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 Glycerides category covers aliphatic (fatty) acid esters of glycerol. The category contains both well-defined and UVCB substances with aliphatic acid carbon chain lengths of C2 (acetate) and C7-C22, which are mostly linear saturated and even numbered. Some of the substances in the category contain unsaturated fatty acids (e.g. oleic acid in 2,3-dihydroxypropyl oleate, CAS 111-03-5 or general fatty acids C16-22 (even) unsaturated in Glycerides, C14-18 and C16-22-unsatd., mono- and di-, CAS 91744-43-7). Some category members contain branched fatty acids. Branching is mostly methyl groups (e.g. isooctadecanoic acid, monoester with glycerol, CAS 66085-00-5 or 1,2,3-propanetriyl triisooctadecanoate, CAS 26942-95-0). In one category member the branching cannot be precisely located (Glycerides, C16-18 and C18-unsatd., branched and linear mono-, di- and tri, ELINCS 460-300-6). Hydroxylated fatty acids are present in three substances (Castor oil, CAS 8001-79-4; castor oil hydrogenated, CAS 8001-78-3 and 2,3-dihydroxypropyl 12-hydroxyoctadecanoate, CAS 6284-43-1). Hydroxylation occurs on C12 of stearic acid in all these substances. Acetylated chains are present in the last part of the category, comprising fatty acids from C8 to C18 (even) and also C18 unsaturated, additionally a C18 acetylated fatty acid is present with the acetic acid located in C12 position (e.g. Glycerides, castor oil mono-, hydrogenated acetates / 12-acetoxy-octadecanoic acid, 2,3-diacetoxy, CAS 736150-63-3). All glycerides build mono-, di- and tri-esters in variable proportions.

Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. glycerol) with an organic acid (e.g. acetic, stearic or oleic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by the transfer of a proton from the acid catalyst to the acid to form an alkyloxonium ion. The carboxylic acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to the carbonyl carbon of the acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al., 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Mono-, di- and tri-esters are the final products of esterification with glycerol.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby substances may be considered as a category provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity, the substances listed below are allocated to the category of Glycerides.

Glycerides category members include

CAS

EC name

Molecular weight (range in case of UVCBs)

Fatty acids chain length

Degree of esterification

Molecular formula

26402-26-6 (b)

Octanoic acid, monoester with glycerol

218.29

C8

Mono

C11H22O4

142-18-7 (a)

2,3-dihydroxypropyl laurate

274.40

C12

Mono

C15H30O4

25496-72-4

Oleic acid, monoester with glycerol

356.54

C18:1

Mono

C21H40O4

111-03-5

2,3-dihydroxypropyl oleate

356.54

C18:1

Mono

C21H40O4

66085-00-5

Isooctadecanoic acid, monoester with glycerol

358.55

C18iso

Mono

C21H42O4

6284-43-1

2,3-dihydroxypropyl 12-hydroxyoctadecanoate

374.56

C18OH

Mono

C21H42O5

620-67-7

Propane-1,2,3-triyl trisheptanoate

428.60

C7

Tri

C24H44O6

538-23-8

Glycerol trioctanoate

470.68

C8

Tri

C27H50O6

538-24-9

Glycerol trilaurate

639.00

C12

Tri

C39H74O6

122-32-7

1,2,3-propanetriyl trioleate

885.43

C18:1

Tri

C57H104O6

555-43-1

Glycerol tristearate

891.48

C18

Tri

C57H110O6

26942-95-0

1,2,3-propanetriyl triisooctadecanoate

891.48

C18iso

Tri

C57H110O6

91052-47-0

Glycerides, C16-18 mono-

330.51 - 358.56

C16, C18

Mono

C19H38O4; C21H42O4

91744-09-1

Glycerides, C16-18 and C18-unsatd. mono-

330.51 - 358.56

C16, C18; C18uns.

