |
85005-25-0 |
Neopentyl Glycol Diisostearate (Fatty acids, C14-18 and C18-unsatd., branched and linear, esters with neopentyl glycol) |
C18iso |
NPG |
Di |
C33H64O4 |
524.86 - 637.07 |
12 |
78-16-0 |
2-ethyl-2-[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate |
C7 |
TMP |
Tri |
C27H50O6 |
470.68 |
13 |
91050-88-3 |
Fatty acids, C6-18, triesters with trimethylolpropane |
C6-18 |
TMP |
Tri |
C24H44O6; C30H56O6; C36H68O6; C42H80O6; C48H82O6; C54H104O6 |
428.60 – 849.40 |
14 |
97281-24-8 |
Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane |
C8-10 |
NPG and TMP |
Di/Tri |
C21H40O4 |
356.54 - 596.94 |
15 |
189120-64-7 (c) |
Fatty acids, C7-8, triesters with trimethylolpropane |
C7-8 |
TMP |
Tri |
C27H50O6 |
470.68 – 512.78 |
16 |
11138-60-6 (d) |
DecanoicFatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol |
C8-10 |
TMP |
Tri |
C30H56O6 |
512.78 - 596.94 |
17 |
91050-89-4 |
Fatty acids, C8-10, triesters with trimethylolpropane |
C8-C10 |
TMP |
Tri |
C30H56O6 |
512.78 - 596.94 |
18 |
85566-29-6 |
Fatty acids, coco, triester with trimethylolpropane |
C12 C14 C16 |
TMP |
Tri |
C42 H80 O6 |
681.08 - 849.4 |
19 |
(Formerly 85186-89-6) |
Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane |
C8 C10 C14 C16 C16 C18 C18:2 |
TMP |
Tri |
C30H56O6 C60H110O6 |
512.76 - 933.56 |
20 |
403507-18-6 |
Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane |
C16-18, C18uns |
TMP |
Di / Tri |
C38H43O5 |
579.76 - 933.56 |
21 |
68002-79-9 |
Fatty acids, C14-18 and C16-18 unsatd., triesters with trimethylolpropane |
C14-18, C18:1 |
TMP |
Tri |
C48H92O6 |
765.72 - 933.56 |
22 |
(Formerly 85005-23-8) EC 931-531-4 |
Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane |
C16 C18 C18uns |
TMP |
Di/Tri |
C48H92O6 |
347 – 933.6 |
23 |
91050-90-7 |
Fatty acids, C16-18, triesters with trimethylolpropane |
C16-18 |
TMP |
Tri |
C54H104O6 |
849.40 - 933.56 |
24 |
68002-78-8 |
Fatty acids, C16-18 and C18 unsatd., triesters with trimethylolpropane |
C16-18, C18uns |
TMP |
Tri |
C54H104O6 |
849.40 - 933.56 |
25 |
(Formerly 57675-44-2) EC 931-461-4 |
Fatty acids, C16-18, even numbered and C18-unsatd. triesters with Propylidynetrimethanol |
C16 C18 C18:1 |
TMP TMPTO |
Tri |
C54H104O6 |
361 - 932 |
26 |
85186-92-1 |
Fatty acids, C14-18 and C16-18-unsatd., mixed esters with neopentyl glycol and trimethylolpropane |
C16 C16:1 C18 C18:1 |
TMP + NPG |
Di/Tri |
C37H68O4 |
577 - 927.5 |
27 |
68541-50-4 |
2-ethyl-2-(((1-oxoisooctadecyl) oxy)methyl)-1,3-propanediyl bis (isoocta decanoate) |
C18iso |
TMP |
Tri |
C60H116O6 |
933.56 |
28 |
15834-04-5 |
2,2-bis[[(1-oxopentyl)oxy]methyl] propane-1,3-diyl divalerate |
C5 |
PE |
Tetra |
C25H44O8 |
472.62 |
29 |
85116-93-4 |
Fatty acids, C16-18 (even numbered), esters with pentaerythritol |
C16-18 |
PE |
Mono-Tetra |
C21H42O5 |
374.56 - 1201.99 |
30 |
85711-45-1 |
Fatty acids, C16-18 and C18-unsatd., esters with pentaerythritol |
C16-18, C18:1 |
PE |
Mono-Tetra |
C21H42O5 |
374.56 – 1193.93 |
31 |
25151-96-6 |
2,2-bis(hydroxymethyl)-1,3-propanediyl dioleate |
C18:1 |
PE |
Mono-Tri |
C41H76O6 |
665.04 – 929.48 |
32 |
67762-53-2 |
Fatty acids, C5-9 tetraesters with pentaerythritol |
C5-9 |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
33 |
(Formerly 68441-94-1) |
Reaction mass of Heptanoic acid 3-pentanoyloxy-2,2-bis-pentanoyloxymethyl-propyl ester, Heptanoic acid 2-heptanoyloxymethyl-3-pentanoyloxy-2-pentanoyloxymethyl-propyl ester and Heptanoic acid 3-heptanoyloxy-2-heptanoyloxymethyl-2-pentanoyloxymethyl-propyl ester |
