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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Qualifier:
no guideline followed
Principles of method if other than guideline:
¹⁴C labelled test substances were applied to the dorsal skin using a plaster for a 24 hour period. Immediately following application each animal was placed in a container to measure expiratory excretion. At the end of the exposure period the treated area of skin was excised and dissolved using tissue solubiliser. The carcass was homogenised in a blender with sodium hydroxide. An aliquot of the homogenate was then dried and combusted for determination of radioactivity. The effect of different solvents and concentration of the solvent was also investigated. The role of skin irritation in absorption of test substance was examined.
GLP compliance:
no
Radiolabelling:
yes
Remarks:
14-Carbon
Species:
mouse
Strain:
other: HR/De
Sex:
not specified
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
24 hour exposure
Remarks:
Doses / Concentrations:
0.05, 0.5, 5, 50%
No. of animals per sex per dose / concentration:
3 hairless mice/group
Control animals:
no
Type:
excretion
Results:
The expiratory excretion rate of lauryl alcohol (dodecanol) was 91%; for the other alcohols including decan-1-ol, at least 65% of the absorbed dose was excreted as CO₂ in the expired air.

The publication reported in full the results only for lauryl alcohol (Dodecanol C12) arriving at a value for the expiratory excretion rate which was the ratio of amount of 

compound excreted via expired air to the amount absorbed. It  was 91% for lauryl alcohol. The respiratory excretion rates for all the other alcohols 

investigated were >65% although the actual data is not reported. Following skin application of lauryl alcohol about 2.84 % of  the administered dose  was absorbed. Of this absorbed dose >90% was excreted in expired air (CO2).

Absorption decreased with increasing carbon chain length. The absorption rate was investigated in different solvents (squalene, castor oil, triethyl 

citrate (TEC). The percutaneous absorption rate of undiluted n-octanol was 50%, this was increased in squalene but decreased in castor oil or TEC This was also reported with the other alcohols tested and the tendency was more pronounced at higher concentrations.

The degree of skin irritation reported in the study was proportionally related to the degree of percutaneous absorption.

Conclusions:
Interpretation of results: other: no or very low bioaccumulation potential based on study results
Absorption of decan-1-ol (5% solution in castor oil) was approximately 4.5%; absorption of 100% decan-1-ol was approximately 7%. Absorption of the alcohols tested decreased with increasing carbon chain length and was affected by solvent and concentration; 50% of undiluted octan-1-ol was absorbed, compared with approximately 15% of a 5% solution. The expiratory excretion rate of lauryl alcohol (dodecan-1-ol) was 91%. For the other alcohols, including decan-1-ol, at least 65% of the absorbed dose was excreted as CO₂ in the expired air for the other alcohols.
Executive summary:

The publication reported in full the results only for lauryl aclohol (Dodecanol, C12) arriving at a value for the expiratory excretion rate which was the ratio of amount of 

compound excreted via expired air to the amount absorbed. It  was 91% for lauryl alcohol. The respiratory excretion rates for all the other alcohols 

investigated were >65% although the actual data is not reported. Following skin application of lauryl alcohol about 2.84 % of  the administered dose  was absorbed. 

Of this absorbed dose >90% was excreted in expired air (CO2).

The absorption rate was investigated in different solvents (squalene, castor oil, triethyl citrate (TEC). The percutaneous absorption rate of undiluted n-octanol was 50%, this was increased in squalene but decreased in castor oil or TEC. This was also reported with the other alcohols tested and the tendency was more pronounced at higher concentrations. Overall the study showed that absorption decreased with increasing carbon chain length

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP
GLP compliance:
not specified
Radiolabelling:
yes
Species:
mouse
Strain:
other: HR/De
Sex:
not specified
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Remarks:
also tested in three solvent vehicles: TEC, castor oil and squalane.
Duration of exposure:
24 hours
Doses:
Up to 100% concentration in three vehicles and undiluted
No. of animals per group:
3
Control animals:
no
Dose:
100%
Parameter:
percentage
Absorption:
ca. 7 %
Remarks on result:
other: 24 hours

The percentage absorbance of dose 14C-decyl alcohol (decanol) = ca 8 %. At least 65% of the absorbed dose is excreted as carbon dioxide in the expired air.

When tested diluted in solvent vehicles, the degree of absorption was influenced by the concentration and the type of solvent that was used.

For n-decyl alcohol in squalane, the fraction of the dose that was absorbed varied between approximately 5% of the applied dose at 50% concentration to approximately 27% of the applied dose at 0.5% concentration.

For n-decyl alcohol in castor oil, approximately 5% of the applied dose was absorbed at all tested concentrations (<0.1% - 50%).

For n-decyl alcohol in TEC (triethyl citrate), approx 5 -7% of the applied dose was absorbed at concentations of 0.5 -50%.