Mono

C19H38O4; C21H42O4; C21H40O4

85536-07-8

Glycerides, C8-10 mono- and di-

218.29 - 400.60

C8, C10

Mono and di

C11H22O4; C13H26O4; C19H36O5; C23H44O5

91052-49-2

Glycerides, C12-18 mono- and di-

274.40 - 625.04

C12, C14, C16, C18

Mono and di

C15H30O4; C21H42O4; C27H52O5; C39H76O5

67701-33-1

Glycerides, C14-18 mono- and di-

302.45 - 625.02

C14, C16, C18

Mono and di

C17H34O4; C21H42O4; C31H60O5; C39H76O5

67784-87-6

Glycerides, palm-oil mono- and di-, hydrogenated

302.45 - 625.02

C14, C16, C18

Mono and di

C17H34O4; C21H42O4; C31H60O5; C39H76O5

91845-19-1

Glycerides, C16-18 and C18-hydroxy mono- and di-

330.51 - 657.02

C16, C18 C18OH

Mono and di

C19H38O4; C21H42O4; C35H68O5; C39H76O5; C21H42O5; C39H76O7

97358-80-0

Isooctadecanoic acid, mono- and diesters with glycerol

358.57 - 625.02

C18iso

Mono and di

C21H42O4; C39H76O5

91744-13-7

Glycerides, C14-18 and C16-22-unsatd. mono- and di-

302.45 - 733.20

C14, C16, C18, C16, C18 and C22uns.

Mono and di

C17H34O4; C21H42O4; C19H36O4; C25H48O4; C31H60O5; C39H76O5; C35H64O5; C47H88O5

31566-31-1

stearic acid, monoester with glycerol

330.51 - 325.03

C16, C18

Mono and di

C19H38O4; C21H42O4; C35H68O5, C39H76O5

85251-77-0

Glycerides, C16-18 mono- and di-

330.51 - 625.03

C16, C18

Mono and di

C19H38O4; C21H42O4; C35H68O5; C39H76O5

91744-32-0

Glycerides, C8-10 mono-, di- and tri-

218.29 - 554.84

C8, C10

Mono, di and tri

C11H22O4; C13H26O4; C19H36O5; C23H44O5; C27H50O6; C33H62O6

91052-28-7

Glycerides, C14-18 and C16-18-unsatd. mono-, di- and tri-

302.46 - 885.46

C14, C16, C18, C16:1, C18:1, C18:2, C18:3

Mono, di and tri

C17H34O4; C21H42O4; C19H36O4; C21H40O4; C31H60O5; C39H76O5; C35H64O5; C39H72O5; C45H86O6; C57H110O6; C51H92O6; C57H104O6

91052-54-9

Glycerides, C16-18 mono-, di- and tri-

330.50 - 891.48

C16, C18

Mono, di and tri

C19H38O4; C21H42O4; C35H68O5; C39H76O5; C51H98O6; C57H110O6

91744-20-6

Glycerides, C16-18 and C18-unsatd. mono-, di and tri-

330.51 - 891.50

C16, C18, C18uns.

Mono, di and tri

C19H38O4; C35H68O5; C51H98O6; C21H40O4; C39H72O5; C57H104O6

no CAS

ELINCS 460-300-6: Glycerides, C16-C18 and C18-unsaturated, branched and linear mono-, di- and tri-

330.51 - 891.50

C16, C18, C18uns., branched and linear

Mono, di and tri

C19H38O4; C35H68O5; C51H98O6; C21H40O4; C39H72O5; C57H104O6

97722-02-6

Glycerides, tall-oil mono-, di-, and tri-

356.54 - 885.43

C16, C18, C20,C18uns.

