Oligo

Endpoint summary

Description of key information

Available toxicokinetic data on sucrose esters in rats suggest extensive hydrolysis in the gastrointestinal tract to the respective fatty acids and sucrose prior to absorption. Intact monoesters are absorbed only to small amounts. Thus, it can be expected that oligoesters (di-, tri- and tetraesters) are unlikely to be absorbed intact. Based on physico-chemical parameters the dermal and inhalation absorption potential is considered to be low. Fatty acids C16-18(even numbered), oligoesters with sucrose will be hydrolysed in the gastrointestinal tract to sucrose and the respective fatty acids (palmitic and stearic acid). There is no evidence of tissue accumulation of absorbed intact monoesters. Fatty acids mainly distribute into fat tissue, lymph nodes and liver, while sucrose is metabolised in the intestinal mucosa to glucose and fructose, which can then be incorporated in the standard metabolic pathways of glycolysis and gluconeogenesis. Fatty acids are degraded by mitochondrial β-oxidation and used for energy generation. Sucrose esters, including Fatty acids C16-18(even numbered), oligoesters with sucrose (no CAS), are mainly excreted as CO2 in the expired air as a result of metabolism. Incompletely hydrolysed sucrose esters appear to be excreted in the faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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, 2017), an assessment of the toxicokinetic behaviour of the test 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 physico-chemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017) and taking into account further available information from source substances.

Fatty acids C16-18(even numbered), oligoesters with sucrose (no CAS) is a UVCB substance covering mono-, di-, tri-, tetra-, penta-, hexa-, hepta-, and octaesters of stearic and palmitic acid with sucrose at varying proportions.

The substance is a solid (powder) at room temperature with low water solubility (0.509 mg/L at 20 °C), a log Pow > 5 and a vapour pressure of <133 Pa at 25 °C.

Absorption

The major routes by which the test substance can enter the body are via the lung, the gastrointestinal tract, and the skin. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility (ECHA, 2017).

Oral

Generally the smaller the molecule the more easily it may be taken up. Molecular weights below 500 are favourable for absorption; molecular weights above 1000 do not favour absorption. However, the absorption of highly lipophilic substances (log Pow >4) may be limited by the inability to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. Lipophilic compounds may be taken up by micellar solubilisation by bile salts; this mechanism is important for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (ECHA, 2017). Fatty acids C16-18(even numbered), oligoesters with sucrose (no CAS) has a molecular weight ranging from 580.7 to 2474.0 g/mol, a water solubility <1 mg/L and a log Pow >5, thus low oral absorption is presumed.

The available data on acute and repeated dose oral toxicity support a conclusion of no/low toxicity.

In an acute oral toxicity study conducted with the target substance Fatty acids C16-18(even numbered), oligoesters with sucrose (no CAS) in male and female rats no mortality occurred (key study, 1996). Swollen abdomen observed one day after administration was resolved within 2 days after administration. Therefore, the LD50 is > 2000 mg/kg bw.

A combined chronic oral toxicity (14 rats/sex/dose for 52 weeks) and carcinogenicity study (50 rats/sex/dose for 104 weeks) was performed with the source substance sucrose palmitate stearate (no CAS) in rats similar to OECD guideline 453 (key study, 2002). Based on the absence of treatment-related adverse effects, the NOAEL was found to be 5% in the diet, equivalent to 1970 mg/kg bw/day in males and 2440 mg/kg bw/day in females.

Metabolic studies in vitro and in rats, dogs and humans show that sucrose esters of fatty acids are extensively hydrolysed in the gastrointestinal tract into well-known food constituents prior to absorption, that only small amounts of intact monoesters are absorbed, and that incompletely hydrolysed sucrose esters appear to be excreted in the faeces. It is unlikely that di- and higher esters are absorbed intact. There is no evidence of tissue accumulation of the absorbed monoesters. They are completely metabolised to carbon dioxide or integrated into other endogenous constituents (EFSA 2004). Further it was shown from studies on oligoesters, that the degree of absorption is inversely related to the degree of esterification of the sucrose moiety (Noker, 1997; Shigeoka, 1984).

Overall, available studies indicate that the test substance is predicted to undergo hydrolysis in the gastrointestinal tract and absorption of the hydrolysis products sucrose and fatty acids rather than the parent substance is likely.

Dermal

The dermal uptake of solids is generally expected to be lower than that of liquid substances. Dry particulates will have to dissolve into the surface moisture of the skin before uptake can begin. Additionally, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility of the substance is below 1 mg/L, dermal uptake is likely to be low. For substances with 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 (ECHA, 2017)

The dermal permeability constant Kp of the substance was calculated for four representatives of the UVCB substance Fatty acids C16-18(even numbered), oligoesters with sucrose using DermwinTM (v.2.02) and taking into account a determined log Pow of 5 and a water solubility of 0.51 mg/L.

	Molecular weight	Estimated Kp [cm/h]
Monoester C16	580.7	0.00182
Diester C18	875.2	4.04E-005
Pentaester C18	1674.6	1.32E-009
Octaester C18	2473.9	4.3E-014

The dermal absorption of the test substance is anticipated to be very low.

