Registration Dossier

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 51 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 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 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 testsLikewiseall 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

former CAS 85186-86-3

Name: Fatty acids, C8-10 and C18-unsatd., diesters with neopentyl glycol.

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

C18:2

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
C69H132O8
C77H148O8

374.56 - 1201.99

32

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

33

25151-96-6

2,2-bis(hydroxymethyl)-1,3-propanediyl dioleate

C18:1

PE

Mono-Tri

C41H76O6
C59H108O7

665.04 – 929.48

34

67762-53-2

Fatty acids, C5-9 tetraesters with pentaerythritol

C5-9

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

C5, C7

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

C5-9

PE

Tetra

C25H44O8
C41H76O8

472.62 – 697.04

37

146289-36-3

Pentaerythritol ester of pentanoic acids and isononanoic acid

C5, C5iso, C9iso

PE

Tetra

C25H44O8
C41H76O8

472.62 – 697.04

38

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

39

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

40

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

41

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

42

68441-68-9

Decanoic acid, mixed esters with octanoic acid and pentaerythritol

C8-10

PE

Tetra

C37H68O8
C45H84O8

640.93 – 753.14

43

85586-24-9

Fatty acids, C8-10, tetraesters with pentaerythritol

C8-10

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

C8

C10

C12

C14

C16

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

C16-18

PE

Tetra

C69H132O8
C77H148O8

1089.7 -1201.99

46

19321-40-5

Pentaerytritol tetraoleate

C16:1 C18:1 C18:2

PE

Tetra

C69H124O8
C77H132O8
C77H140O8

1081.72 - 1193.93

47

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

48

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

49

68440-09-5

Fatty acids, lanolin, esters with pentaerythritol

C10-28

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

C5-9

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

C8-10 C8iso

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).

 

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (Formerly CAS No. 85005-89-6) 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropanewas 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, 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropaneis a clear organic liquid. It is poorly water soluble (< 0.92 mg/L, Brekelmans, 1997a) with a molecular weight of 849.40- 933.56 g/mol, a log Pow > 5.99 (Brekelmans, 1997b) and a vapour pressure of 0.00063 Pa at 20 °C (van Rijsbergen, 1997).

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 g/mol are favorable for oral absorption (ECHA, 2012). As the molecular weight of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is 849.40-933.56 g/mol and therefore, 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane as its molecular weight is >500 g/mol and log Pow above the given range of ‑0.4 to 5.6.

The log Pow > 5.99 of the substance suggests that Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is favourable for absorption 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).

In the gastrointestinal tract (GIT), 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 almost completely absorbed (Mattsson and Volpenheim, 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 a 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, probably the results of different rates of hydrolysis in the intestinal lumen (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. One acute oral toxicity study was available for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane. At a concentration of 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Busschers, 1997).

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) ofFatty acids, C5-10, esters with pentraerythritol (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 members of the polyol esters category which are structurally related to Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane 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.

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. Trimethylolpropane (TMP, parental polyol) as well as the fatty acids will be formed, even if according to the available literature hydrolysis is not assumed to be rapid for pentaerythriol- and dipentaerythritol-ester and in general for polyol esters with more than three ester groups (multiple linked polyol esters) due probably to steric hindrance. In-vitro the hydrolysis rate of Pentaerythritol tetraoleate when compared with the hydrolysis rate of the triglyceride Glycerol trioleate was very slow (Mattson and Volpenhein, 1972). Since it is assumed that esters of polyols (pentaerythritol, dipentaerythritol and trimethylolpropane) have the same metabolic fate, TMP polyol esters are expected to be hydrolysed slowly as well.

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 TMP, on the basis of its physical-chemical properties (molecular weight 134.2 g/mol, log Pow -0.47, water solubility >100 mg/L, OECD SIDS), will readily dissolve into the gastrointestinal fluids.

In summary the above discussed physical-chemical properties of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane. 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 favors dermal absorption, above 500g/mol the molecule may be too large (ECHA, 2012). As the molecular weight of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is 849.40- 933.56 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). Read-across performed with the substances Fatty acids, C16-18, triesters with trimethylolpropane (CAS # 91050-90-7) and Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS # 403507-18-6) show that the test substance is not considered as skin irritating in humans (Steiling, 1989 and Sanders, 2002). Therefore, an enhanced penetration of the substance due to local skin damage can be excluded.

