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Additional information

Justification for grouping of substances and read-across

In the following, the key elements of the justification for grouping of substances into the category Dimerised Fatty Acids and its Derivates and for read-across among the category substances are presented in summary. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, through the use of alternative methods, for example, in vitro methods or qualitative or quantitative structure-activity relationship models or from 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 in the following table are allocated to the category of Dimerised Fatty Acids and its Derivatives.

 

 

ID #

CAS No.

EC No.

Common Name

Chemical Name

#1

61788-89-4

500-148-0

Dimer

Fatty acids, C18-unsaturated, dimers

#2

68937-90-6

500-239-5

Trimer

Fatty acids, C18-unsaturated, trimers

#3

68783-41-5

500-231-1

Hydrogenated dimer

Fatty acids, C18-unsaturated, dimers, hydrogenated,

#4

71808-39-4

615-494-9

Crude dimer

Fatty acids, C16-C18 and C18-unsaturated, dimerized

#5

68955-98-6

273-295-9

Monomer acid

Fatty acids, C16-18 and C18-unsaturated, branched and linear

#6

68201-37-6

269-214-1

Hydrogenated monomer acid

Octadecanoic acid, branched and linear

#7

30399-84-9

250-178-0

 

Isooctadecanoic acid

 

 

Grouping of substances into this category is based on:

(1) common functional groups:

The general overall profile is restricted to substances that are products or by-products of the dimerisation of C16-18-unsaturated fatty acids. As UVCB substances derived from natural sources, members of this category are chemically similar as they are all essentially a complex mixture of C16-C18 unsaturated and saturated, branched and linear fatty acids, their monomers, dimers and trimers with varying structural geometric isomers, such as acyclics, cyclics and possible aromatics and polycyclics as well. In the category family, all substances have an overlap in regard to their composition. Thus, the Dimerised Fatty Acids and its Derivatives category covers monomers, dimers and trimers derived from C16-C18 unsaturated fatty acids, as well as their hydrogenated products in different proportions and in accordance with their corresponding production and purification processes;

(2) common precursors and/or the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals:

Regarding common precursors, Dimerised Fatty acids are commercial products industrially processed by unspecific dimerisation of typical, (unsaturated) fatty acids of the parent triglycerides, which consist of a combination of oleic acid (cis-9-Octadecenoic acid), linoleic acid (cis, cis- 9,12-Octadecadienoic acid) and linolenic acid (cis, cis, cis- 9,12,15-Octadecadienoic acid). Specific raw materials also contain small amounts of unsaturated fatty acids based on 16 carbons. Dimeric acids (C36) are the major product, although substantial amounts of monomeric (C18) and trimeric (C54) acids are also produced. All products contain unsaturated or saturated, linear, branched and cyclic hydrocarbons with carbon chain length C16 or C18 which result from the hydrogen transfer reactions, double bond isomerisations and alkyl chain branching which occurs during the reaction, leading to a very complex product composition (Koster et al. 1998).

For the dimerised fatty acids described within this category the “Crude Dimer” (Substance #4, CAS 71808-39-4) is used as feedstock for the further production route of “monomeric dimerised fatty acids”, "dimeric dimerised fatty acids” and "trimeric dimerised fatty acids”. Within this process the Crude Dimer is subject to a fractional distillation pathway which yields the Standard Dimer (substance #1) and Trimer (substance #2), and also by hydrogenation of the corresponding dimer it also yields the Hydrogenated Dimer (substance #3). In parallel, the fraction of monomer mixture (substance #5) and its derivatives (substances #6 and #7), are also obtained as by-product of the dimerisation process. Substance #6, Hydrogenated monomer acid, can in fact be considered to be an intermediate of this process between the Monomer acid (substance #5) and the Isooctadecanoic acid (substance #7).

Concerning the likelihood of common breakdown products via biological processes, as discussed in the assessment of toxicokinetic behaviour given below, all members of the category are considered to follow the same ADME pathways of fatty acids given their chemical nature. Shortly, after oral exposure unsaturated monomeric C16-C18 fatty acids are more readily absorbed than saturated fatty acids such as octadecanoic and isooctadecanoic acid (but still less absorbed than fatty acids of shorter chain length). Cyclic fatty acids which may be found in mono- and dimeric acid mixtures are also absorbed to a similar extent as the corresponding linear fatty acids. Very low absorption is expected for dimeric and trimeric fatty acids via the gastrointestinal tract due to their molecular weight, thus much of the ingested substance is excreted in the faeces. Absorbed fatty acids undergo rapid metabolisation (via β- or ω-oxidation) and excretion either in the expired CO2or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic and aromatic fatty acids.

