2,2-dimethyl-1,3-propanediyl dioctanoate

Endpoint summary

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 (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	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
6	85186-95-4	Fatty acids, C12-16, esters with neopentyl glycol	C12-16	NPG	Di	C29H56O4 C37H72O4	468.75 - 580.97
7	91031-85-5	Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters	C12-14	NPG	Di	C29H56O4 C33H64O4	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 C41H76O4	580.98 - 637.07
9	42222-50-4	2,2-dimethyl-1,3-propanediyl dioleate	C16-18, C18uns	NPG	Di	C37H72O4 C41H76O4	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 C41H80O4 C41H76O4	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 C25H48O4 C30H56O6 C36H68O6	356.54 - 596.94
15	189120-64-7 (c)	Fatty acids, C7-8, triesters with trimethylolpropane	C7-8	TMP	Tri	C27H50O6 C30H56O6	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 C36H68O6	512.78 - 596.94
17	91050-89-4	Fatty acids, C8-10, triesters with trimethylolpropane	C8-C10	TMP	Tri	C30H56O6 C36H68O6	512.78 - 596.94
18	85566-29-6	Fatty acids, coco, triester with trimethylolpropane	C12 C14 C16	TMP	Tri	C42 H80 O6 C48 H92 O6 C54 H104 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 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 C42H45O5 C42H47O5 C54H104O6 C60H110O6 C60H116O6	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 C60H110O6 C60H116O6	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 C60H116O6 C60H116O6	347 – 933.6
23	91050-90-7	Fatty acids, C16-18, triesters with trimethylolpropane	C16-18	TMP	Tri	C54H104O6 C60H116O6	849.40 - 933.56
24	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
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 C60H110O6 C60H116O6	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 C41H76O4 C60H116O6	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 C69H132O8 C77H148O8	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 C23H44O5 C23H46O5 C69H132O8 C77H148O8 C77H140O8	374.56 – 1193.93
31	25151-96-6	2,2-bis(hydroxymethyl)-1,3-propanediyl dioleate	C18:1	PE	Mono-Tri	C41H76O6 C59H108O7	665.04 – 929.48
32	67762-53-2	Fatty acids, C5-9 tetraesters with pentaerythritol	C5-9	PE	Tetra	C25H44O8 C41H76O8	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 C29H52O8 C31H56O8	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 C41H76O8	472.62 – 697.04
35	146289-36-3	Pentaerythritol ester of pentanoic acids and isononanoic acid	C5, C5iso, C9iso	PE	Tetra	C25H44O8 C41H76O8	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 C45H84O8	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 C45H84O8	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 C45H84O8	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 C33H60O8 C41H76O8	472.62 – 753.14
40	68441-68-9	Decanoic acid, mixed esters with octanoic acid and pentaerythritol	C8-10	PE	Tetra	C37H68O8 C45H84O8	640.93 – 753.14
41	85586-24-9	Fatty acids, C8-10, tetraesters with pentaerythritol	C8-10	PE	Tetra	C37H68O8 C45H84O8	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 C43H80O8 C45H84O8 C47H88O8 C49H92O8 C51H96O8 C53H100O8 C55H104O8 C57H106O8	640.95 - 1202.03
43	91050-82-7	Fatty acids, C16-18, tetraesters with pentaerythritol	C16-18	PE	Tetra	C69H132O8 C77H148O8	1089.7 -1201.99
44	19321-40-5	Pentaerytritol tetraoleate	C16:1 C18:1 C18:2	PE	Tetra	C69H124O8 C77H132O8 C77H140O8	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 C77H104O8 C77C148O8	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 C77H148O8 C93H180O8	977.57 – 1426.42
47	68440-09-5	Fatty acids, lanolin, esters with pentaerythritol	C10-28	PE	Tetra	C45H84O8 C49H92O8 C69H132O12 C77H148O8 C121H236O C117H228O8	753.14 - 1819.16
48	85536-35-2	Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol	C5-9	PE & DiPE	Tetra	C25H44O8 C41H76O8 C40H70O13 C60H110O13	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 C45H84O8 C41H76O8 C58H106O13 C70H130O13 C64H118O13	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 experimental studies available in which the toxicokinetic behaviour of 2,2-dimethyl-1,3-propanediyl dioctanoate (CAS 31335-74-7) 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), an assessment of the toxicokinetic behaviour of the substance 2,2-dimethyl-1,3-propanediyl dioctanoate was conducted based 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, 2008) and taking into account futher available information on the polyol ester category from which data was used for read-across to cover data gaps.

