Heptanoic acid, mixed esters with pentaerythritol and valeric acid

Endpoint summary

Additional information

The polyol esters category comprises aliphatic esters of polyfunctional alcohols containing two to six reactive hydroxyl groups and one to four 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 esters with 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 tetra-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 alcohol (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 Likewise 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 esterification	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 (b)	1,3-Propoanediol, 2,2-dimethyl-, C5-9 carboxylates	C5-9	NPG	Di	C15H28O4 C23H44O4	272.38 – 384.59
4	70693-32-2	Decanoic acid, mixed esters with neopentyl glycol and octanoic acid	C8-10	NPG	Di	C21H40O45 C25H48O4	356.54 - 412.65
5	former CAS 85186-86-3	Fatty acids, C8-10 (even numbered) and C16 and C18-unsatd., esters with Neopentylglycol	C8-10 C16-18 C18uns.	NPG	Di	C21H40O4 C25H48O4 C37H72O4 C41H80O4 C41H76O4	356.54 – 637.07
6	85186-86-3	Fatty acids, C8-18 and C18-unsatd., esters with neopentyl glycol	C8-18 C18:1	NPG	Di	C21H40O4 C29H56O4 C41H76O4	356.54 - 633.04
7	85186-95-4	Fatty acids, C12-16, esters with neopentyl glycol	C12-16	NPG	Di	C29H56O4 C37H72O4	468.75 - 580.97
8	91031-85-5	Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters	C12-14	NPG	Di	C29H56O4 C33H64O4	468.75 - 524.86
9	85116-81-0	Fatty acids C14-18 and C16-18 unsatd, esters with neopentyl glycol	C16, C18:1	NPG	Di	C37H72O4 C41H76O4	580.98 - 637.07
10	91031-27-5	Fatty acids, C6-18, 2,2-dimethyl-1,3-propanediyl esters	C6-18	NPG	Di	C37H72O4 C41H76O4	580.98 - 637.07
11	42222-50-4	2,2-dimethyl-1,3-propanediyl dioleate	C16-18, C18uns	NPG	Di	C37H72O4 C41H76O4	580.98 - 633.06
12	67989-24-6	9-Octadecenoic acid (Z) -, ester with 2,2-dimethyl-1,3-propanediol	C18:1	NPG	Di	C41H76O4	633.04
13	85005-25-0	Neopentyl Glycol Diisostearate (Fatty acids, C14-18 and C18-unsatd., branched and linear, esters with neopentyl glycol)	C18iso	NPG	Di	C33H64O4 C41H80O4 C41H76O4	524.86 - 637.07
14	78-16-0	2-ethyl-2-[[(1-oxoheptyl) oxy]methyl]propane-1,3-diyl bisheptanoate	C7	TMP	Tri	C27H50O6	470.68
15	91050-88-3	Fatty acids, C6-18, triesters with trimethylolpropane	C6-18	TMP	Tri	C24H44O6; C30H56O6; C36H68O6; C42H80O6; C48H82O6; C54H104O6	428.60 – 849.40
16	97281-24-8	Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane	C8-10	NPG and TMP	Di/Tri	C21H40O4 C25H48O4 C30H56O6 C36H68O6	356.54 - 596.94
17	189120-64-7 (c)	Fatty acids, C7-8, triesters with trimethylolpropane	C7-8	TMP	Tri	C27H50O6 C30H56O6	470.68 – 512.78
18	11138-60-6 (d)	Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol	C8-10	TMP	Tri	C30H56O6 C36H68O6	512.78 - 596.94
19	91050-89-4	Fatty acids, C8-10, triesters with trimethylolpropane	C8-C10	TMP	Tri	C30H56O6 C36H68O6	512.78 - 596.94
20	85566-29-6	Fatty acids, coco, triester with trimethylolpropane, reaction product of coconutoil fatty acids and trimethylolpropane	C12 C14 C16	TMP	Tri	C42 H80 O6 C48 H92 O6 C54 H104 O6	681.08 - 849.4
21	(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 C18:1	TMP	Tri	C30H56O6 C60H110O6 C60H110O6	512.76 - 933.56
22	403507-18-6	Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane	C16-18, C18uns	TMP	Di / Tri	C38H43O5 C42H45O5 C42H47O5 C54H104O6 C60H110O6 C60H116O6	579.76 - 933.56
23	68002-79-9	Fatty acids, C16-18 (even numbered) and C16-18 unsatd. (even numbered), triesters with trimethylolpropane	C16-18, C18:1	TMP	Tri	C54H104O6 C60H110O6 C60H116O6	849.40 – 933.56
24	(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	C54H104O6 C60H116O6 C60H116O6	849.40 – 933.56
25	91050-90-7	Fatty acids, C16-18, triesters with trimethylolpropane	C16-18	TMP	Tri	C54H104O6 C60H116O6	849.40 - 933.56
26	68002-78-8	Fatty acids, C16-18 and C18 unsatd., triesters with trimethylolpropane	C16-18, C18uns	TMP	Tri	C54H104O6 C60H110O6 C60H116O6	849.40 - 933.56
27	(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	Tri	C54H104O6 C60H110O6 C60H116O6	361 - 932
28	85186-92-1	Fatty acids, C16, C18 and C18-unsatd., mixed esters with neopentyl glycol and trimethylolpropane	C16 C18 C18:1	TMP + NPG	Di/Tri	C37H68O4 C41H76O4 C54H104O6 C60H110O6 C60H116O6	577 - 927.5
