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

Endpoint summary

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 - 582.91	C2; C8, C10, C12, C14, C16, C18, C18uns.	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, 2012), 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, 2012) and taking into account further available information from members of the Glycerides category. There are no studies available in which the toxicokinetic behaviour of Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) has been investigated.

The substance Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (UVCB) is a mixed triester of glycerol, acetic acid (C2) and fatty acids with linear, even-numbered chain lengths ranging from C8 (octanoic acid) to C18 (octadecanoic acid), also including monounsaturated C18:1 fatty acids.

Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates has a molecular weight range of 302.36 - 582.91 g/mol. The substance is a pale yellow liquid at 20 °C with a melting point of -8 °C at normal pressure (O'Connor, 2009) and a water solubility of 8.75 mg/L at 20°C and pH = 5.5 - 6 (O'Connor, 2009). A log Pow of > 6.5 at 30 °C and pH = 5 (O'Connor, 2009) and a vapour pressure of 0.00045 Pa at 25 °C (O'Connor, 2009) were determined for the substance.

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

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, 2012).

The physicochemical characteristics (log Pow and water solubility) of the substance and the molecular weight distribution are in a range suggestive of moderate absorption from the gastrointestinal tract subsequent to oral ingestion.

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, 2012).

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 structurally related substance Glycerides, castor-oil-mono, hydrogenated, acetates (CAS 736150-63-3), rapid ester hydrolysis in intestinal fluid simulant was confirmed (Jensen, 2002).

The substance Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates is therefore anticipated to be enzymatically hydrolysed to glycerol acetic acid and even-numbered fatty acids ranging from C8 (octanoic acid) to C18 (octadecanoic acid) as well as the monounsaturated C18:1 fatty acids.

Following hydrolysis, the resulting products free glycerol, free fatty acids, acetic acid 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 carboxylic acids can therefore begin already in the stomach. In general, for intestinal absorption short-chain or unsaturated carboxylic 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 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%. A high rate of absorption was also demonstrated in a feeding study with soybean oil in rats, resulting in oral absorption of 95 -98% when administered at 17% of the diet (Nolen, 1972). Furthermore, for palmitic acid it was shown that absorption rate was depending on the form in which it was fed, i.e. absorption was greatest when palmitic acid was fed as β-palmitoyl diolein, and least when it was fed as the free acid (Mattson and Volpenhein, 1962).

In conclusion, based on the available information, the physicochemical properties and molecular weight of Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates suggest moderate 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, 2012).

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.

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, 2012).

No data is available on skin irritation or skin sensitisation for the substance itself. However, data are available for the structurally related substances Glycerides, C14-18 mono- and di- (CAS 67701-33-1), C12-C18 trialkyl glyceride (CAS 67701-26-2) and Glycerides, C14-18 and C16-22-unsatd. mono- and di-, (CAS 91744-13-7), which all caused slight, but fully reversible skin irritation reactions in rabbits. Furthermore, skin sensitisation studies in guinea pigs did not show any skin sensitisation reactions for the structurally related substances Propane-1,2,3-triyl trisheptanoate (CAS 620-67-7), Glycerides, C16-18 and C18-hydroxy mono- and di- (CAS 91845-19-1) and Glycerol tristearate (CAS 555-43-1). Based on studies on structural analogues, Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates is not expected to cause any skin irritation and sensitisation reactions, which might enhanced penetration of the substance due to local skin damage and thus increase dermal absorption.

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

Inhalation

Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates is a liquid with low vapour pressure (0.00045 Pa at 25 °C), thus being of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapours, gases, or mists is not 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, 2012).

As for oral absorption, the molecular weight, log Pow and water solubility are suggestive of absorption across the respiratory tract epithelium either by 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, 2012).

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 (Bergström, 1951). 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; Matulka, 2009).

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 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; Adolph, 1999).

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.

References

Adolph, M. (1999). Lipid Emulsions in Parenteral Nutrition.Ann Nutr Metab. 43(1):1-13.

Aungst B. and Shen D.D. (1986). Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York, US.

Barry, R.J.C. et al. (1967). HANDLING OF GLYCERIDES OF ACETIC ACID BY RAT SMALL INTESTINE IN VITRO. J. Physiol., 185, 667-683

Borgström, B. (1951). On the Mechanism of the Intestinal Fat Absorption. Acta Chem. Scand. (5):643-646.