Due to their physico-chemical properties, the dermal absorption potential of all category members is expected to be low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low. In support of this, in vitro and in vivo data available for several fatty acids indicate that the skin penetration potential decreases with increasing chain length; and

(3) constant pattern in the changing of the potency of the properties across the category:

The category of Dimerised Fatty Acids and its Derivatives is based on similarities in physicochemical and toxicological properties and 2 sub-categories were further defined on the basis of their environmental fate and environmental toxicity. The first sub-category covers three monomeric (#5 -7) (by-) products of the dimerisation process (readily biodegradable substances). The second sub-category covers the predominately oligomers (#1 -4) (dimeric and trimeric products) of dimerisation based on their lack of biodegradability and the environmental fate.

- Physicochemical properties: substances are liquid to viscous under ambient conditions, the boiling point determination is not anticipated because of a thermal decomposition, the vapour pressure under ambient conditions is negligible and thus photodegradation in air is not relevant, all substances show low water solubility.

-Toxicological properties: no human health hazards were identified from the available data from all category members. Thus, the tested substances showed no acute oral toxicity, no skin or eye irritation, no skin sensitisation, no genetic toxicity in vitro, no indications for toxicity to reproduction and, with a subchronic oral NOAEL (rat, male) of 741 mg/kg bw/day, a low level of toxicity after repeated oral exposure.

- Environmental fate and eco-toxicological profiles:

Sub-category 1 (#5 - #7): The substances have no hydrolysable groups. Therefore they are not susceptible to hydrolysis. Photodegradation would not be expected under normal environmental conditions. The predicted logKoc is in the range of 4-4.5. Introducing double bonds and branching has no significant effect on the estimated values. Similar for biodegradation, the comparability of linear and essentially-linear monomeric fatty acids is demonstrated by the consistency of data for ready biodegradability of substances containing branched, linear and unsaturated components. Aliphatic carboxylic acids are generally highly efficiently metabolised and there is limited potential for uptake and retention or bioaccumulation for the parent fatty acids and their biotransformation products.

Substances of this sub-category have low water solubility. No toxicity was observed in any of the tests for aquatic organisms for all three trophic levels, up to the limit of water solubility. By considering the ready biodegradability (> 60% within 28d) and low potential of exposure a long term terrestrial and sediment toxicity is not expected.

Sub-category 2 (#1 - #4): The substances have no potential hydrolysable groups. Therefore they are not susceptible to hydrolysis. Photodegradation would not be expected under normal environmental conditions. The estimated log Koc is > 5. The adsorption potential of substances in this sub-category increases with chain length, i. e. the degree of polymerisation. Introducing double bonds and branching has no significant effect on the estimated values. The members of this sub-category are not readily biodegradable in the environment. Aliphatic carboxylic acids are generally highly efficiently metabolised and there is limited potential for uptake and retention or bioaccumulation for the parent fatty acids and their biotransformation products.

Substances of this sub-category have negligible water solubility (< 0.52 mg/L below the limit of detection, respectively). No toxicological effects were observed in any of the short-term tests carried out with freshwater and marine species of three trophic levels (fish, Daphnia, algae) or long-term test with fish (Danio rerio), for substances within the category up to the water solubility of the tested substances, therefore category members Dimerised Fatty Acids and its derivatives can be regarded as not harmful for aquatic organisms. However, the environmental behaviour (not readily biodegradable, high adsorption potential) of the substances indicate that if released to soil, the exposure of terrestrial organisms to longer chain dimers and trimers cannot be excluded.

In accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, in order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of human health hazards. Thus where applicable, human health effects are predicted from adequate and reliable data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach).

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2008), assessment of the toxicokinetic behaviour of the substance was conducted to the extent that can be derived from the relevant available information on physicochemical and toxicological characteristics. Furthermore, the available information on structurally related substances, namely naturally occurring even-numbered C16-C18 saturated and unsaturated fatty acids such as palmitic, stearic, oleic and linoleic acid, was also taken into account.

All of the members of this category of substances are derived from C16-C18 unsaturated fatty acids and, consequently, consist of monomers, dimers, trimers and isomers of mainly C16-C18 fatty acids in different proportions and in accordance with their corresponding production and purification processes. C16-C18 saturated and unsaturated fatty acids such as palmitic, stearic, oleic and linoleic acid occur naturally in different vegetable oils. Upon heating, vegetable oil fatty acids may undergo isomerisation (e. g. cyclisation, branching) as well as di- and oligomerisation.