The substance 2,2-dimethyl-1,3-propanediyl dioctanoate is a diester of octanoic acid and 2,2-dimethyl-1,3-propanediol (neopentylglycol) which meets the definition of a mono-constituent substance based on the analytical characterization. The substance is a clear organic liquid. It is poorly water soluble (< 0.05 mg/L; Frischmann, 2012) with a molecular weight of 356.54 g/mol, a log Pow of 7.66 (Blum, 2011) and a vapour pressure < 666.7 Pa at 20 °C (Ousby, 1995).

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 Kow) value and the water solubility. The log Kow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008).

Oral

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 2,2-dimethyl-1,3-propanediyl dioctanoate is 356.54 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), Ghose et al. (1999)) is applied to 2,2-dimethyl-1,3-propanediyl dioctanoate, 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 of 7.66 suggest that 2,2-dimethyl-1,3-propanediyl dioctanoate 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).

In the gastrointestinal (GI) tract, metabolism prior to absorption via enzymes of the microflora may occur. In fact, after oral ingestion, fatty acid esters with glycerol (glycerides) are rapidly hydrolised 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 acids/ alcohol combinations 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). Experimental data with Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5), which is structurally similar to 2,2-dimethyl-1,3-propanediyl dioctanoate, showed, that pancreatic digestion results in a degradation of the ester of almost 90% within 4 hours (Oßberger, 2012). On the basis of the literature available, it can assumed that 2,2-dimethyl-1,3-propanediyl dioctanoate, being a diester of medium chain fatty acids and alcohol moiety, undergoes stepwise chemical changes in the gastro-intestinal fluids as a result of enzymatic hydrolysis after oral ingestion. The physico-chemical characteristics (e.g. physical form, water solubility, molecular weight, log Pow, vapour pressure, etc.) of the resulting cleavage products, fatty acids and the alcohol, 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. The highly lipophilic fatty acids are absorbed by micellar solubilisation (Ramirez et al., 2001), whereas the alcohol is readily dissolved into the gastrointestinal fluids and absorbed from the gastrointestinal tract because of its physical-chemical parameters (MW = 104.15 g/mol), log Pow= 0.12 at 25 °C), moderate water solubility (OECD SIDS, 2013).

The available data on oral acute and repeated dose toxicity of the test substance and the structurally related analogue substances (Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol, CAS 68855-18-5; Fatty acids, C7-8, triesters with trimethylpropane , CAS 189120-64-7; Fatty acids, C5-10 , esters with pentaerythritol, CAS 68424-31-7; Pentaerythritol ester of pentanoic acids and isononanoic acid , CAS 146289-36-3; Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane, CAS 403507-18-6) are also considered for assessment of oral absorption. An acute oral study conducted with the test substance and an acute oral toxicity study on Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5 )showed LD50 values > 2000 mg/kg bw and no systemic effects (Robinson, 1993 and Doyle, 1996). In the 28-day repeated dose toxicity study performed with the Fatty acids, C7-8, triesters with trimethylpropane (CAS 189120-64-7), no toxicologically relevant effects were noted up to and including the highest dose level of 1000 mg/kg bw/day in male and female rats. An increased amount of hyaline droplets (the main constituent of which is alpha-2µ-globulin) in the proximal cortical tubular epithelium was confirmed microscopically in the cytoplasm of the renal cortical tubular epithelial cells in male rats treated with 300 and 1000 mg/kg bw/day, respectively. However this phenomenon is widely accepted to be specific to the male rat and as such is considered to have no relevance to man (Trimmer, 2000). In a further study, repeated dietary administration (28-day) of Fatty acids, C5-10 , esters with pentaerythritol (CAS 68424-31-7) to rats, did not induce any evidence of overt toxicity up to and including the high dose level of 1450 mg/kg bw/day for male rats and 1613 mg/kg bw/day for female rats(Brammer, 1993). 

Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) showed no systemic effects up to the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL ≥1000 mg/kg bw/day; Müller, 1998).

A further 90-day oral feeding toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) displayed no toxicologically relevant effects and therefore the NOAEL was set as > 1000 mg/kg bw/day.

The above described studies show that different category members of the polyol esters category which are structurally related to 2,2-dimethyl-1,3-propanediyl dioctanoate revealed a low potential for toxicity after acute and repeated exposure, although no assumptions can be made regarding the absorption potential based on the experimental data. 

Overall, a systemic bioavailability of 2,2-dimethyl-1,3-propanediyl dioctanoate and/or the respective cleavage products in humans is considered likely after oral uptake of the substance.