Conclusions:
Of a dose of undiluted 1-14C-decyl alcohol applied to the skin of nude mice for 24 hours, 8 % was absorbed.
Executive summary:

Of a dose of undiluted 1-14C-decyl alcohol applied to the skin of nude mice for 24 hours, 8% was absorbed.

Description of key information

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - dermal (%):
7

Additional information

Decan-1-ol is a colourless liquid with a vapour pressure of <5 Pa at 20°C.

Absorption

Based on comparative in vitro skin permeation data and dermal absorption studies in hairless mice, aliphatic alcohols show an inverse relationship between absorption potential and chain length with the shorter chain alcohols having a significant absorption potential. In a well conducted in vivo percutaneous absorption study using mice, the percutaneous absorption rate of decanol was ca 7%. (Iwata et al., 1987). This was confirmed in a reliable in vitro study, where the percutaneous absorption rate of decanol (10% (w/w) FRM in 9:1 (v/v) ethanol: water mixture) using unoccluded porcine skin was ca 8% (Berthauld et al., 2011).

Read across from a well conducted in vitro study using human skin and a structural analogue myristyl alcohol (C14-alcohol), gave a percutaneous absorption rate of 1.2% at 6 hours and 6.3% at 24 hours (P&G, 2008). This confirms the findings of the Iwata paper that aliphatic alcohols show an inverse relationship between absorption potential and chain length. A reliable study which investigated the in vitro percutaneous absorption of decanol using human skin over an 8 hour exposure, and occluded conditions reported a potential absorption of 66%. However it is likely that the occluded conditions of the experiment were the likely factor for such a high percutaneous absorption rate (Buist et al., 2010).

Based on the in vitro studies with mouse (Iwata et al., 1987) and porcine (Berthauld et al., 2011) skin, the absorption of decan-1-ol via intact skin under normal conditions, used in the chemical safety assessment, is 10%.

Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols. With regards to the blood-brain barrier chain-length dependant absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length (Gelman, 1975). Taking into account the efficient biotransformation of the alcohols and the physicochemical properties of the corresponding carboxylic acids the potential for elimination into breast milk is considered to be low.

 

Distribution

Absorbed decan-1-ol potentially could be widely distributed within the body (OECD, 2006). However, as a result of the rapid and efficient metabolism, it is not anticipated that decan-1-ol will remain in the body for any significant length of time.

 

Metabolism

Summary

Long chain fatty alcohols are synthesised within cells and are therefore found within organisms and occur naturally in the environment. Endogenous and exogenous long chain alcohols are metabolised in catabolic (breakdown) and anabolic (synthesis) pathways. Cellular metabolism can cycle between long chain alcohols and their corresponding acids. Alcohols are used as building blocks in the synthesis of lipids for energy storage. Pathways exist for the conversion of alcohols to acids. It is therefore concluded that, should systemic exposure occur to anthropogenic long chain alcohols, mammals including test species and humans share common pathways for their metabolism and the products of metabolism are naturally-occurring metabolites.

Formation of fatty alcohols

It is well-known that naturally-occurring fatty alcohols are to be found in cells of microorganisms, plants, and animals (Weber and Mangold, 1982; Kolattukudy, 1975, 1976).

Fatty alcohols are formed from fatty acids as initial steps in the synthesis of lipids (involving formation of esters by reaction of acids with glycerol); they are also part of the pathways of the catabolism of alcohols to produce energy. The interconversion of fatty alcohols and fatty acids is described in detail below, and has been described as the fatty alcohol cycle (Rizzo et al., 1987; Figure 1 attached). Rizzo et al. demonstrated that both synthesis and oxidation of fatty alcohols takes place within cultured skin fibroblasts. Fatty alcohol is oxidised to the corresponding aldehyde, which is followed by further oxidation to fatty acid, via an enzyme complex (see below). In turn, fatty acids can be converted via the corresponding aldehyde to fatty alcohol. Cells incubated in radioactive palmitate[1] (salts or esters of hexadecanoic acid, C16) showed increased levels of labelled hexadecanol. In the presence of non-labelled hexadecanol, and labelled palmitate, cellular levels of labelled hexadecanol increased up to 10-fold, which suggests that rapid metabolism of palmitate to hexadecanol is occurring.

When incubated in the absence of fatty acid and the presence of labelled hexadecanol, cells rapidly oxidised hexadecanol to palmitic acid (hexadecanoic acid) (Rizzo et al., 1987). Double labelling demonstrated simultaneous interconversion of hexadecanol and palmitic acid. Shorter and longer alcohols are also oxidised by fatty alcohol: NAD oxidoreductase (FAD). In living organisms products from the pathway would be incorporated into other molecules and transported from the cells. More recently, understanding of the fatty acid cycle has helped in the understanding of metabolic disease (Rizzo W.B., 2011; James, P.F., 1990). Cells from individuals lacking an effective part of the enzyme complex accumulate long chain fatty alcohols.