Based on QSAR a dermal absorption value for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane of 1.14E-02 to 1.97E-02 mg/cm2/event (low) was calculated (Episuite 4.1, DERMWIN 2.01, 2013). Based on this value, the substance has a 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 849.40- 933.56 is less than 1 mg/L and log Pow is >10, dermal uptake is likely to be very low.

The available data on dermal toxicity on structural related substancesFatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol(CAS 11138-60-6 ) and Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are also considered for assessment of dermal absorption.

An acute dermal toxicity studies was available forFatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol(CAS 11138-60-6). At a concentration of up to 2000 mg/kg bw in rats no signs of systemic toxicity were seen (Blanset, 1997).

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 Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropaneF in humans is considered as very low.

Inhalation

Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropaneFhas a low vapour pressure of 0.00063 Pa at 20 °C thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane can be taken up by micellar solubilisation.

Esterases present in the lung lining fluid may also hydrolyse the substance, hence making the resulting alcohol and 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 three ester bounds is considered to be slow (Mattson und Volpenhein, 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 on the structurally related substances Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7) and Fatty acids C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) are considered for the assessment of the respiratory absorption.

In an acute inhalation toxicity read-across study conducted with Fatty acids, C5-10, esters with pentraerythritol (CAS 68424-31-7, Parr-Dobrzans, 1994) in rats bodyweight, bodyweight gain and lung weights for all treated animals were within normal limits and there were no gross pathological findings. In general, animals showed rapid recovery from effects seen (reversible and consistent clinical signs as hunched position, chromodacryorrhea, piloerection, stains around the nose and wet fur).

The medium lethal concentration in the rat is considered to be in excess of 5.1 mg/L. In the 90-day repeated dose toxicity study performed with the Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2, Dulbey, 1992), 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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropaneF is considered not to be higher than absorption through the intestinal epithelium.

Overall, a systemic bioavailability of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane 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 of estimated to be >10 implies that Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropaneFmay have the potential to accumulate in adipose tissue (ECHA, 2012).

However, as absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane 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 trimethylolpropane and fatty acids will undergo esterase-catalyzed hydrolysis, leading to the cleavage products respective alcohol and the fatty acids.

The log Pow of the first cleavage product trimethylolpropane is -0.47 and it is highly soluble in water (>100 g/L) (OECD SIDS, 2013). Consequently, there is no potential for trimethylolpropane 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 rate of absorption.

As discussed above absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is considered very low based on its physico-chemical characterisation as poor water solubility and high molecular weight.

Nevertheless, esters of trimethylolpropane and fatty acids will undergo chemical changes as a result of slow enzymatic hydrolysis, leading to the cleavage products trimethylolpropane and the different fatty acids.

Trimethylolpropane, a small, water-soluble substance 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, 2013).

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 cleavage products, trimethylolpropane and fatty acids can be distributed in the organism.

Metabolism

On the basis of the properties of the test substance characteristics a low absorption of Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is predicted.

The hydrolysis of esterified alcohol with more than three ester groups is assumed to be slow as discussed above. This is supported by in vivo studies in rats, in which a decrease in absorption was observed with increasing esterification. For example, for the polyol ester Pentaerythritol tetraoleate ester an absorption rate of 64% and 90% (25% and 10% of dietary fat) was observed while 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 another polyol ester (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, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane is probably hydrolysed to the corresponding alcohol (trimethylolpropane) and fatty acids by esterases.

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 other cleavage product trimethylolpropane due to its physico-chemical properties (low molecular weight, low log Pow, and solubility in water) is easily absorbed and can either remain unchanged or may further be metabolized or conjugated (e.g. glucuronides, sulfates, etc.) to polar products that are excreted in the urine (OECD SIDS, 2013).

Excretion

On the basis of the low absorption data the main route of excretion for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (parental substance) is expected to be excreted via faeces.

Assuming that hydrolysis for Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (parental substance) takes place fatty acids and trimethylolpropane as breakdown products will occur in the body. 

Potential cleavage products, the fatty acid components (C16-18 and C18-unsatd.) 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 trimethylolpropane may either further be metabolized or conjugated to polar products (e.g. glucuronides, sulfates, etc.) or excreted unchanged via urine (OECD SIDS, 2013).

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