Glycerides, C16-18 and C18-unsatd., deodorizer distillates

Endpoint summary

Additional information

Glycerides

When taken up orally, glycerides are split in the intestinal lumen into glycerol and fatty acids with the help of lipases and bile secretions, then move into enterocytes. The triglycerides are rebuilt in the enterocytes from their fragments and packaged together with cholesterol and proteins to form chylomicrons. These are excreted from the cells, collected by the lymph system and transported to the large vessels near the heart before entering the blood. Eventually, the triglycerides bind to the membranes of hepatocytes, adipocytes or muscle fibers, where they are either stored or oxidized for energy. When the body requires fatty acids as a source of energy, the hormone glucagon signals the breakdown of the triglycerides by hormone-sensitive lipases to release free fatty acids. The fatty acids are then broken down by stepwise elimination of C2-units in the mitochondrial β-oxidation. Alternate oxidation pathways can be found in the liver (ω-oxidation) and the brain (α-oxidation) (HERA, 2002). The C2-units are esterified to acetyl-coenzyme A which directly enters the citric acid cycle where it is converted to carbon dioxide and energy (MacDonald, 1973; Robinson, 1973; Chen and Farese, 2002). Not all fatty acids present as triglycerides are used for energy production: after metabolisation in the liver, redistribution to phospholipids and sterol esters may for example also occur (Mead and Fillerup, 1957; McArthur et al., 1999).

Glycerides with alkyl chain lengths between C8 to18, including C18-unsatd. are generally poorly water soluble have an estimated log Pow > 6 and molecular weights > 500. As such, uptake into the stratum corneum of skin and further transfer into the epidermis are likely to be low (REACH guidance document R7.C (May 2008)).

Fatty acids

Upon ingestion, fatty acids are directly taken up into the cells lining the intestines (enterocytes), then transported mainly in the form of triglycerides via the lymph to various tissues (see below). The fatty acids may then be stored in the form of triglycerides as a source of energy or redistributed to phospholipids and sterol esters (conversion mainly in the liver) (Mead and Fillerup, 1957; McArthur et al., 1999).

The extent of absorption in the gastro-intestinal system varies depending on the chain length of the fatty acids and their degree of saturation. Generally, short-chain fatty acids are better absorbed than the long chain counterparts. Also, absorption decreases with increasing saturation (MacDonald, 1973; Robinson, 1973; Chen and Farese, 2002). In an overview by the Cosmetic Ingredient Review Panel (CIR, 1987), stearic acid (C18) was cited as being the most poorly absorbed of the common fatty acids

Only limited information could be located on dermal penetration of fatty acids. In dermal application studies in the rat (Butcher, 1951), linoleic acid was shown to penetrate the epithelium rapidly and reach the vascular system. Oleic acid was also reported to penetrate the epithelium of rats, possibly via hair follicles, but only minute amounts were seen in the blood vessels. Ricinoleic acid on the other hand was retained mainly in the outer strata of the epidermis. Other authors have noted that skin permeability increases with the lipophilic nature of a compound (Scheuplein, 1965; CIR, 1987). Dermal uptake of fatty acids has also been studied with fatty acid soaps. The C₁₀and C₁₂soaps show the greatest skin penetration of human epidermis. Also, percutaneous absorption of sodium laurate is greater than that of most other anionic surfactants (HERA, 2002).

Tocopherols

The toxicokinetics of tocopherols has been extensively studies in humans, in particular due to the Vitamin E activity. α-tocopherol is the most active of all homologues, followed by β-, γ-, and δ-tocopherol. Only certain isomers are retained in human plasma, i.e. the RRR-α-tocopherol and the 2R-stereoisomers, RSR-, RRS- and RSS-α-tocopherol (Traber, 1999).