Mono, di and tri

C21H40O4; C39H72O5; C57H104O6

77538-19-3

Docosanoic acid, ester with 1,2,3-propanetriol

414.66 - 1059.80

C22

Mono, di and tri

C25H50O4; C47H92O5; C69H134O6

91744-28-4

Glycerides, C12-18 di- and tri-

456.70 - 891.50

C12, C14, C16, C18

Di and tri

C27H52O5; C39H76O5; C39H74O6; C57H110O6

68606-18-8

Glycerides, mixed coco, decanoyl and octanoyl

470.69 - 807.32

C8, C10, C12, C14, C16

Di and tri

C27H50O6; C33H62O6; C39H74O6; C45H86O6; C51H98O6

65381-09-1

Decanoic acid, ester with 1,2,3-propanetriol octanoate

470.69 - 554.85

C8, C10

Tri

C27H50O6; C33H62O6

73398-61-5

Glycerides, mixed decanoyl and octanoyl

470.69 - 554.85

C8, C10

Tri

C27H50O6; C33H62O6

85536-06-7

Glycerides, C8-18

470.68 - 891.48

C8, C10, C12, C14, C16, C18

Tri

C27H50O6; C57H110O6

67701-26-2

Glycerides, C12-18

639.01 - 891.48

C12, C14, C16, C18

Tri

C39H74O6; C57H110O6

67701-30-8

Glycerides, C16-18 and C18-unsatd.

807.32 - 891.48

C16, C18; C18uns.

Tri

C21H40O4; C39H72O5; C57H104O6

8001-79-4

Castor oil

933.43

C18:1(OH)

Tri

C57H104O9

8001-78-3

Castor oil, hydrogenated

939.48

C18OH

Tri

C57H110O9

97593-30-1

Glycerides, C8-21 and C8-21-unsatd. mono- and di-, acetates

330.42 - 442.63

C2; C10

Tri (FA mono, diacetate)

C17H30O6; C25H46O6

97593-30-1

Glycerides, C8-21 and C8-21-unsatd. mono- and di-, acetates

358.47 - 498.74

C2; C12

Tri (FA mono, diacetate)

C19H34O6; C29H54O6

93572-32-8

Glycerides, palm-oil mono-, hydrogenated, acetates

372.54 - 400.59

C2; C16

Tri (FA mono, diacetate)

C21H40O5; C23H44O5

91052-13-0

Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates

302.36 - 442.63

C2; C8, C10, C12, C14, C16, C18, C18uns.

Mono, di and tri

C15H26O6; C19H34O6; C21H38O6; C25H46O6

736150-63-3

Glycerides, castor-oil-mono, hydrogenated, acetates (main component: 12-acetoxy-octadecanoic acid (2,3-diacetoxy)propyl ester [CAS 330198-91-9])

500.67

C2; C18Ac

Tri (FA mono, diacetate)

C27H48O8

no CAS (c, d)

Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)

-

C2-C18 (even numbered), C18uns.

Tri

-

no CAS (c, d)

mixture of mono-, di-, and triglycerides of lauric acid

274.40 - 639.00

C12

Mono, di and tri

C15H30O4; C27H52O5; C39H74O6

no CAS (c, d)

Modified triglyceride. Main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol

833.36 - 859.39

C16, C18, C18uns.

Tri

C53H100O6; C55H102O6

56-81-5 (c)

Glycerol

92.09

--

--

C3H8O3

111-14-8 (c)

Heptanoic acid

130.18

C7

--

C7H14O2

112-85-6 (c)

Docosanoic acid

340.58

C22

--

C22H44O2

(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) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco )toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

(d) Assessment of toxicological properties is conducted also taking into account available data on mixtures of synthetic and/or naturally occurring glycerides (e.g. vegetable oils), which cannot be identified by a (single) CAS/EC number. The test materials short-, medium- and long-chain triglycerides (SCT, MCT, LCT) and their combinations (e.g. MLCT, SALATRIM – a SLCT) comprise triesters of glycerol with fatty acid chain lengths of C2 and C4 (short-chain), C8 and C10 (medium-chain) and C18 saturated/unsaturated (long-chain). The substance “mixture of mono-, di-, and triglycerides of lauric acid” comprises mono-, di and triesters of glycerol with dodecanoic acid (C12). The substance “Modified triglyceride” contains main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol, comprising triesters of glycerol with hexadecanoic (C16) and (9Z)-Octadec-9-enoic acid (C18:1). Available data on identity and composition of the individual test material for a given study is provided in the technical dossier.