29	68541-50-4	2-ethyl-2-(1-oxoisooctadecyl) oxy) methyl) -1,3-propanediyl bis (isoocta decanoate)	C18iso	TMP	Tri	C60H116O6	933.56
30	15834-04-5	2,2-bis[[(1-oxopentyl) oxy]methyl] propane-1,3-diyl divalerate	C5	PE	Tetra	C25H44O8	472.62
31	85116-93-4	Fatty acids, C16-18 (even numbered), esters with pentaerythritol	C16-18	PE	Mono-Tetra	C21H42O5
32	85711-45-1	Fatty acids, C16-18 and C18-unsatd., esters with pentaerythritol	C69H132O8	PE	Mono-Tetra	C21H42O5 C23H44O5 C23H46O5 C69H132O8 C77H148O8 C77H140O8	374.56 - 1193.93
33	25151-96-6	2,2-bis(hydroxymethyl) -1,3-propanediyl dioleate	C77H148O8	PE	Mono-Tri	C41H76O6 C59H108O7	665.04 - 929.48
34	67762-53-2	Fatty acids, C5-9 tetraesters with pentaerythritol	C16-18, C18:1	PE	Tetra	C25H44O8 C41H76O8	472.62 - 697.04
35	(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	C23H44O5	PE	Tetra	C27H48O8 C29H52O8 C31H56O8	472.62 - 584.84
36	(Formerly 68424-30-6-)	Tetraesters from esterification of pentaerythritol with pentanoic, heptanoic and isononanoic acids	C23H46O5	PE	Tetra	C25H44O8 C41H76O8	472.62 - 697.04
37	146289-36-3	Pentaerythritol ester of pentanoic acids and isononanoic acid	C69H132O8	PE	Tetra	C25H44O8 C41H76O8	472.62 - 697.04
38	68424-31-7	Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids	C77H148O8	PE	Tetra	C25H44O8 C45H84O8	472.62 - 753.14
39	68424-31-7	Tetra-esterification products of C5, C7, C8, C10 fatty acids with pentraerythritol	C77H140O8	PE	Tetra	C25H44O8 C45H84O8	472.62 - 753.3
40	68424-31-7	Fatty acids, C7, C8, C10 and 2-ethylhexanoic acid, tetraesters with pentaerythritol	C18:1	PE	Tetra	C25H44O8 C45H84O8	472.62 - 753.3
41	71010-76-9	Decanoic acid, mixed esters with heptanoic acid, octanoic acid, pentaerythritol and valeric acid	C59H108O7	PE	Tetra	C25H44O8 C33H60O8 C41H76O8	472.62 - 753.14
42	68441-68-9	Decanoic acid, mixed esters with octanoic acid and pentaerythritol	C5-9	PE	Tetra	C37H68O8 C45H84O8	640.93 - 753.14
43	85586-24-9	Fatty acids, C8-10, tetraesters with pentaerythritol	C41H76O8	PE	Tetra	C37H68O8 C45H84O8	640.93 - 753.14
44	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	C5, C7	PE	Tetra	C37H68O8 C43H80O8 C45H84O8 C47H88O8 C49H92O8 C51H96O8 C53H100O8 C55H104O8 C57H106O8 C61H116O8 C69H132O8	640.95 - 1089.80
45	91050-82-7	Fatty acids, C16-18, tetraesters with pentaerythritol	C29H52O8	PE	Tetra	C69H132O8 C77H148O8	1089.70 -1201.99
46	19321-40-5	Pentaerytritol tetraoleate	C31H56O8	PE	Tetra	C69H124O8 C77H132O8 C77H140O8	1081.72 - 1193.93
47	68604-44-4	Fatty acids, C16-18 and C18-unsatd., tetraesters with pentaerythritol		PE	Tetra	C69H132O8 C77H104O8 C77C148O8	1089.78 - 1201.99
48	62125-22-8	2,2-bis[[(1-oxoisooctadecyl) oxy]methyl]-1,3-propanediyl bis(isooctadecanoate)	C5-9	PE	Tetra	C61H116O8 C77H148O8 C93H180O8	977.57 - 1426.42
49	68440-09-5	Fatty acids, lanolin, esters with pentaerythritol	C41H76O8	PE	Tetra	C45H84O8 C49H92O8 C69H132O12 C77H148O8 C121H236O C117H228O8	753.14 - 1819.16
50	85536-35-2	Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol	C5, C5iso, C9iso	PE & DiPE	Tetra	C25H44O8 C41H76O8 C40H70O13 C60H110O13	472.62 - 697.04; 758.98 - 1039.51
51	189200-42-8	Fatty acids, C8-10 mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol	C41H76O8	PE & DiPE	Tetra	C37H68O8 C45H84O8 C41H76O8 C58H106O13 C70H130O13 C64H118O13	640.93 - 1179.77

a) Category members subjected 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 Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 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, trimethylolpropane, 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 (calculated) 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).

As explained above the polyol esters category does not need to be grouped with respect to their environmental effects. All poylol esters have a similar profile having the same environmental fate properties; low water solubility, low mobility in soil, ready biodegradability, low persistence and low bioaccumulation potential. Additionally all polyol esters do not show toxicological effects up to the water solubility limit. Nevertheless for an easier overview the category was organized into three groups, which are characterized according to their major alcohol moiety (NPG, TMP or PE).