Cohen, M. et al. (1971). Lipolytic activity of human gastric and duodenal juice against medium and long chain triglycerides. Gastroenterology 60(1):1-15.

Cosmetic Ingredient Review Expert Panel (CIR) (1983). Final report on the safety assessment of Isostearic acid.J. of the Am. Coll. of Toxicol.2(7):61-74

Cosmetic Ingredient Review Expert Panel (CIR) (1986). Final Report on the Safety Assessment of Glyceryl Ricinoleate. J Am Coll Tox 7(6):721-739

Cosmetic Ingredient Review Expert Panel (CIR) (1987) Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid.J. of the Am. Coll. of Toxicol.6(3):321-401.

Cosmetic Ingredient Review Expert Panel (CIR) (2004). Final report of the amended safety assessment of Glyceryl Laurate, Glyceryl Laurate SE, Glyceryl Laurate/Oleate, Glyceryl Adipate, Glyceryl Alginate, Glyceryl Arachidate, Glyceryl Arachidonate, Glyceryl Behenate, Glyceryl Caprate, Glyceryl Caprylate, Glyceryl Caprylate/Caprate, Glyceryl Citrate/Lactate/Linoleate/Oleate, Glyceryl Cocoate, Glyceryl Collagenate, Glyceryl Erucate, Glyceryl Hydrogenated Rosinate, Glyceryl Hydrogenated Soyate, Glyceryl Hydroxystearate, Glyceryl Isopalmitate, Glyceryl Isostearate, Glyceryl Isostearate/Myristate, Glyceryl Isostearates, Glyceryl Lanolate, Glyceryl Linoleate, Glyceryl Linolenate, Glyceryl Montanate, Glyceryl Myristate, Glyceryl Isotridecanoate/Stearate/Adipate, Glyceryl Oleate SE, Glyceryl Oleate/Elaidate, Glyceryl Palmitate, Glyceryl Palmitate/Stearate, Glyceryl Palmitoleate, Glyceryl Pentadecanoate, Glyceryl Polyacrylate, Glyceryl Rosinate, Glyceryl Sesquioleate, Glyceryl/Sorbitol Oleate/Hydroxystearate, Glyceryl Stearate/Acetate, Glyceryl Stearate/Maleate, Glyceryl Tallowate, Glyceryl Thiopropionate, and Glyceryl Undecylenate. Int J Toxicol. 2004;23 Suppl 2:55-94.

Cosmetic Ingredient Review Expert Panel (CIR) (2007). Amended final report on the safety assessment of glyceryl dilaurate, glyceryl diarachidate, glyceryl dibehenate, glyceryl dierucate, glyceryl dihydroxystearate, glyceryl diisopalmitate, glyceryl diisostearate, glyceryl dilinoleate, glyceryl dimyristate, glyceryl dioleate, glyceryl diricinoleate, glyceryl dipalmitate, glyceryl dipalmitoleate, glyceryl distearate, glyceryl palmitate lactate, glyceryl stearate citrate, glyceryl stearate lactate, and glyceryl stearate succinate. Int J Toxicol. 26 Suppl 3:1-30.

Dias, F.F. and Alexander, M. (1971). Effect of chemical structure on the biodegradability of aliphatic acids and alcohols. Applied Microbiology 22(6): 1114-1118.

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

Elder, R.L. ed (1980). Final Report of the Safety Assessment for Caprylic/Capric Triglyceride. J Environ Pathol Toxicol 4:105-120

Elder, R.L. ed (1982). Final Report on the Safety Assessment of Glyceryl Stearate and Glyceryl Stearate/SE. J Am Coll Tox 1:169-192

Elder, R.L. ed (1986). Final Report on the Safety Assessment of Glyceryl Oleate. J Am Coll Tox 5:391-413

FDA - Select Committee on GRAS Substances (SCOGS) (1975) Glycerin and Glycerides. http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=142. Report No.: 30. Company study no.: ID Code 56-81-5.

Greenberger, N.J. et al. (1966). Absorption of medium and long chain triglycerides: factors influencing their hydrolysis and transport. J Clin Invest 45(2):217-227.