The mammalian alcohol dehydrogenase system is a group of pathways which catalyse the conversion of alcohols and aldehydes, which includes different forms of the enzymes which vary in substrate specificity. The alcohol dehydrogenases (ADHs) are divided into six classes, denoted by ADH1-ADH6. Five of the six classes of alcohol dehydrogenase have been identified in humans. One of the classes, ADH3, is the ancestral form of all mammalian ADHs, and has been traced in all living species investigated. The alcohol dehydrogenase system is considered to be able to detoxify a wide range of alcohols and aldehydes without the generation of toxic radicals (Höög, J-O. et al., 2001). 

Long chain alcohols are also able to be used as substrates in the synthesis of wax esters and of ether glycerolipids (Rizzo W.B., 2011; Shuobo et al., 2012). Synthesis of wax esters has been demonstrated by incorporating genes from a number of bacterial and mammalian organisms into yeast and measuring the transformation of long chain alcohols to waxes (Shuobo et al., 2012). Most of the enzymes were more active in using longer chain alcohols (C12-C20), though the mouse enzyme also used decanol as a substrate. Long chain alcohols are also precursors of lipids in animal tissues (Weber and Mangold, 1982). However, synthesis of complex lipids is less important than metabolism to the corresponding acid via the (fatty) alcohol dehydrogenase system; in the study by Rizzo the majority of [1-14C]hexadecanol was converted to hexadecanoic acid (Rizzo W.B., 1987).

Intracellular concentrations of long chain alcohols

Data on intracellular concentrations of individual alcohols is not easy to find, though it is probably low. The cellular concentration of hexadecanol is reported to be 137 ± 58 pmol/mg protein (Rizzo, 1987). Protein was total cell protein. The low intracellular concentrations is considered to reflect the conversion of long chain alcohols to other substances via catabolic and anabolic pathways. It is not easy to convert such a concentration into mass alcohol per total mass of an organism, since it would depend upon cell type, but reasonable assumptions would convert this into concentrations approaching µg/g.

Decanol and other long chain alcohols are used in pharmaceutical formulations, and their role in promotion of skin penetration has been studied (Kanikkannan N, 2002; Raut et al., 2014). Deuterated alcohols including decanol have been investigated in vivo (in humans) to determine the effect of dermal application on skin lipid content (Dias, M. et al., 2008). It is reported that decanol did not change skin lipid content.

Intracellular concentrations of dodecanol have been assessed in a study on Chinese hamster ovary cells. Strain CHO-K1 (wild-type for fatty alcohol:NAD+ oxidoreductase activity), were reported to have lower intracellular concentrations than a mutant strain FAA.1 which was deficient in FA:NAD+ oxidoreductase activity. The cell had been incubated in serum-supplemented medium[2]. See Table 1 below for data presented in this publication.

Table 1 Fatty alcohol levels in CHO-K1 cells

Cell line

Fatty alcohol level, μg/mg protein

14:0

16:0

18:0

18:1

CHO-K1

0.019

0.021

0.029

0.003

FAA.1

0.068

1.970

1.220

0.962

 

Long chain aliphatic alcohols are metabolised by a pathway that also acts on alkanes and fatty acids (Mudge, 2008; Veenstra et al., 2009). Alkanes may be oxidised to alcohols and alcohols converted via short-lived aldehydes to fatty acids. It is notable that fatty acids obtained from natural sources are exempt from REACH, due to inclusion in REACH Annex V paragraph 8. The fatty acids produced by the action of alcohol dehydrogenase followed by aldehyde dehydrogenation enter the β-oxidation cycle producing acetyl-CoA products (and a propionyl‑CoA from odd chain-length molecules) and ATP. These enzymes are found in the soluble fraction of various tissues, and are relatively non-specific, accepting a wide variety of substrates (de Wolf and Parkerton, 1999). The products enter into the metabolic processes of the cells. Both alcohol (FAD) and aldehyde dehydrogenase (FALDH) enzymes (used in conversion to fatty acids) are ubiquitous in the plant and animal kingdoms but the location of the relevant enzyme system, the chemical specificity and the rate at which the reaction occurs differ between phyla and species. There are many publications in the public domain which describe the cellular metabolism of alcohols and the ubiquity of the enzymes involved (Höög, J-O et al., 2001; Duester, G et al., 1999; Menzel et al., 2001).