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, 2017).

The available data from an in vivo study conducted in rabbits according to OECD guideline 404 provide no indications for skin irritating effects of Fatty acids C16-18(even numbered), oligoesters with sucrose in rabbits. No signs of skin irritation and no skin sensitisation were observed in a study conducted in guinea pigs according to OECD guideline 406 (Buehler). Therefore, no enhanced penetration of the substance due to skin damage is expected. Taking all the available information into account, the dermal absorption potential is considered to be low.

Inhalation

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. Measurement of particle size distribution was done using a laser diffraction method according to ISO 13320:2009. The median particle diameter was found to be 24 µm with ≈ 32% smaller than 15 µm (regarded as the fraction reaching the alveoli) and ≈ 8.4% smaller than 5 µm. Based on the particle size distribution, exposure via inhalation route is in principle possible. However, systemic exposure to Fatty acids C16-18(even numbered), oligoesters with sucrose after inhalation is regarded to be limited due to various reasons. The largest fraction of the poorly water-soluble particles with a size of > 5 µm will most probably be settling in the nasopharyngeal region, less than 8.4% are likely to settle in the tracheo-bronchial or pulmonary regions. Particles depositing in the nasopharyngeal region will be coughed or sneezed out or swallowed, those depositing in the tracheo-bronchial region will mainly be cleared from the lungs by the mucociliary mechanism and swallowed. Phagocytosis and transport to the blood via the lymphatic system is the only way of uptake. Only few particles will reach the pulmonary alveoli and would mainly be engulfed by alveolar macrophages, either translocated to the ciliated airways or carried into the pulmonary interstitium and lymphoid tissues (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 3.0 June 2017). Even if the substance is taken up systemically after inhalation exposure, no systemic toxicity is expected.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical 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, 2017).

The distribution upon oral administration of sucrose esters was evaluated in rats. Groups of four male rats were fed diets containing 1% or 5% sucrose esters for 1, 2, or 4 weeks. The 4 weeks feeding group included additional groups for studies of 3 days, 1 week and 2 weeks of recovery. The amount of sucrose mono-palmitate (SMP) and mono-stearate (SMS) in the blood plasma and organ tissues were determined. In the 1% group the SMP concentrations remained almost constant in plasma and tissues during the 4 weeks and were close to or below the limits of detection (0.01-0.06 μg/g). At the 5% level slightly increased levels of SMP were seen with similar amounts detected at the various sampling points, with the highest concentrations in the liver (0.3-0.4 μg/g) followed by the kidney, lung, spleen, heart and plasma. SMP and SMS levels of all tissues were below the limit of detection 3 days after completion of the 28-day treatment (EFSA 2004).

As a part of a chronic toxicity and carcinogenicity study, plasma and liver concentrations of SMP and SMS were measured in 5 rats per sex and group after 2-years of daily oral administration of sucrose esters. Plasma SMP concentrations were below or close to the detection limit at all dose levels whereas the plasma levels of SMS in the 1%, 3% and 5% dose groups were 0.03, 0.05 and 0.15 μg/mL and 0.02, 0.08 and 0.06 μg/mL in males and females, respectively (EFSA, 2004). Thus, there was no time dependent accumulation of sucrose monoesters in the liver.

As discussed for oral absorption, Fatty acids C16-18(even numbered), oligoesters with sucrose are hydrolysed in the gastrointestinal tract prior to absorption. Therefore, distribution and accumulation of the hydrolysis products is considered the most relevant.

After being absorbed, fatty acids are (re-)esterified along with other fatty acids into triglycerides and released in chylomicrons into the lymphatic system. Chylomicrons are transported in the lymph to the thoracic duct and subsequently to the venous system. On 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 (Bloom et al., 1951; IOM, 2005; Johnson, 1990; Lehninger, 1993; NTP, 1994; Stryer, 1996). In contrast, sucrose is metabolized in the intestinal mucosa to glucose and fructose; these are transported by the portal vein to the liver where they are rapidly metabolized (Stryer, 1996; Noker, 1997).

There is a continuous turnover of stored fatty acids, as these are constantly metabolised to generate energy and then excreted as CO₂. Accumulation of fatty acids takes place only if their intake exceeds the caloric requirements of the organism. In contrast, sucrose is metabolised in the intestinal mucosa to glucose and fructose; these are transported by the portal vein to the liver where they are rapidly metabolised and incorporated into physiological pathways (Lehninger, 1993; Noker et al. 1997).

Metabolism

As discussed previously, Fatty acids C16-18(even numbered), oligoesters with sucrose are expected to be hydrolysed to sucrose and fatty acids in the gastrointestinal tract prior to absorption. The extent of absorption and metabolism is inversely related to the degree of esterification (Noker, et al. 1997; Shigeoka, 1984). Only small amount of intact monoesters which escape hydrolysis are expected to be absorbed. Some hydrolysis occurs in the presence of blood esterase: however, the rate is extremely slow compared to the other enzyme systems like in the gastrointestinal tract (Shigeoka, 1979). Absorbed monoesters are completely metabolized to carbon dioxide or integrated into other endogenous constituents (Shigeoka, 1984, Noker, 1997: summarised in WHO, 1980, WHO, 1995, WHO, 1998 and EFSA, 2004).