 

Grouping of substances into this category is based on:

(1) common functional groups: all members of the Glycerides category are esters of a tri-functional alcohol (glycerol) with one or more carboxylic (fatty) acid(s) chain(s). The alcohol moiety (glycerol) is common to all category members. The fatty acid moiety comprises carbon chain lengths of C2 (acetate) and from C7-C22 (uneven/even-numbered) and includes mainly linear saturated alkyl chains, but also unsaturated, branched, hydroxylated and acetylated chains bound to the alcohol, resulting in mono-, di-, and tri-esters; and

(2) common precursors and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals: all members of the Glycerides category result from esterification of glycerol with the respective fatty acid(s). Esterification is, in principle, a reversible reaction (hydrolysis). Thus, the glycerol and fatty acid moieties are simultaneously precursors and breakdown products of Glycerides. For the purpose of grouping of substances, enzymatic hydrolysis in the gastrointestinal tract and/or liver is identified as the biological process, by which the breakdown of Glycerides result in structurally similar chemicals. Furthermore, hydrolysis represents the first chemical step in the absorption, distribution, metabolism and excretion pathways anticipated to be similarly followed by all Glycerides (CIR, 1984, 2004, 2007; Elder, 1990, 1982, 1986; FDA, 1975; Johnson, 2001; Lehninger, 1998; NTP, 1994; Stryer, 1996; WHO, 1967, 1974, 1975, 1979, 2001). Hydrolysis is catalysed by a class of enzymes known as lipases, a subgroup of carboxylesterases. In general, Glycerides are enzymatically hydrolysed in the small intestine to glycerol and corresponding carboxylic acid(s), and in the case of di- and triglycerides also to monoglycerides (with the ester bond at the sn-2 position). Following hydrolysis, glycerol is readily absorbed through the gastrointestinal tract and can be re-esterified to form endogenous glycerides or be metabolised to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which can be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Being a polar molecule, glycerol can also be readily excreted in the urine. Fatty acids are likewise readily absorbed by the intestinal mucosa and distribute systemically. Fatty acids are a source of energy. They are either re-esterified into triacylglycerols and stored in adipose tissue, or enzymatically degraded for energy primarily via β-oxidation. Alternative oxidation pathways (alpha- and omega-oxidation) are available and are relevant for degradation of branched fatty acids. Unsaturated fatty acids require additional isomerization prior to enter the β-oxidation cycle. Acetate, resulting from hydrolysis of acetylated Glycerides, is readily absorbed and feeds naturally into physiological pathways of the body and can be utilized in oxidative metabolism or in anabolic syntheses; and

(3) constant pattern in the changing of the potency of the properties across the category: the available data show similarities and trends within the category in regard to physicochemical, environmental fate, ecotoxicological and toxicological properties. For those individual endpoints showing a trend, the pattern in the changing of potency is clearly and expectedly related to the length of the fatty acid chains and the degree of substitution of glycerol (mono-, di- or triester).

a) Physicochemical properties:

The physico-chemical properties of the category members are similar or follow a regular pattern over the category. The patterns observed depend on the fatty acid chain length and the degree of esterification (mono-, di- or triester).

The molecular weight of the category members (glycerol esters) ranges from 218.29 to 1059.80 g/mol. The physical state is related to the chain length of the fatty acid moiety, the degree of saturation and the number of ester bonds. Thus, monoesters of short- and long-chain fatty acids (C8-C12) as well as unsaturated (C18:1) fatty acids and C18OH are solids, whereas monoesters of branched fatty acids (C18iso) are liquids. Triesters of shorter-chain fatty acids (C8-12) as well as unsaturated (C18:1) and branched longer-chain acids (C18iso) are liquids. The physical state of mixtures of mono-, di- and tri-esters depends on the amount of different esters. Mono-, di- and triesters of shorter-chain fatty acids are liquid (C8-12), mono-, di- and triesters of longer-chain fatty acids are solids (C14-18, C18OH and also C18iso). The turning point of this property seems to be fatty acids C12. In addition, mono- and diesters with a certain amount of unsaturated acids are liquids. Following the described pattern the UVCB triesters of shorter-chain fatty acids (C8-14) and unsaturated fatty acids (C18:1 and C18:1OH) are liquids. For the glycerides with acetic acid (mainly monoester of fatty acids and diester of acetic acid) the turning point seems to be the fatty acid chain length C14/C16. Below this point the substances are liquid, above this point category members are solid.