C5, C7 |
PE |
Tetra |
C27H48O8 |
472.62 - 584.84 |
34 |
(Formerly 68424-30-6) |
Tetraesters from esterification of pentaerythritol with pentanoic, heptanoic and isononanoic acids |
C5-9 |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
35 |
146289-36-3 |
Pentaerythritol ester of pentanoic acids and isononanoic acid |
C5, C5iso, C9iso |
PE |
Tetra |
C25H44O8 |
472.62 – 697.04 |
36 |
68424-31-7 (e) |
Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids |
C5-10 |
PE |
Tetra |
C25H44O8 |
472.62 – 753.14 |
37 |
68424-31-7 (f) |
Tetra-esterification products of C5, C7, C8, C10 fatty acids with pentraerythritol |
C5 C7 C8 C10 |
PE |
Tetra |
C25H44O8 |
472.62 - 753.3 |
38 |
68424-31-7 (g) |
Fatty acids, C7, C8, C10 and 2-ethylhexanoic acid, tetraesters with pentaerythritol |
C5 C7 C8 C10 |
PE |
Tetra |
C25H44O8 |
472.62 - 753.3 |
39 |
71010-76-9 |
Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid |
C5-10 |
PE |
Tetra |
C25H44O8 |
472.62 – 753.14 |
40 |
68441-68-9 |
Decanoic acid, mixed esters with octanoic acid and pentaerythritol |
C8-10 |
PE |
Tetra |
C37H68O8 |
640.93 – 753.14 |
41 |
85586-24-9 |
Fatty acids, C8-10, tetraesters with pentaerythritol |
C8-10 |
PE |
Tetra |
C37H68O8 |
640.93 – 753.14 |
42 |
85049-33-8 |
Fatty acids, C8, C10, C12, C14, C16 esters with pentaerythritol, reaction product of coconut oil fatty acids, C8-C10 fatty acid mix and Pentaerythritol |
C8 C10 C12 C14 C16 |
PE |
Tetra |
C37H68O8 |
640.95 - 1202.03 |
43 |
91050-82-7 |
Fatty acids, C16-18, tetraesters with pentaerythritol |
C16-18 |
PE |
Tetra |
C69H132O8 |
1089.7 -1201.99 |
44 |
19321-40-5 |
Pentaerytritol tetraoleate |
C16:1 C18:1 C18:2 |
PE |
Tetra |
C69H124O8 |
1081.72 - 1193.93 |
45 |
68604-44-4 |
Fatty acids, C16-18 and C18-unsatd., tetraesters with pentaerythritol |
C18, C18:1, C18:2 |
PE |
Tetra |
C69H132O8 |
1089.78 - 1201.99 |
46 |
62125-22-8 |
2,2-bis[[(1-oxoisooctadecyl)oxy]methyl]-1,3-propanediyl bis(isooctadecanoate) |
C14-C22iso |
PE |
Tetra |
C61H116O8 |
977.57 – 1426.42 |
47 |
68440-09-5 |
Fatty acids, lanolin, esters with pentaerythritol |
C10-28 |
PE |
Tetra |
C45H84O8 |
753.14 - 1819.16 |
48 |
85536-35-2 |
Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol |
C5-9 |
PE & DiPE |
Tetra |
C25H44O8 |
472.62 - 697.04; 758.98 - 1039.51 |
49 |
189200-42-8 |
Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol |
C8-10 C8iso |
PE & DiPE |
Tetra |
C37H68O8 |
640.93 – 1179.77 |
a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font
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) As part of the original submission to the U.S. EPA CAS 189120-64-7 was only considered as a supporting chemical nevertheless it is now considered appropriately as a member of the TMP ester group due to its structural homology and similar toxicological properties (U.S. EPA, 2010)
d) Note: decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CASRN 11138-60-6), was considered by the U.S. EPA not to fit into the above TMP ester group as it was determined to contain an unesterified hydroxyl group and thus would be structurally different from the other category members; however – according to the present specification - this is not the case.The substance CAS 11138-60-6 is specified with >80% triester of C8 and C10. (U.S. EPA, 2010)
e) CAS 68434-31-7 – Lead registrant