Gubicza, L., Kabiri-Badr, A., Keoves, E., Belafi-Bako, K. (2000): Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Institute of the National Academies (IOM) (2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). The National Academies Press. http://www.nap.edu/openbook.php?record_id=10490&page=R1

Johnson W Jr; Cosmetic Ingredient Review Expert Panel. (2001). Final report on the safety assessment of trilaurin, triarachidin, tribehenin, tricaprin, tricaprylin, trierucin, triheptanoin, triheptylundecanoin, triisononanoin, triisopalmitin, triisostearin, trilinolein, trimyristin, trioctanoin, triolein, tripalmitin, tripalmitolein, triricinolein, tristearin, triundecanoin, glyceryl triacetyl hydroxystearate, glyceryl triacetyl ricinoleate, and glyceryl stearate diacetate. Int J Toxicol. 2001;20 Suppl 4:61-94.

Johnson, R.C. et al. (1990). Medium-chain-triglyceride lipid emulsion: metabolism and tissue distribution.Am J Clin Nutr 52(3):502-508.

Lehninger, A.L., Nelson, D.L. and Cox M.M. (1998). Prinzipien der Biochemie. 2. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer Verlag.

Lilja, J., Wärna, J., Salmi, T., Petterson, L.J., Ahlkvist, J., Grénman, H., Rönneholm, M., Murzin, D.Y. (2005): Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst.Chemical Engineering Journal, 115(1-2): 1-12.

Lippel, K. (1973). Activation of branched and other long-chain fatty acids by rat liver microsomes. Journal of Lipid Research 14:102-109.

Liu, Y., Lotero, E., Goodwin, J.G. Jr. (2006): A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis, 242 (2): 278-286.

Mattson, F.H. and Volpenhein, R.A. (1962). Rearrangement of Glyceride Fatty Acids During Digestion and Absorption. J Biol Chem 237:53-5.

Mattson, F.H. and Volpenhein, R.A. (1964). THE DIGESTION AND ABSORPTION OF TRIGLYCERIDES. J Biol Chem 239:2772-2777.

Mattson, F.H. and Volpenhein, R.A. (1966). Carboxylic ester hydrolases of rat pancreatic juice. J Lipid Res 7(4):536-543.

Mattson, F.H. and Volpenhein, R.A. (1968). Hydrolysis of primary and secondary esters of glycerol by pancreatic juice. J Lipid Res 9(1):79-84.

Matulka, R.A. (2009). Lack of toxicity by medium chain triglycerides (MCT) in canines during a 90-day feeding study. Food Chem Toxicol. 47(1):35-39

National Toxicology Program (NTP) (1994) Comparative toxicology studies of Corn Oil, Safflower Oil, and Tricaprylin (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as vehicles for gavage. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr426.pdf (2011-12-19). Report No.: C62215. Owner company: U.S. Department of Health and Human Services, Public Health Services, National Institutes of Health.

Nolen, G.A. (1972). Effect of Various Restricted Dietary Regimens on the Growth, Health and Longevity of Albino Rats. J Nutr. 102(11):1477-1493.

Radzi, S.M., Basri, M., Salleh, A.B., Ariff, A., Mohammed, R., Rahman, M.B.A., Rahman, R.N.Z.R.A. (2005): High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica.Electronic Journal of Biotechnology 8: 292-298.

Stryer, L. (1996). Biochemie. 4. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer Verlag.

US EPA (2004).  Risk Assessment Guidance for Superfund (RAGS), Volume I: Human Health Evaluation Manual (Part E, Supplemental Guidance for Dermal Risk Assessment) Interim. http://www.epa.gov/oswer/riskassessment/ragse/index.htm

WHO (1974). Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents: Acetic Acid and Its Potassium and Sodium Salts. WHO Food Additives Series No. 5.

WHO (1975). Toxicological evaluation of some food colours, thickening agents, and certain other substances: Triacetin. WHO Food Additives Series No. 8.

WHO (1979). Castor Oil. WHO Food Additives Series No. 14.

WHO (2001). Safety Evaluation of Certain Food Additives and Contaminants: Aliphatic Acyclic Diols, Triols, and Related Substances. WHO Food Additives Series No. 48.

World Health Organization (WHO) (1967). Toxicological Evaluation of Some Antimicrobials, Antioxidants, Emulsifiers, Stabilizers, Flour-Treatment Agents, Acids and Bases: Acetic Acid and Fatty Acid Esters of Glycerol. FAO Nutrition Meetings Report Series No. 40A, B, C.

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.