Also the boiling points are following a pattern: Increasing molecular weight results in increasing boiling temperatures. For a molecular weight of below 300 g/mol the boiling point is around 170 °C (C12 monoester), between a molecular weight of 350 to 480 g/mol the boiling point is between 230-300 °C. Above 300 g/moles the decomposition of the substances is probable. Also the acetate esters have boiling points >300 °C. According to Blake et al. (J. Chem. Eng. Data, 1961, 6, 87-98), esters of long chain acids with β‑hydrogen atoms in the alcohol moiety (i.e. alcohols with C3, e.g. propanol) decompose in the range between 262 and 283 °C. Since for longer chains the boiling temperature is higher, esters of fatty acids esterified with alcohols ≥ C3 and having a molecular weight exceeding 300 amu have a boiling point >300 °C and decompose before boiling.

All category members are non-volatile with a vapour pressure <0.01 Pa at temperature of 20 °C, mainly based on (Q)SAR calculation.

The n-octanol/water partition coefficient increases with increasing chain length and increasing degree of esterification (e.g. C8 monoester: 1.71; C7 triester: 8.86; C22 triester >15). A positive correlation with the overall number of CH2 units is observed.

The water solubility decreases accordingly with increasing chain length or increasing overall number of CH2 units (20-60 mg/L for C8 monoester to <0.05 mg/L for C7 triester; <4 mg/L for C18:1 monoester to <0.05 mg/L for C18iso monoester). The cut-off value for water solubility below 1 mg/L seems to be the C16 to C18 monoester. For higher degree of esterification (di and triesters) other limits are applicable: a C12 diester at least has a water solubility of below 1 mg/L, the C7 triester has solubility well below 1 mg/L. The water solubility depends on the method used for testing and for analysis of test item. Testing by GC-MS is more selective than testing by TOC/DOC method, GC-MS results are therefore lower than results obtained by TOC. Nevertheless a correlation between increasing molecular weight and decreasing water solubility can be found.

b) Environmental fate and ecotoxicological properties:

The members of the Glycerides category are readily biodegradable and show low bioaccumulation potential in biota. Hydrolysis is not a relevant degradation pathway for these substances, due to their ready biodegradability and estimated half-lives in water > 250 days at pH 7 and 25 days at pH 8 (HYDROWIN v2.00).The majority of the Glycerides category members have log Koc values > 3, indicating potential for adsorption to solid organic particles. Therefore, the main compartments for environmental distribution of these substances are expected to be soil and sediment, with the exception of 2,3-dihydroxypropyl laurate (CAS 142-18-7), for which a log Koc < 3 is reported. Therefore, this substance will be most likely available in the water phase. Nevertheless, all substances are readily biodegradable, indicating that persistency in the environment is not expected. The volatilization potential of the Glycerides category members is negligible, based on vapour pressure values ranging from < 0.0001 Pa to < 5 Pa at 20°C. Nevertheless, if released into the atmosphere, these substances are expected to be rapidly photodegraded in view of their estimated half-lives in air, ranging from 1.5 to 20.7 hours (AOPWIN 1.92 program). Based on the above information, accumulation in air, subsequent transportation through the atmosphere and deposition into other environmental compartments is not anticipated. Regarding aquatic toxicity, acute and chronic values obtained in tests conducted on fish, invertebrates, algae and microorganisms showed no adverse effects in the range of the water solubility of the substances (or the highest attainable solubility in aqueous medium), with the exception of Glycerides, palm-oil mono-, hydrogenated, acetates (CAS 93572-32-8). Even though it cannot be excluded that for this substance the observed effects are due to physical interference with undissolved test material (particulate material observed in test solutions), the NOEC value of the algae test is < 1 mg/L (0.565 mg/L) and within the water solubility range of the substance (1.3-7.4 mg/L). Therefore, a conservative approach is applied and the substance classified as environmental hazard Chronic category 3, according to Regulation (EC) No. 1272/2008. Based on the available data, no toxicity to aquatic microorganisms, sediment and terrestrial organisms is to be expected for the substances of the Glycerides category.