f) Separate registration of CAS 68434-31-7
g) Separate registration of CAS 68434-31-7 (2-ethylhexanoic acid)
Grouping of substances into the polyol esters category is based on:
(1) common functional groups: the substances of the category are characterized by ester bond(s) between an polyhydroxy alcohol (e.g., neopentylglycol (NPG), trimethylolpropane (TMP), pentaerythritol (PE)) and one to four carboxylic fatty acid chains. On the basis of the alcohol moiety the polyol esters category is organized into three groups: neopentylglycol, trimethlypropane, pentaerythritol esters. The fatty acid chains comprise carbon chain lengths ranging from C5 to C28, mainly saturated but also mono unsaturated C16 and C18, polyunsaturated C18, branched C5 and C9, branched C14 – C22 are included into the category.
(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: the members of the category result from esterification of the alcohol with the respective fatty acid(s). Esterification is, under certain conditions, a reversible reaction. Hydrolysis of the ester bond results in the original reactants, alcohol and carboxylic acid. Thus, the alcohol and fatty acid moieties are simultaneously precursors and breakdown products of the category members.
After oral ingestion, polyol esters of the respective polyol and fatty acids will undergo stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In the gastrointestinal (GI) tract, metabolism prior to absorption via enzymes of the gut microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are seen to be rapidly hydrolyzed by ubiquitously expressed esterases and the cleavage products are almost completely absorbed (Mattsson and Volpenhein, 1972a). In general, it is assumed that the hydrolysis rate varies depending on the fatty acid chain length and grade of esterification (Mattson and Volpenhein, 1969; Mattson and Volpenhein, 1972a,b). With regard to the polyol esters, a lower rate of enzymatic hydrolysis in the GI tract was observed for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b). In vitro hydrolysis rate of pentaerythritol esters was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b). Moreover, in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased, probably the results of different rates of hydrolysis in the intestinal lumen (Mattson and Volpenhein, 1972c).
Based on this, polyol esters are capable of being enzymatically hydrolysed to generate alcohol and the corresponding fatty acids. NPG, TMP and PE esters may show different rates of enzymatic hydrolysis depending on the number of ester bonds and the alcohol involved. Nevertheless, the metabolic fate of the substances is the same, as it is expected, that all of the polyol ester substances will be hydrolyzed over a period of time. The resulting products are subsequently absorbed into the bloodstream. The fatty acids, as potential cleavage products on the one hand, are stepwise degraded via beta–oxidation in the mitochondria. Even numbered fatty acids are degraded via beta-oxidation to carbon dioxide and acetyl-CoA, with release of biochemical energy. The metabolism of the uneven numbered fatty acids results in carbon dioxide and an activated C3-unit, which undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1994). The alternative pathways of alpha- and omega-oxidation, can be found in the liver and the brain, respectively (CIR, 1987).