For the purpose of assessment of toxicokinetic behaviour, read-across from C16-18 saturated and unsaturated fatty acids as such and/or contained in (heat-treated) vegetable oils is justified in accordance with Annex XI, Item 1.5 of Regulation (EC) 1907/2006, based on common functional groups (C16-C18 fatty acids, monomeric or iso- and/or dimerised upon heating), on common precursors (all fatty acids considered here are the result of the same endogenous lipid biosynthesis pathways in plants) and common breakdown products via biological processes (fatty acid metabolism, e. g. via mitochondrial β-oxidation). Therefore, available data on absorption, distribution, metabolism and excretion of natural fatty acids and heated vegetable oils were considered for the assessment of toxicokinetic behaviour of the category members.

Absorption

Fatty acids, C18-unsaturated, dimers (hydrogenated and not hydrogenated) and isooctadecanoic acid have been tested in acute oral toxicity studies, resulting in LD50 values greater than 5000 and 2000 mg/kg bw, respectively, without signs of toxicity or any other effects. These studies therefore provide no adequate evidence for potential absorption or non-absorption via the oral route. However, given that all members of the category are lipophilic and show low water solubility, absorption via the gastrointestinal tract may still occur by micellar solubilisation followed by transport via the lymphatic system and esterification with glycerol as described for some fatty acids (CIR, 1987, 2001; IOM, 2002). For fatty acid dimers this also appears to be true, as indicated in a 13-week feeding study in rats in which aggregation of macrophages, some of which were pigmented, were seen on microscopic examination of the mesenteric lymph nodes and the spleen. The incidence and amount of pigmented macrophages was dose-dependent (Spurgeon and Hepburn, 1993).

The oral bioavailability of the substances within the category is expected to strongly depend on molecular weight, chain length and degree of unsaturation. According to the “Lipinski Rule of Five” (Lipinski et al. (2001)) which was refined by Ghose et al. (1999), poor absorption or permeation of substances is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight is greater than 500 and the n-octanol/water partition coefficient is greater than 5. When applying the “Rule of Five” to the substances within the category, except for the monomers, a low to negligible absorption after oral administration is expected. This hypothesis is supported by the available study results on surrogate substances.

In general, short-chain or unsaturated fatty acids are more readily absorbed than long-chain, saturated fatty acids. Among common fatty acids, stearic acid (C18:0) is the most poorly absorbed. Thus, the absorption of palmitic (16:0), stearic (18:0), oleic (18:1) and linoleic (18:2) acid from vegetable oils has been shown to be 75, 62, 92 and 94%, respectively, in studies with human infants (Jensen et al., 1986; IOM, 2005). Increasing chain length is suggested to slightly decrease digestibility (Bernard and Carlier, 1991; CIR, 1987; Clayton and Clayton, 1982; Opdyke, 1979).

Long-chain saturated fatty acids in the intestinal lumen are less readily solubilised into mixed micelles than are unsaturated fatty acids. Due to the alkaline conditions of the intestine, they can form insoluble soaps with divalent cations (such as calcium) and be excreted. After being absorbed, long-chain saturated fatty acids are esterified along with other fatty acids into triglycerides and released in chylomicrons. 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 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 (CIR, 2001; IOM, 2005).

As a result of the dimerisation reaction, cyclic and aromatic isomers of fatty acids may be present in some of the substances within the category. With respect to oral absorption, studies on cyclic monomers of fatty acids have shown that they are well absorbed and may become incorporated in different tissues (Boatella-Riera et al., 2000; Iwaoka and Perkins, 1978).

Dimeric and oligomeric fatty acids appear to be less absorbed than monomeric acids, as indicated by studies carried to investigate the absorption, distribution and excretion of the polymeric fraction of heated cooking oils of vegetable origin.

Heated refined soybean oil, heated Primor colza oil and triglycerides containing 9-(2'-Propyl benzene) nonanoic acid or 9-(2'-Propyl cyclohex-4'-en-1'-yl) nonanoic acid were administered to thoracic-cannulated rats (ca. 3 mL/kg bw, single dose) and the lymph was continuously collected for 48 h. Approximately 4% of the total polymerised fatty acids, 53% of the total monomeric oxidised fatty acids and 96% of the total cyclic monomers of fatty acids were absorbed as determined by analysis of the recovered lymphatic fatty acids (Combe et al., 1981).