Upon oral uptake, α-tocopherol is absorbed unchanged from the small intestine by passive diffusion. Tocotrienol esters are first hydrolysed by pancreatic esterase (Bjørneboe et al., 1990). Absorption occurs mostly in the upper and middle thirds of the small intestine (Tomassi and Silano, 1986; Fiume, 2002) and absorbed substance enters the lymphatic circulation (Devron, 1999). The uptake efficiency of tocopherol and its esters is generally considered to be variable. In rats given a single bolus of α-tocopherol intraduodenally, absorption was reported to be approximately 40%(Bjørneboe et al., 1990), whereas when α-tocopherol acetate was given as slow continuous infusion into the duodenum, absorption was 65% (Traber et al., 1986). In another study, the appearance of α-tocopherol in the lymph was negligible in the 2-4 hours following intraduodenal dosing, peaking 4-15 hours after feeding (Bjørneboe et al., 1986). Intestinal absorption via the lymphatic system was 15.4%. In human studies over 24 hours, absorption of α-tocopherol and its acetate ester was in the range of 21-86%. However, determination under experimental conditions may not reflect dietary reality.

α-tocopherol is rapidly transferred in plasma from chylomicrons to plasma lipoproteins, to which it binds non-specifically. The vitamin is taken up by the liver and released in low density lipoprotein (Traber et al., 1988; Combs, 1992). Most absorbed tocopherols are transported unchanged to the tissues. In non-adipose cells, vitamin E is localised almost exclusively in the membranes. Kinetic studies indicate that such tissues have two pools of the vitamin: a ’labile’, rapidly turning over pool, and a ’fixed, slowly turning over pool. The labile pools predominate in such tissues as plasma and liver, as the tocopherol contents of those tissues are depleted rapidly under conditions of vitamin E deprivation. In contract, the adipose vitamin E resides predominately in the bulk lipid phase, which appears to be a fixed pool of vitamin, thus, it is only slowly metabolised from this tissue (Bjørneboe et al., 1990, Combs, 1992; Basu and Dickerson, 1996). Tissue tocopherol contents tend to be related exponentially to vitamin E intake and show no deposition or saturation thresholds. As a result, tissues vary considerably in tocopherol contents in a manner that is not related to their lipid content (Machlin, 1984).

Tocopherols are generally well absorbed through human skin (Fiume, 2002).

Sterols and sterol esters

Observations in animals and humans have shown that plant sterols and sterol esters are generally poorly absorbed when taken up orally, with the highest absorption occuring for campesterol. Consumption of sterols nevetherless leads to a small but dose-related increase in plasma concentrations in short-term studies.In repeated dose rat studies, sitosterol and sitostanol were found in the adrenals, ovary and stomach at low concentrations, campestanol in the adrenals, ovaries and intestinal epithelia, and campesterol in the adrenals, spleen, intestinal epithelia, ovaries, liver and bone marrow. Excretion is via the faeces as both free sterol and sterol esters (SCF, 2003; ANZFA, 2001).

The toxicokinetics of sterol esters after oral uptake are comparable to those of sterols as they are hydrolysed tofree sterols in the intestine as part of the normal digestive process (ANZFA, 2001).

No information could be found on absorption via the dermal route. However, given their high octanol/water partition coefficient (log Pow >> 8, see Section 1.3), sterols and sterol esters are not expected to be taken up through skin to a significant degree (as per Table R 7.12-3, REACH Endpoint specific guidance R.7c of May 2008).

Squalene

Animal studies indicate that squalene is poorly absorbed from the gastro-intestinal tract and slowly absorbed through the skin. Absorption occurs through the lymphatic vessels (similar to cholesterol), with partial cyclization to sterols during the transit through the intestinal wall. Absorbed squalene is preferentially converted to bile acids in the liver (CIR, 1982).

Little information could be found on absorption via the dermal route. However, given its high octanol/water partition coefficient (log Pow >> 8, see Section 1.3), squalene is not expected to be taken up through skin to a significant degree (as per Table R 7.12-3, REACH Endpoint specific guidance R.7c of May 2008). This is in line with what was seen in a study by Butcher (1951) who saw little evidence that squalene penetrated through the skin of rats when applied dermally.