c) Toxicological properties:

The available data shows that the category of Glycerides is characterised by a lack of change of the potency of toxicological properties. No human health hazard is identified. Thus, all available studies consistently show that Glycerides are not acutely toxic via the oral, dermal and inhalation routes. The available animal and human studies indicate that Glycerides are not skin or eye irritating and not skin sensitising. All available in vitro and in vivo genetic toxicity studies are negative for the induction gene mutations in bacteria and mammalian cells and of chromosome aberrations or micronuclei in mammalian cells. No adverse effects were observed up to, including and even well above the limit dose of 1000 mg/kg bw/day in the available short- and long-term toxicity studies via the oral route. Likewise, no reproductive toxicity effects were observed in any of the available studies.

 

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, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

 

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2008) and taking into account further available information from members of the Glycerides category. There are no studies available in which the toxicokinetic behaviour of 1,2,3-propanetriyl trioleate (CAS No. 122-32-7) has been investigated.

The substance 1,2,3-propanetriyl trioleate is a triester of glycerol and octadecenoic acid (C18:1, oleic acid).

1,2,3-propanetriyl trioleate has a molecular weight of 885.43 g/mol. The substance is a clear yellowish liquid at 20 °C (BASF, 2009) with a melting point of -18 °C at normal pressure (Ooms, 2011), a very low water solubility of<0.05 mg/L (Frischmann, 2012), calculated log Pow>10 (HSDB, 2011) and calculated vapour pressure of < 0.0001 Pa at 20 °C (Nagel, 2012).

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2008).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) which would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2008).

The physicochemical characteristics (log Pow and water solubility) of the substance are in a range suggestive of absorption by micellar solubilisation subsequent to oral ingestion. However, the high molecular weight of the test substance will most probably complicate its absorption.

This assumption of a limited oral absorption is confirmed by the available data on chronic oral toxicity. Rats fed with Triolein (CAS No. 122-32-7) at 25% in diet (25000 mg/kg bw/day) for 10 weeks showed no differences in body weight gain nor did necropsy reveal any lesions, which might be due to either low absorption or non-toxic properties of the test substance (Cosmetic Ingredient Review (CIR), 2001).

 

The potential of a substance to be absorbed in the (GI) tract may be influenced by chemical changes taking place in GI fluids as a result of metabolism by GI flora, by enzymes released into the GI tract or by hydrolysis. These changes will alter the physicochemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2008).

It is well-accepted knowledge that triglycerides (e.g. from dietary fat) undergo hydrolysis by lipases (a class of ubiquitous carboxylesterases) prior to absorption; and there is sufficient evidence to assume that all of the mono-, di- and triglycerides contemplated within the category of Glycerides will likewise undergo enzymatic hydrolysis in the GI tract as the first step in their absorption, distribution, metabolism and excretion (ADME) pathways as summarised below.