Dermal

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 2,2-dimethyl-1,3-propanediyl dioctanoate is 356.54 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, 2008). As 2,2-dimethyl-1,3-propanediyl dioctanoate 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 0.00003 mg/cm²/event (very low) was predicted for 2,2-dimethyl-1,3-propanediyl dioctanoate (Danish EPA, 2010). 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, 2012). As the water solubility of 2,2-dimethyl-1,3-propanediyl dioctanoate is less than 1 mg/L, dermal uptake is likely to be low.

The available data on dermal acute and repeated dose toxicity of the structurally related substances within the polyol esters category, 2-dimethyl-1,3-propanediyl dioleate (CAS # 42222-50-4), and C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) are also considered for assessment of dermal absorption. 

In an acute dermal toxicity study conducted with the substance 2-dimethyl-1,3-propanediyl dioleate (CAS # 42222-50-4) showed LD50 > 2000 mg/kg bw and no systemic effects (Haferkorn, 2012). In the 90-day repeated dose toxicity study performed with the 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 molecular weight (>100), the high log Pow value and the fact that the substance is not irritating to skin implies that dermal uptake of 2,2-dimethyl-1,3-propanediyl dioctanoate in humans is considered as very low. Inhalation

2,2-dimethyl-1,3-propanediyl dioctanoate has a vapour pressure of < 666.7 Pa (<5 mmHg) at 20°C. QSAR calculations for the substance revealed a lower value of 2.89E-005 Pa at 20 °C (SPARC (v4.6)). Lipophilic compounds with a log Kow > 4, that are poorly soluble in water (1 mg/L or less), like 2,2-dimethyl-1,3-propanediyl dioctanoate, can be taken up by micellar solubilisation.

An acute inhalation toxicity study was performed with the structural related substance Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5). Rats were exposed nose-only to > 5.22 mg/L of an aerosol for 4 hours (Griffith, 2012). No mortality occurred and no toxicologically relevant effects were observed at the end of the observation period.

The available data on inhalation repeated dose toxicity the structurally related substance, C5-9, tetraesters with pentaerythritol (CAS# 67762-53-2) is also considered for assessment of inhalative absorption. In the 90-day repeated dose toxicity study performed with the 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.

Overall, taken the physico-chemical parameters and the (acute and repeated) inhalation toxicity data into consideration absorption via inhalation is assumed to be likely and as high as via the oral route in a worst case approach.

Accumulation

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. Due to the high log Pow of 7.66, 2,2-dimethyl-1,3-propanediyl dioctanoate may have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as further described in the section metabolism below, esters of alcohols and fatty acids undergo, depending of the fatty acid chain length, esterase-catalysed hydrolysis, leading to the cleavage products fatty acids and alcohol moiety.

Neopentyl glycol is the first cleavage product of 2,2-dimethyl-1,3-propanediyl dioctanoate. The second cleavage product, octanoic acid, can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, octanoic acid is 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, 2008).

2,2-dimethyl-1,3-propanediyl dioctanoate undergoes chemical changes as a result of enzymatic hydrolysis, leading to the cleavage products neopentyl glycol and octanoic acid. Neopentyl glycol, a rather small will be distributed in aqueous compartments of the organism and may also be taken up by different tissues through aqueous channels and pores. Octanoic acid is also distributed in the organism and can be taken up by different tissues. It 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, neopentyl glycol and octanoic tanoic acid, will be distributed in the organism.

Metabolism

Esters of fatty acids are hydrolysed to the corresponding alcohol and fatty acids 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.

The first cleavage product, neopentyl glycol, undergoes to conjugation with glucuronic acid and be excreted in the urine (Gessner, 1960.)

The second cleavage product, octanoic acid, is stepwise is metabolized by beta-oxidation. Even numbered fatty acids are degraded via beta-oxidation to carbon dioxide and acetyl-CoA, with release of biochemical energy (Stryer, 1996).

The potential metabolites following enzymatic metabolism of 2,2-dimethyl-1,3-propanediyl dioctanoate were predicted using the OECD QSAR ToolBox 2.3.0 (OECD, 2011). QSAR calculations of the substance 2,2-dimethyl-1,3-propanediyl dioctanoate predicted potential metabolites using liver, skin and microbial simulators. 22 liver, 2 skin, and 90 microbial metabolites were predicted

Excretion

No data on excretion of 2,2-dimethyl-1,3-propanediyl dioctanoate is available. Based on the data for the hydrolysis described above, fatty acids and neopentyl glycol as breakdown products will occur in the body to a high extent. Potential cleavage products, the fatty acid components will be metabolized for energy generation and afterwards mainly excreted by expired air as CO2,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 aboveWith regard to the cleavage products, the main route for elimination of the alcohol is renal excretion via the urine (Gessner, 1960).

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.