Methyl esters of the oxidation products obtained from heat-abused randomised labelled corn oil were fed to thoracic duct-cannulated rats (1 g, single administration). The lymph was collected and the lipids were analysed by thin-layer chromatography (TLC) and radioassayed. A maximum absorption of the methyl esters of the non-volatile oxidation products did not occur until 21 to 48 h after it had been fed, and only 31.2% was absorbed within 48 h after its administration (Perkins et al., 1970). Details on the composition of the non-volatile oxidation products, as to the proportion of mono- and polymeric fatty acids, were not given.

In a digestibility study, rats were fed olive oil, oil heated at 180 °C for 150 h and 1:1 unheated/heated mixtures12 and 20% in basal fat-free diet for 14 days. Analysis of faecal lipids indicated high digestibility of nonpolar fatty acid monomers (94.8% on average). Oxidised fatty acid monomers from heated olive oil had an apparent average absorption of 76.7%. Nonpolar dimers had the lowest average digestibility (10.9%), while oxidised dimers and polymers showed higher apparent absorbability, ranging from 22.7% to 49.6% (Márquez-Ruiz et al., 1992).

In a lymph cannulation study, rats were given14C-labelled dimeric acid methyl esters via gastric intubation. After 12 h only 0.4% of the radioactivity was recovered in the lymph (Hsieh and Perkins, 1976).

Other studies investigating the systemic distribution and excretion of14C-labelled dimeric fatty acid methyl esters provide further evidence for a low level of oral absorption of dimeric fatty acids, as described below.

Distribution

Absorbed saturated and unsaturated fatty acids are distributed all over the organism and can be uptaken by different tissues. Proposed uptake mechanisms range from passive diffusion to facilitated diffusion or a combination of both (Abumrad et al., 1984; Harris et al., 1980). Fatty acids can be stored as triglycerides (98% occurring in adipose tissue depots), be incorporated into cell membranes or they are oxidised via the β-oxidation and tricarboxylic acid cycle pathways of catabolism (Masoro, 1977; CIR 1987, 2001; IOM, 2005).

In studies with rats orally given methyl esters of uniformly labelled cyclic fatty acid monomers, low levels of radioactivity were recovered from the gastrointestinal tract (ca. 1.62%), liver (ca. 0.97%), epidydimal (ca. 0.38%) and perirenal fat (ca. 0.58%) at 48 h post-administration (Iwaoka and Perkins, 1978).

The fraction of orally bioavailable dimeric fatty acids appears to follow the same pattern of distribution. In rats fed14C-labelled dimeric acid methyl esters via gastric intubation, about 0.115% of the administered test material was incorporated in the liver and metabolised to different lipid classes. Only ca. 0.04-0.05% was incorporated in epidydimal and perirenal fat, respectively. In comparison, rats given14C-labelled methyl oleate showed that ca. 0.4, 3.7 and 6% of the administered dose was incorporated in the liver, epidydimal and perirenal fat, respectively. In average, ca. 34% were expired as14CO2and ca. 0.9% excreted via urine (Hsieh and Perkins, 1976).

In another study, methyl esters of14C-labelled dimeric fatty acids prepared from uniformly labelled methyl oleate by the method of Paschke et al. (1964) were orally given to rats by gavage. At 48 h post-administration, rats were killed and selected organs were removed for analysis. A low level of incorporation was observed in the liver (ca. 5.5%) and the adipose tissues analysed (Epidydimal and perirenal fat: ca. 1.4 and 1.7%, respectively) (Perkins and Taubold, 1978).

Accumulation

As mentioned above, fatty acids can be stored as triglycerides in adipose tissue depots or be incorporated into cell membranes. At the same time, fatty acids are also required as a source of energy. Thus, stored fatty acids underlie a continuous turnover as they are permanently metabolised and excreted. Bioaccumulation of fatty acids takes place, if their intake exceeds the caloric requirements of the organism.

Cyclic isomers of fatty acids appear to be metabolised into polar metabolites, which cannot be further degraded by β- or ω-oxidation and which are rapidly excreted via urine (Iwaoka and Perkins, 1976). In a similar way after oxidative degradation of the C-chain(s), aromatic isomers of fatty acids are expected to be metabolised into polar molecules by enzymes of the Phase I and II metabolism followed by excretion in the urine. Therefore, no significant accumulation is expected.

The available information indicates that dimeric (and consequently higher oligomerised) fatty acids are poorly absorbed and that the absorbed fraction follows the same pattern of metabolism and excretion as the monomeric acids. Thus, no significant bioaccumulation in adipose tissue is expected.