In the gastrointestinal tract, gastric and intestinal (pancreatic) lipase activities are the most important. Triglycerides are hydrolysed by gastric and pancreatic lipases with high specificity for the sn1- and sn3-positions. For the remaining monoester at the sn2-position (2-monoacylglycerol), there is evidence that it can either be absorbed as such by the intestinal mucosa or isomerize to 1-monoacylglycerol, which can then be hydrolysed. The rate of hydrolysis by gastric and intestinal lipases depends on the carbon chain length of the fatty acid moiety. Thus, triesters of short-chain fatty acids are hydrolysed more rapidly and to a larger extent than triesters of long-chain fatty acids. (Barry et al., 1966; Cohen et al.,1971; Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1964, 1966, 1968; WHO, 1967, 1975). In a recent study conducted with the substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3), rapid ester hydrolysis in intestinal fluid simulant was confirmed (Jensen, 2002).

The substance 1,2,3-propanetriyl trioleate is therefore anticipated to be enzymatically hydrolysed to glycerol and octadecenoic acid (C18:1).

Following hydrolysis, the resulting products free glycerol, free fatty acids and (in the case of di- and triglycerides) 2-monoacylglycerols are absorbed by the intestinal mucosa. Within the epithelial cells, triglycerides are reassembled, primarily by re-esterification of absorbed 2-monoacylglycerols. Thus, free glycerol is readily absorbed independently of the fatty acids and little of it is re-esterified. As for hydrolysis, the absorption rate of free fatty acids is chain length-dependent. The absorption of short-chain fatty acids can therefore begin already in the stomach. In general, for intestinal absorption short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. However, the absorption of saturated long-chain fatty acids is increased if they are esterified at the sn2-position of glycerol (Greenberger et al., 1966; IOM, 2005; Mattson and Volpenhein, 1962, 1964). Recently a study was conducted with 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester, serving as surrogate for the substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3) to investigate the pharmacokinetics, tissue distribution, excretion and mass balance of radioactivity in rats after a single oral dose of the test material (St-Pierre, 2004). The results of the study showed that the test material, specifically the fatty acid moiety, was readily absorbed from the gastrointestinal tract, systemically distributed and metabolised. Based on the reported data on mass balance of radioactivity, absorption was higher than 80%.

In conclusion, based on the available information, the physicochemical properties and molecular weight of 1,2,3-propanetriyl trioleate suggest weak oral absorption. However, the substance is anticipated to undergo enzymatic hydrolysis in the gastrointestinal tract and absorption of the ester hydrolysis products rather than the parent substance is likely. The absorption rate of the hydrolysis products is considered to be high.

Dermal

The dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-10000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high. For substances with a log Pow above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Log Pow values above 6 reduce the uptake into the stratum corneum and decrease the rate of transfer from the stratum corneum to the epidermis, thus limiting dermal absorption (ECHA, 2008).

The physicochemical properties (log Pow and water solubility) of the substance and the molecular weight are in a range suggestive of low absorption through the skin.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The Kp is thus 7.44E-02 cm/h. Considering the water solubility (< 0.00005 mg/cm³), the dermal flux is estimated to be ca. 3.72E-06 mg/cm²/h.

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose. (ECHA, 2008).

For the test substance itself, no data are available with regard to skin irritation/corrosion. Data on skin sensitisation show that the substance is not sensitising in humans (Van Joost, 1981; Malmkvist Padoan, 1990). Furthermore, no member of the Glycerides category is considered to be skin irritating or skin sensitising either, since the results of all available studies do not fulfil the criteria for the corresponding classification according to Regulation (EC) 1272/2008. Therefore, no enhanced penetration of the substance due to skin damage is expected.

Overall, taking all available information into account, the dermal absorption potential is considered to be very low.

Inhalation

1,2,3-propanetriyl trioleate is a liquid with low vapour pressure (< 0.0001 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 significant.

However, the substance may be available for respiratory absorption in the lung after inhalation of aerosols, if the substance is sprayed (e.g. as a formulated product). 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, 2008).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of micellar solubilisation.

Overall, systemic bioavailability is considered likely after inhalation of aerosols with aerodynamic diameters below 15 µm.

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. 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).

As discussed under oral absorption, mono-di- and triesters of glycerol undergo enzymatic hydrolysis in the gastrointestinal tract prior to absorption. Therefore, assessment of distribution and accumulation of the hydrolysis products is considered more relevant.