An in vitro study of the biotransformation of linear and multiple-branched fatty alcohols (C12, C14) has been conducted (Menzel et al.,2001), with the intention to examine the pathway and relative rate of metabolism of linear compared to branched alcohol structures. The in vitro test system used either pig liver or fish (rainbow trout) liver homogenate as the source of the metabolic enzymes, and substance-specific GC analysis to follow the conversion of the alcohols into the corresponding fatty acids over a ten day period. The results demonstrated that in pig liver homogenate an intensive metabolism of the alcohols to the corresponding fatty acids takes place, with half-lives 3.8 d for C12, 6.7 d for C14 and 8 d for C12 branched alcohols. Photometric measurements of the esterase activity indicated that the fish liver homogenate was at least ca. ten times less active; this was ascribed to the overall lower metabolic activity of cold-blooded animals though the possible role of method of sample preparation is noted, though the exploration of these matters was not the objective of this study. The conclusion of this study was that linear C12 alcohol was degraded more rapidly than the C12 multiply-branched equivalent, by a factor of ca. 2.5.

Mammalian synthesis of alcohols begins with formation of fatty acids, formed by Type I synthesis in mammals. Type I synthesis is a series of reactions in a single complex produces hexadecanoic acid (C16), occasionally C18 is formed. In addition, subsequent reactions can produce longer chains, and unsaturation of the C9-C10 bond. Some essential fatty acids cannot be synthesised because they have an unsaturated bond at a different position in the molecule. Fatty acids can be elongated or shortened by addition or removal of two-carbon units in normal metabolic processes (Mudge, 2005; Mudge, 2008; Lehninger, 1993). Fatty alcohols are formed from fatty acids through the two step fatty acid reductase (FAR) process, involving fatty acyl-CoA dehydrogenase which converts a fatty acyl-CoA into a fatty alcohol and CoASH.

Metabolic degradation of long chain alcohols

The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial β -oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficiently broken down in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in the β-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, β-oxidation continues as with saturated carboxylic acids (WHO, 1999). 

An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via ω- or ω-1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chain-shortening pathway for branched aliphatic acids (Verhoeven et al., 1998). The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al, 1971 a and b and Mukherjee et al. 1980). A small fraction of the aliphatic alcohols (generally less than 10%) may be eliminated unchanged or as the glucuronide or sulfate conjugate (Kamil et al., 1953; McIsaac and Williams, 1958). Studies using labelled hexadecanol found up to 23% free phospholipid in the blood. Phospholipid, triglyceride and diacyl glyceryl ether were found to have taken up significant radiolabel. This indicates that this substance is incorporated into normal lipid metabolism pathways (Friedberg, 1976). It is considered that decan-1-ol would also be incorporated into lipid metabolic pathways. Saturated linear primary alcohols have been evaluated by JECFA who concluded that “1-decanol is oxidised to decanal which is rapidly oxidised to decanoic acid; decanoic acid is metabolised via the fatty acid and tricarboxylic acid pathways.” (JECFA, 1999). Other saturated linear primary alcohols with different chain lengths (C4-C16 inclusive) are metabolised in a similar way (JECFA, 1999).

A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single carbon unit is removed before the C2 elimination can proceed.

   

Elimination

When rats were given an oral dose of 1-octanol, a close analogue of decan-1-ol, only trace amounts (<0.5%) of unchanged alcohol were detected in the faeces (Miyazaki, 1955). Faecal recoveries of unchanged alcohol were 20 and 50%, respectively, when rats were given an oral dose of the higher alcohols 1-hexadecanol and 1-octadecanol (McIsaac and Williams, 1958; Miyazaki, 1955).

 

Following the 24-hour application of the close analogue 1-dodecanol (radiolabelled with 14C) to skin of hairless mice, more than 90% of the absorbed dose was excreted in expired air and 3.5% was eliminated in the faeces and urine after 24 hours; only 4.6% of the absorbed dose [representing 0.13% of the applied dose] remained in the body (Iwata et al. 1987). A similar general pattern of extensive and rapid excretion would also be expected for decan-1-ol.

 

The glucuronic acid conjugates formed during the metabolism of most aliphatic alcohols are excreted in the urine (Wasti, 1978; Williams, 1959). For 1-octanol, 9.5% of an oral dose was excreted by rabbits in urine as glucuronide (Kamil et al. 1953). Although lipophilic alcohols such as 1 -decanol have the physiochemical potential to accumulate in breast milk, rapid metabolism to the corresponding carboxylic acid followed by further degradation suggests that breast milk can only be, at most, a minor route of elimination from the body (OECD, 2006). 

 

[1] Palmitic acid is the common name for hexadecanoic acid. Radiolabelled palmitic acid (1-14C or 9,10-3H) was bound to fatty acid-free bovine serum albumen in a 1:1 ratio, The protocol used for extraction of fatty acid and fatty alcohol enabled both free and esterified fatty acids and alcohols to be measured.

[2] Ham’s F-12 medium containing 10% (vol/vol) foetal bovine serum supplemented with 1 mM glutamine.

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