Metabolism

The β-oxidation of fatty acids takes place in most vertebrate tissues using an enzyme complex for a series of oxidation and hydration reactions which result in the cleavage of acetate groups as acetyl CoA. The alkyl chain length is reduced by 2 carbon atoms in each β-oxidation cycle, thus releasing acetic acid. Another carboxyl group remains on the shortened alkyl chain for further β-oxidation. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerisation reaction is required. Alternative pathways for oxidation can be found in the liver (ω-oxidation) and the brain (α-oxidation) (CIR, 1987). Thus iso-fatty acids such as isooctadecanoic acid have been found to be activated by acyl coenzyme A synthetase of rat liver homogenates (Lippel, 1973) and to be metabolised to a large extent by ω-oxidation (CIR, 1983).

The14CO2expired by rats orally given dimers probably arises from β- or ω-oxidation of the dimeric fatty acid, followed by oxidation of the resulting Acetyl-CoA into water and CO2during the tricarboxylic acid cycle (Hsieh and Perkins, 1976).

The cyclic portion of mono- and dimers cannot be degraded by β- or ω-oxidation and is probably hydroxylated or conjugated, which are common detoxification mechanisms of cyclic compounds, leading to polar metabolites readily excreted via urine (Iwaoka and Perkins, 1976). Likewise, after oxidative degradation of aromatic fatty acids, the remaining structure can be excreted in the urine after conjugation with glycine or glutamine in a similar way as in the case of benzoic and phenylacetic acid, respectively (WHO, 2000; Caldwell et al., 1980). The aromatic ring structure itself can also serve as substrate of Phase I metabolism enzymes (cytochrome P450) followed by the formation of hydrophilic conjugates (e. g. glucuronide and sulfate conjugates) in Phase II metabolism and excretion via urine.

Excretion

In general, fatty acids are entirely catabolised by oxidative processes resulting in carbon dioxide and water as the principal excretion products. Small amounts of ketone bodies arising from the oxidation of fatty acids are excreted via the urine (IOM, 2005).

Metabolised fatty acids are mainly excreted via expired CO2. The turnover of14C-labelled surfactants of increasing chain length (soap solutions of fatty acid sodium salts) was tested in rats after intraperitoneal and subcutaneous application. Decanoic acid (C10:0), dodecanoic acid (C12:0), tetradecanoic acid (C14:0), hexadecanoic acid (C16:0) and octadecanoic acid (C18:0) were given in a single dose (ca. 1.09, 1.18, 1.36, 1.55 and 1.64 mg/kg bw, respectively) to groups of 6 rats per test substance, 3 animals treated i. p., the other 3 by injection. Total urine, faeces and expired air were collected for 6 h and analysed radiometrically. At 6 h post-application, all animals were sacrificed and prepared for14C-determination in the carcass. The turnover of the14C-surfactants in the rat showed that there was no significant difference in the rate or route of excretion of14C given by intraperitoneal or subcutaneous administration. The main route of excretion was as14CO2in the expired air at 6 h after administration. The remaining material was incorporated in the body. Longer fatty acid chains are more readily incorporated than shorter chains. At ca. 1.55 and 1.64 mg/kg bw, 71% of the C16:0 and 56% of the C18:0 was incorporated and 21% and 38% was excreted as14CO2, respectively (Howes, 1975).

Studies with rats orally given methyl esters of uniformly labelled cyclic fatty acid monomers indicated that, after 48 h, ca. 40% of the total radioactivity is found in the urine (ca. 60% thereof being excreted within the first 12 h). About 14% of the total radioactivity was expired as14CO248 h post-administration, with a peak expiration at 4-6 h. (Iwaoka and Perkins, 1978).

Methyl esters of the oxidation products obtained from heat-abused randomised labelled corn oil were fed to thoracic duct-cannulated rats (1 g, single administration). 18.7% of the dose was metabolised within 48 h after its administration. Approximately 7.6% of the radioactivity was found in the carcass, 1% in the liver, 5.9% in the gastrointestinal tract, 4.5% in the urine, and 62.8% in the faeces (Perkins et al., 1970).

Rats fed14C-labelled dimeric acid methyl esters via gastric intubation excreted ca. 1% of the labelled material via urine and ca. 2% as CO2. Ca. 80% of the radioactivity was recovered in the gastrointestinal tract and the faeces (Hsieh and Perkins, 1976).