Absorbed glycerol is readily distributed throughout the organism and can be re-esterified to form endogenous triglycerides, be metabolised and incorporated into physiological pathways or be excreted in the urine. After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Fatty acids of carbon chain length ≤ 12 may be transported as the free acid bound to albumin directly to the liver via the portal vein, instead of being re-esterified. Chylomicrons are transported in the lymph to the thoracic duct and eventually to the venous system. Upon contact with the capillaries, enzymatic hydrolysis of chylomicron triacylglycerol fatty acids by lipoprotein lipase takes place. Most of the resulting fatty acids are taken up by adipose tissue and re-esterified into triglycerides for storage. Triacylglycerol fatty acids are likewise taken up by muscle and oxidized for energy or they are released into the systemic circulation and returned to the liver (IOM, 2005; Johnson, 1990; Johnson, 2001; Lehninger, 1998; NTP, 1994; Stryer, 1996; WHO, 2001).

Stored fatty acids underlie a continuous turnover as they are permanently metabolised for energy and excreted as CO2. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

In the study by St-Pierre (2004) with 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester (surrogate of Glycerides, castor-oil-mono, hydrogenated, acetates (CAS No. 736150-63-3)), systemic distribution of the radiolabelled material was confirmed in rats. Radioactivity was detected in all tissues and organs sampled (adipose tissue, gastrointestinal tract and content, kidneys and adrenals, liver, thymus and the remaining carcass) with highest levels recovered in the gastrointestinal tract, liver and the remaining carcass. Due to excretion and absorption of the radiolabelled material, the radioactivity content in the gastrointestinal tract decreased rapidly over the course of the study (168 h). This was similar for the radioactivity recovered in liver, whereas the radioactivity found in the carcasses was nearly constant at the selected time points, indicating that the radiolabelled material may have been distributed to other tissues than the ones selected for analyses. Based on the results of this study, no bioaccumulation potential was observed for 12-acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester.

Metabolism

Glycerol can be metabolised to dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which can then be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Fatty acids are degraded by mitochondrial β-oxidation which takes place in the most animal tissues and uses an enzyme complex for a series of oxidation and hydration reactions resulting in the cleavage of acetate groups in form of acetyl CoA. The alkyl chain length is thus reduced by 2 carbon atoms in each β-oxidation cycle. The complete oxidation of unsaturated fatty acids such as oleic acid requires an additional isomerisation step. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Thus iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates and to be metabolised to a large extent by ω-oxidation. Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl CoA, through which they are completely oxidized to CO2. Acetate, resulting from hydrolysis of acetylated Glycerides, is readily absorbed and feeds naturally into physiological pathways of the body and can be utilized in oxidative metabolism or in anabolic syntheses (CIR, 1983, 1987; IOM, 2005; Lehninger, 1998; Lippel, 1973; Stryer, 1996; WHO, 1967, 1974, 1975, 2001).

Excretion

As far as Glycerides are not hydrolysed in the gastrointestinal tract, they are excreted in the faeces.

In general, the hydrolysis products glycerol and fatty acids are catabolised entirely by oxidative physiologic pathways ultimately leading to the production of carbon dioxide and water. Glycerol, being a polar molecule can readily be excreted in the urine. Small amounts of ketone bodies resulting from the oxidation of fatty acids are excreted via the urine (Lehninger, 1998; IOM, 2005; Stryer, 1996).

In rats given a single dose of 12-[1-14C]acetoxy-octadecanoic acid-2,3-diacetoxy-propyl ester at 5000 mg/kg bw, the mean total recovery of radioactivity in the excreta of the 72 h period post-dose was 108.5% of the dose (urine, 6.5%; faeces, 24.5%; CO2, 77%; and cage wash, 0.5%). Most of the recovered radioactivity (97.5%) was excreted by 24 h post dose (St-Pierre, 2004). The results thus confirm that Glycerides are mainly excreted as CO2 in the expired air as a result of metabolism.

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