Polyols (NPG, TMP and PE) are - due to their physical-chemical properties (low molecular weight, low log Pow, and solubility in water) - easily absorbed and can either remain unchanged (i.e. those with more than three ester groups such as PE) or are expected to be further metabolized or conjugated (e.g. glucuronides, sulfates, etc.) into polar products that are excreted via urine (Gessner et al, 1960; Di Carlo et al., 1965).
(3) constant pattern in the changing of the potency of the properties across the category:
(a) Physico-chemical properties: The molecular weight of the category members ranges from 272.38 (C5 diester with NPG component of 1,3-propanediol, 2,2-dimethyl-, C5-9 carboxylates, CAS 85711-80-4) to 1819.16 g/mol (C28 tetraester with PE component of Fatty acids, lanolin, esters with pentaerythritol, CAS 68440-09-5). The physical appearance is related to the chain length of the fatty acid moiety, the degree of saturation and the degree of esterification. Thus, esters up to a fatty acid chain length of C14 are liquid (e.g. Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters, CAS 91031-85-5), above a chain length of C16 esters are solids (e.g. Fatty acids, C16-18, triesters with trimethylolpropane, CAS 91050‑90‑7). Esters with unsaturated or branched longer chain fatty acids (C18:1, C18:2, C18iso) are liquid (Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane, CAS 403507-18-6). For all category members the vapour pressure is low (<0.001 Pa, calculated). The octanol/water partition coefficient increases with increasing fatty acid chain length and degree of esterification, ranging from log Pow = 4.71 (C5 diester with NPG component) to log Pow >20 (e.g. C18 triester with TMP component) and above for long chain fatty acid polyesters. This trend is also applicable for log Koc (3.2 to 30.23), with increasing log Koc based on C-chain length. The water solubility for all category members is low (<1 mg/L or even lower); and
(b) Environmental fate and ecotoxicological properties: Considering the low water solubility and the potential for adsorption to organic soil and sediment particles, the main compartment for environmental distribution is expected to be the soil and sediment for all category members. Nevertheless, although they are expected to have a low mobility in soil, persistency in these compartments is not expected since the members of the category are readily biodegradable. Evaporation into air and the transport through the atmospheric compartment is not expected since the category members are not volatile based on the low vapour pressure. Moreover, bioaccumulation is assumed to be low based on available metabolism data. All available experimental data indicate that the members of the polyol esters category are not harmful to aquatic organism as no toxic effects were observed up to the limit of water solubility for any of the category members.
(c) Toxicological properties: The available data indicate that all the category members show similar toxicological properties. No category member showed acute oral, dermal or inhalation toxicity, no skin or eye irritation properties, no skin sensitization. The category members are of low toxicity after repeated oral exposure and are not mutagenic or clastogenic, they have not shown indications for reproduction toxicity or effects on intrauterine development.
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 and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data of category members by interpolation to the target substances/member within the category in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the structurally closest category member(s) is/are chosen for read-across, whilst taking regard to the requirements of adequacy and reliability of the available data. 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 Fatty acids, C8-10, tetraesters with pentaerythritol (CAS No. 85586-24-9) has been investigated.
Therefore, in accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behavior of the substance Fatty acids, C8-10, tetraesters with pentaerythritol was conducted on 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 polyol esters category from which data was used for read-across to cover data gaps. The UVCB substance Fatty acids, C8-10, tetraesters with pentaerythritol contains esters of pentaerythritol and C8, C10 fatty acids. It is an organic liquid which is poorly water soluble (< 0.15 mg/L, Frischmann, 2012) with a molecular weight of 640 – 753 g/mol, a log Pow > 10 (Hopp, 2011) and a vapour pressure of < 1.42E-13 Pa at 20 °C (Hinze, 2012).