In another metabolic study, methyl esters of14C-labelled dimeric fatty acids prepared from uniformly labelled methyl oleate by the method of Paschke et al. (1964) were orally given to rats by gavage. Animals were placed in metabolic cages for 48 h and urine, faeces and expired CO2were collected. In average, ca. 85% of the recovered radioactivity was found in the gastrointestinal tract and faeces, ca. 1% in urine and ca. 5% in the expired CO2. Based on the study results, the authors concluded that the absorption of noncyclic dimers via the gastrointestinal tract appears to be limited to ca. 10%, which is then metabolised (Perkins and Taubold, 1978).

Taken together, the available data allow the recognition of trends in toxicokinetic behaviour of mono- and oligomeric fatty acids, which are likely to apply to the members of the category. Hence, after oral exposure unsaturated monomeric C16-C18 fatty acids are more readily absorbed than saturated fatty acids such as octadecanoic and isooctadecanoic acid (but still less absorbed than fatty acids of shorter chain length). Cyclic fatty acids which may be found in mono- and dimeric acid mixtures are also absorbed to a similar extent as the corresponding linear fatty acids. Very low absorption is expected for dimeric and trimeric fatty acids via the gastrointestinal tract, thus much of the ingested substance is excreted in the faeces. Absorbed fatty acids undergo rapid metabolisation and excretion either in the expired CO2or as a hydroxylated or conjugated metabolite in the urine in the case of cyclic and aromatic fatty acids.

Dermal absorption

There is no information available on the dermal absorption of fatty acids, C18 -unsaturated, dimers or other members of the category.

However due to their physicochemical properties, the skin penetration potential of all category members is expected to be low. Penetration of the stratum corneum is facilitated by high lipophilicity, but because of the low solubility in water, transfer into the epidermis and hence dermal uptake is likely to be low. In addition, for dimerised and trimerised fatty acids large molecular weights are expected (around 500 and above), and therefore dermal absorption can be regarded as negligible for these category members.

In support of this, data available for several fatty acids indicate that the skin penetration both in vivo (rat) and in vitro (rats and human) decreases with increasing chain length. Thus, after 24 h exposure about 0.14% and 0.04% of C16 and C18 soap solutions are absorbed through human epidermis applied in vitro at 217.95 µg C16/cm² and 230.77 µg C18/cm². At 22.27 µg C16/cm² and 24.53 µg C18/cm², about 0.3% of both C16 and C18 soap solutions is absorbed through rat skin after 6 h exposure in vivo (Howes, 1975).

As mentioned above, all category members are derived from unsaturated fatty acids. Fatty acids, tall-oil (which predominantly contains C18 unsaturated fatty acids) as well as some C16-C18 fatty acids, isostearic (isooctadecanoic) acid and diesters of dilinoleic acid (dimer acid) have been assessed for their safety in the context of cosmetic use. On the basis of the data from studies using animals and humans, it was concluded that these materials are safe as cosmetic ingredients in the present practices of use (CIR, 1983, 1987, 1989, 2003).

 

References (not in IUCLID)

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Bernard, A. and Carlier, H. (1991). Absorption and intestinal catabolism of fatty acids in the rat: effect of chain length and unsaturation. Experimental Physiology 76:445-455

Caldwell et al. (1980) in Extrahepatic metabolism of drugs and other foreign compounds, GRAM T.E. Ed., MTD Press, Lancaster UK, 453-492.

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

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.

CIR (1987) Final report on the safety assessment of Tall Oil Acid.J. of the Am.Coll. ofToxicol.8(4):769-776.

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CIR (2003) Final Final Report on the Amended Safety Assessment of Diisopropyl Dimer Dilinoleate, Dicetearyl Dimer Dilinoleate, Diisostearyl Dimer Dilinoleate, Dioctyl Dimer Dilinoleate, Dioctyldodecyl Dimer Dilinoleate, and Ditridecyl Dimer Dilinoleate.J. of the Am. Coll. of Toxicol.22(Suppl. 2):45-61.

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Harris, P., Gloster, J.A. and Ward, B.J. (1980) Transport of fatty acids in the heart. Arch. Mal.Coeur73(6): 595-598.

Iwaoka W. T., Perkins E. G. (1976). Nutritional effects of the cyclic monomers of methyl linolenate in the rat. Lipids 11:349-353

Institute of 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

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

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Opdyke, D.L. (Editor) (1979) Monographs on fragrance raw materials. Stearic acid. Food Cosmet. Toxicol.117(4): 383-8.

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