Sucrose is metabolised in the intestinal mucosa to glucose and fructose, 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 most animal tissues and uses an enzyme complex for a series of oxidation- and hydration reactions, resulting in the cleavage of acetate groups in the form of acetyl-CoA. The alkyl chain length is reduced by 2 carbon atoms during each β-oxidation cycle. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation). Each two-carbon unit resulting from β-oxidation enters the citric acid cycle as acetyl-CoA, through which they are completely oxidised to CO₂(CIR, 1987; IOM, 2005; Lehninger, 1993; Stryer, 1996).

Potential metabolites of four representative constituents were predicted using the QSAR OECD toolbox v4.1 skin metabolism simulator, rat liver S9 metabolism simulator and microbial metabolism simulator.

	Molecular weight	# skin metabolites	# rat liver S9 metabolites	# microbial metabolites
Monoester C16	580.7	14	16	150
Diester C18	875.2	11	18	196
Pentaester C18	1674.6	32	26	455
Octaester C18	2473.9	32	50	1122

Up to 50 hepatic metabolites and up to 32 dermal metabolites were predicted for 4 representative constituents of the test substance. Primarily, the ester bond is broken both in the liver and in the skin, after which the hydrolysis products may be metabolised further. The resulting liver and skin metabolites are the products of alpha-, beta- or omega-oxidation (= addition of hydroxyl group). The ester bond may also remain intact, in which case a hydroxyl group is added to, or substituted with, a methyl group. In general, the hydroxyl groups make the substances more water-soluble and susceptible to metabolism by phase II-enzymes. The metabolites formed in the skin are expected to enter the blood circulation and have the same fate as the hepatic metabolites. Up to 1122 metabolites were predicted to result from all kinds of microbiological metabolism. The high number includes many minor variations in the c-chain length and number of carbonyl- and hydroxyl groups; reflecting the diversity of microbial enzymes identified. Not all of these reactions are expected to take place in the human GI-tract. The results of the OECD toolbox simulation support the information on metabolism routes retrieved in the literature.

There is no indication that Fatty acids C16-18(even numbered), oligoesters with sucrose is activated to reactive intermediates under the relevant test conditions. The experimental studies performed with the target and source substance on genotoxicity (Ames test, in vitro gene mutation in mammalian cells, in vivo micro nucleus test) were consistently negative, with and without metabolic activation. The results of the skin sensitisation studies performed in guinea pigs were likewise negative.

 

Excretion

In general, the hydrolysis products sucrose and fatty acids are catabolised entirely by oxidative physiologic pathways, ultimately leading to the formation of carbon dioxide and water. Small amounts of ketone bodies resulting from the oxidation of fatty acids may be excreted via the urine; however, the major part of the fatty acids will enter an oxidative pathway as described above under ‘Metabolism’ (Lehninger, 1993; IOM, 2005; Stryer, 1996).In the reviews/opinions prepared by the WHO, 1995, WHO, 1998 and EFSA, 2004 and the references therein, several in vitro and in vivo experiments on the excretion of sucrose esters (SE) in rats, dogs and human were evaluated, demonstrating that the non-absorbed fraction of sucrose esters that is not hydrolysed in the gastrointestinal tract will be mainly excreted via the faeces (ECHA, 2004).

In conclusion, sucrose esters, including Fatty acids C16-18(even numbered), oligoesters with sucrose (no CAS), are mainly excreted via the faeces and as CO₂ in the expired air as a result of metabolism.

 

References

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ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017.

EFSA (2004): Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food on Sucrose esters of fatty acids, E 473 and sucroglycerides, E 474 based on a request from the Commission related to Sucrose Esters of Fatty Acids (E 473). The EFSA Journal (2004) 106, 1-24

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

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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.

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Shigeoka, T., Izawa, O., Kitazawa, K. and Yamauchi, F. Studies on the metabolic fate of sucrose esters in rats. Food and Chemical Toxicology, Vol. 22, No. 6, pp 409 - 414

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

WHO (1980). Sucrose esters of fatty acids and sycroglycerides. Prepared by the Twenty fourth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1980. Toxicological Evaluation of Certain Food Additives. WHO Food Additives Series 15.

WHO (1995). Sucrose esters of fatty acids and sycroglycerides. Prepared by the Forty fourth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1995. Toxicological Evaluation of Certain Food Additives and Contaminants. WHO Food Additives Series 35:129-138.

WHO (1998). Sucrose esters of fatty acids and sycroglycerides. Prepared by the Forty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), 1997. Safety Evaluation of Certain Food Additives and Contaminants (49th meeting). WHO Food Additives Series 40:79-81, 1998.