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 favorable for oral absorption (ECHA, 2012). As the molecular weight of Fatty acids, C8-10, tetraesters with pentaerythritol ranges between 640 and 753 g/mol, absorption of the molecule in the gastrointestinal tract is not likely.
Absorption after oral administration is also unexpected when the “Lipinski Rule of Five” (Lipinski et al. (2001), Ghose et al. (1999)) is applied to the substance Fatty acids, C8-10, tetraesters with pentaerythritol, as the log Pow value is above the given range of ‑0.4 to 5.6 and molecular weight is > as 500 g/mol.
The log Pow >10 of the substance Fatty acids, C8-10, tetraesters with pentaerythritol
suggests that the absorption of highly lipophilic substance may therefore be limited by the inability to dissolve into gastrointestinal (GI) fluids but may be enhanced by micellar solubilisation, as this mechanism is of importance for highly lipophilic substances (log Pow >4), who are poorly soluble in water (1 mg/L or less). However, for large molecule the gastrointestinal absorption is not likely to occur. In the gastrointestinal (GI) tract, metabolism prior to absorption via microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolised by ubiquitously expressed esterases and almost completely absorbed (Mattsson and Volpnheim, 1972a). On the contrary, lower rate of enzymatic hydrolysis in the GIT were showed for compounds with more than 3 ester groups (Mattson and Volpenhein, 1972a,b). In vitro hydrolysis rate of pentaerythritol ester was about 2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b).
Moreover in vivo studies in rats demonstrated the incomplete absorption of the compounds containing more than three ester groups. This decrease became more pronounced as the number of ester groups increased (Mattson and Volpenhein, 1972c).
The available data on oral toxicity of the test substance and structurally related substances are also considered for assessment of oral absorption. Acute oral toxicity studies conducted with the test substance and with Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS# 71010-76-9) showed at a concentration of 2000 mg/kg bw in rats no signs of systemic toxicity (Kästner, 1981 and Mallory, 2006). The structurally related substance Pentaerythritol ester of pentanoic acids , mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS # 146289-36-3) showed no systemic effects up the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL ≥1000mg/kg bw/day; Müller, 1998). Therefore, absorption of the intact parental compound or the respective metabolites occurred, resulting in a low order of systemic toxicity. These results suggest that test substance is of low systemic toxicity, either due to low toxicity potency or by a low absorption in combination with a low systemic toxicity. In general, after oral ingestion, aliphatic esters of polyhydroxy alcohol (Polyol) and 1 – 6 fatty acids will undergo chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis. Pentaerythritol (PE, parental polyol) as well as the fatty acids (C8, C10) will be formed, even though the hydrolysis rate of Pentaerythritol tetraoleate is assumed to be low. The physico-chemical characteristics of the cleavage products (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) will 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 will be absorbed in the gastro-intestinal tract.
The highly lipophilic fatty acids will be absorbed by micellar solubilisation (Ramirez et al., 2001). A study by Mattson and Nolen (1972) determined the absorbability of the fatty acid moiety of the complete oleate esters of alcohols containing from one to six hydroxyl groups. The fatty acids of the compounds containing less than four ester groups were almost completely absorbed. As the number of ester groups was increased (erythritol and pentaerythritol tetraoleate and xylitol pentaoleate) the absorbability of the fatty acids decreased but was still present.
The pentaerythritol, having a low molecular weight (136.15 g/mol) and being a highly water-soluble substance (25 g/L, OECD SIDS, 1998), will readily dissolve into the gastrointestinal fluids. After oral administration of 10 mg/kg C14-labled PE to mice, almost half of the administered dose was absorbed from the gastrointestinal tract within 15 minutes (DiCarlo et al., 1965). In summary, the above discussed physico-chemical properties of Fatty acids, C8-10, tetraesters with pentaerythritol and relevant data from available literature on fatty acid esters with more than three ester bonds do not indicate rapid hydrolysis before absorption of Fatty acids, C8-10, tetraesters with pentaerythritol to the respective fatty acids and the polyol pentaerythritol.
On the basis of the above mentioned data, a low absorption of the parent substance is assumed.
Dermal
The smaller the molecule, the more easily it may be taken up. In general, a molecular weight below 100 g/mol favors dermal absorption, above 500 g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of Fatty acids, C8-10, tetraesters with pentaerythritol ranges between 640 and 753 g/mol, a dermal absorption of the molecule is not likely.
If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2012). As Fatty acids, C8-10, tetraesters with pentaerythritol was not tested for skin irritation, read-across from Fatty acids, C5-10, esters with pentaerythritol (CAS# 68424-31-7, Robinson, 1991), and Fatty acids C8-10, mixed esters with diPentaerythritol, isooctanoic acid, Pentaerythritol and triPentaerythritol (CAS# 189200-42-8, Frank, 1995) was applied and in conclusion the substance is not considered as skin irritating in humans. Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.
Based on QSAR dermal absorption values for Fatty acids, C8-10, tetraesters with pentaerythritol between 9.35E-11 and 5.98E-09 mg/cm2/event (very low) were calculated (Episuite 4.1, DERMWIN 2.01, 2012). Based on these values, 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 Fatty acids, C8-10, tetraesters with pentaerythritol is less than 1 mg/L and log Pow is estimated to be >10, dermal uptake is likely to be very low.
The available data on dermal toxicity the structurally related substances, Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) and Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS# 71010-76-9) are also considered for assessment of dermal absorption.
An acute dermal toxicity study was available for Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid (CAS# 71010-76-9). At a concentration of up to 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Mallory, 2006).
In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 2000 mg/kg bw/day in male and female rats.
Overall, the calculated low dermal absorption potential, the low water solubility, the high molecular weight (>100), the high log Pow values and the fact that the substance is not irritating to skin implies that dermal uptake of Fatty acids, C8-10, tetraesters with pentaerythritol in humans is considered as very limited.
Inhalation
Fatty acids, C8-10, tetraesters with pentaerythritol has a low vapour pressure of less than 1.41E-13 Pa at 25 °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 not expected to be 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 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 Fatty acids, C8-10, tetraesters with pentaerythritol can be taken up by micellular solubilisation. Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and fatty acid available for respiratory absorption. Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption However, as discussed above, hydrolysis of fatty acid esters with more than 3 ester bounds is considered to be slow (Mattson und Volpenheim, 1968, 1972a) and the possibility the test substance to be hydrolysed enzymatically to the respective metabolites and its relative absorption is considered to be low as well.
The available data on inhalation toxicity of structurally related substances (Fatty acids, C5-9, tetraesters with pentaerythritol; CAS# 67762-53-2 and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol, CAS# 85536-35-2) are also considered for assessment of inhalation absorption. Three acute inhalation toxicity studies conducted with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2, Mekitarin, 1990; Hoffman, 1999) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS 85536-35-2, Parr-Dobrzansk, 1994) in rats show no effects of systemic toxicity could be observed.
In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2), no toxicologically relevant effects were noted up to and including the highest dose level of 0.5 mg/mL in male and female rats. Therefore, respiratory absorption of Fatty acids, C8-10, tetraesters with pentaerythritol is considered to be not higher than absorption through the intestinal epithelium.
Overall, a systemic bioavailability of Fatty acids, C8-10, tetraesters with pentaerythritol in humans is considered likely after inhalation but not expected to be higher than following oral exposure.
Accumulation
Highly lipophilic substances in general tend 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 >10 implies that Fatty acids, C8-10, tetraesters with pentaerythritol may have the potential to accumulate in adipose tissue (ECHA, 2012).
However, as absorption of Fatty acids, C8-10, tetraesters with pentaerythritol is considered to be very low, the potential of bioaccumulation is very low as well.
Nevertheless, as further described in the section metabolism below, esters of pentaerythritol and fatty acids will undergo esterase-catalyzed hydrolysis, leading to the cleavage products pentaerythritol and the fatty acids
The log Pow of the first cleavage product pentaerythritol is < 0.3 and it is highly soluble in water (25 g/L) (OECD SIDS, 1998). Consequently, there is no potential for pentaerythritol to accumulate in adipose tissue. The other cleavage products, the fatty acids, 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 of the parent substance and cleavage products 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).
Furthermore, the concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption.
As discussed above absorption of Fatty acids, C8-10, tetraesters with pentaerythritol is considered very low based on its physicochemical characterisation as poor water solubility and high molecular weight.
Nevertheless, esters of pentaerythritol and fatty acids will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products pentaerythritol and the different fatty acids. Pentaerythritol, a water-soluble substance (log Pow < 0.3, 25 mg/L) with low molecular weight, will be distributed in aqueous fluids by diffusion through aqueous channels and pores. There is no protein binding and it is distributed poorly in fatty tissues (OECD SIDS, 1998).
The 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 possible cleavage products, pentaerythritol and fatty acids can be distributed in the organism.
Metabolism
On the basis of the properties of the test substance a very low absorption of Fatty acids, C8-10, tetraesters with pentaerythritol is predicted.
As discussed above, hydrolysis of esterified alcohol with more than 3 ester groups is assumed to be slow as discussed above. In in vivo studies in rats, a decrease in absorption was observed with increasing esterification. For example, for Pentaerythritol tetraoleate ester an absorption rate of 64% and 90% (25% and 10% of dietary fat) was observed respectively while the an absorption rate of 100% was observed for Glycerol trioleate when ingested at 100% of dietary fat (Mattson and Nolen, 1972). In addition it has been shown in-vitro that the hydrolysis rate of Pentaerythritol tetraoleate was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972a).
Esters of fatty acids are hydrolysed to the corresponding 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 which 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.
Thus, Fatty acids, C8-10, tetraesters with pentaerythritol are hydrolysed to the corresponding alcohol (pentaerythritol) and fatty acids by esterases, even though the rate of hydrolysis is assumed to be low.
The first cleavage products, fatty acids are stepwise degraded by beta-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. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required. The omega- and alpha-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987).
The second cleavage product pentaerythritol is absorbed rapidly but excreted unchanged. DiCarlo et al. 1965 reported that 10 mg/kg C14-labled PE orally administered to mice was absorbed and excreted rapidly from the gastrointestinal tract. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged PE in the urine and faeces after 4 hours already.
Excretion
On the basis of the low absorption data of the test substance one route of excretion for Fatty acids, C8-10, tetraesters with pentaerythritol is expected to be by biliary excretion via faeces.
However based on the hydrolysis described above, fatty acids and pentaerythritol as breakdown products will occur in the body. Potential cleavage products, the fatty acid components (C8, C10) will be metabolized for energy generation or stored as lipids in adipose tissue or used for further physiological properties e.g. incorporation into cell membranes (Lehninger, 1970; Stryer, 1996). Therefore, the fatty acid components are not expected to be excreted to a significant degree via the urine or faeces but excreted via exhaled air as CO2 or stored as described above.
The other cleavage product pentaerythritol is not metabolized but excreted unchanged via urine. 10 mg/kg C14-labled PE orally administered to mice was absorbed from the gastrointestinal tract rapidly and excreted via urine. Almost half of the administered dose left the gastrointestinal tract within 15 minutes and 68% of the dose appeared as unchanged PE in the urine and faeces after 4 hours (DiCarlo et al., 5. The amount found in faeces was assumed to be contamination from urine due to the setup of the metabolic cages. Additionally, Kutscher (1948) found 85-87% of unaltered PE in the urine of humans ingesting PE.
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