Hydrocarbons, C18-C24, iso-alkanes <2% aromatics

Endpoint summary

Additional information

Hydrocarbons are absorbed through the lung and the gastro-intestinal tract. They are widely distributed and excreted in urine or in exhaled air, depending on volatility. They are metabolised by ω- or ω-1 oxidation to the alcohol, and thence to the fatty acid. Fatty acids derived from hydrocarbons are likely to enter intermediary metabolism (including β–oxidation) and to be excreted in bile, in urine or in exhaled air (as carbon dioxide).

Oral absorption

Experimentally, the absorption of a wide range of hydrocarbons, including individual linear, branched and cyclic paraffins, was investigated in the male C-D rat following oral administration of simple mixtures of equal amounts of 3 or 4 different hydrocarbons at various doses, ranging from 50 to 530 mg/kg bw (Albro and Fishbein, 1970). The absorption of hydrocarbons was found to be inversely proportional to the carbon number according to the following equation (correlation coefficient 0.995; p<0.001):

Percentage retained = 115.9 – (3.94 x number of carbon atoms)

There was no statistically significant difference in the percentage absorbed for different isomers (branched or cyclic) compared to their n-aliphatic isomers (p >0.9). An almost constant percentage was absorbed between 60 and 320 mg/kg bw but at higher doses (up to 530 mg/kg bw) a gradual decrease to 70% of the maximum was observed (Albro and Fishbein, 1970).

This experimentally determined equation predicts that hydrocarbons with carbon numbers greater than 30 are not absorbed to a significant extent.

The validity of the Albro and Fishbein equation has been confirmed for a number of hydrocarbons in different studies. For instance, squalane (2,6,10,15,19,23-hexamethyltetracosane, C₃₀H₆₂) is experimentally used as a marker for balance studies since it is not absorbed to a significant extent (Morgan and Hoffman, 1970; Low et al., 1992) while the radiolabelled marker 1-[¹⁴C]-1-eicosanyl-cyclohexane was absorbed for 11% in a study on the pharmacokinetics of white oils, which is essentially equal to the predicted value of 13% (Halliday et al., 2002).

A large number of (sub)chronic studies has been performed on a wide range of food-grade white oils and waxes. These substances consist of linear, branched and cyclic hydrocarbons with carbon numbers ranging from C14 to C80. In one of these studies, F344 rats, a rat strain known to be most sensitive to accumulation of hydrocarbons, were fed 5 white oils and waxes at a level of 2% in the feed for 28 and 90 days. Chemical characterisation of the absorbed material revealed that hydrocarbons are selectively absorbed between C20 to C35 (Scotterer et al., 2003; Freeman et al., 1993). A summary of the available data on 12 white oils and waxes clearly shows that uptake was inversely related to molecular weight and viscosity but not oil type or processing. It was also clearly shown that substances with hydrocarbon chain lengths C20 to C30 were absorbed to a significant extent whereas substances with hydrocarbon chain lengths C35 to C70 had no significant absorption (Freeman et al., 1993).

The relationship between carbon number and amount retained has been predicted for the registration substance, Hydrocarbons, C18-C24, isoalkanes, <2% aromatics (GS310) and the analogue substance GTL Gasoil (C8-C26). The predictions indicate an inverse relationship between carbon number and amount retained. For example, C10 shows an effective absorption of 77%, which drops to 37% by doubling the carbon chain length to C20 (Table 5.0.1).

Based on the estimated absorption for each carbon number and compositional information (approximated) of GTL Gasoil and GS310 the relative absorption for each carbon number can be estimated (Table 5.0.2). The relative absorption is the amount of the hydrocarbon absorbed (by carbon number) based on its individually calculated absorption and composition (% concentration) in the GTL substance (carbon# relative abs. = carbon# estimated abs. * carbon# conc. /100). From the relative absorption it is estimated that relatively more GTL Gasoil is absorbed than GS310 (48 vs 34% respectively). Therefore, for an oral dose of 5000 mg/kg bw of GT Gasoil, the effective dose would be about 2500 mg/kg bw whereas that of GS310 would be 1500 mg/kg bw. It is therefore reasonable to assume that acute oral data of GTL Gasoil represents a “worse-case” estimation for GS310.

  

Table 5.0.1  Estimated relative oral absorption for carbon numbers based on their approximate composition (concentration) in GTL Gasoil or GS310

Carbon number	Estimated absorption %	GTL Gasoil		GS310 *
		composition (%)	relative absorption (%)	composition (%)	relative absorption (%)
8	84	1	0.1
9	80	1	0.4
10	77	2	1.4
11	73	3	2.4
12	69	5	3.5
13	65	7	4.3
14	61	9	5.3
15	57	9	5.3
16	53	9	4.9	1	0.5
17	49	10	4.7	4	2
18	45	8	3.8	10	4.5
19	41	8	3.2	15	6.2
20	37	7	2.7	16	5.9
21	33	6	2.1	16	5.3
22	29	6	1.7	14	4.1
23	25	4	1.1	10	2.5
24	21	3	0.6	7	1.5
25	17	2	0.3	4	0.7
26	13	1	0.1	3	0.4
Total		100	48	100	34

 

Dermal absorption

Quantitative studies, in vitro or in vivo models demonstrated that hexadecane and docosane do not penetrate below the dermis and are retained primarily in the stratum corneum regardless of vehicle utilised. 95-98% of topically applied n-hexadecane did not penetrate fresh intact porcine skin (Brown et al., 1995). Further studies show that dermal absorption of C10-C12 is low with permeability coefficients inversely proportional to carbon number (Kim et al., 2006).

It is concluded that dermal absorption of the registration substance Hydrocarbons, C18-C24, isoalkanes, <2% aromatics (GS310) will be low, with most of the substance being retained in the stratum corneum. Low dermal penetration with increasing carbon number is predicted for the analogue substance GTL Gasoil (C8-C26), this is supported by the lack of acute toxicity following dermal exposure to GTL Gasoil (SafePharm, 2006).

Conclusion

In conclusion, toxicokinetic studies with various complex substances containing linear, branched and cyclic petroleum-derived hydrocarbons show that absorption is inversely correlated with carbon chain length and independent of isomeric form, preparation process or type of product. Adsorption via the skin of >C16 is negligible. Single constituents with carbon chain lengths up to C30-C35 are absorbed via the gastro-intestinal tract at 2-20% of the amount dosed. However, when present in a mineral oil, hydrocarbons of higher molecular weight, corresponding to chain lengths greater than C32-C35 are not absorbed to any significant extent (Boogaard, 2007). Thus, hydrocarbons in a complex matrix are less bioavailable than as single constituents.

Albro and Fishbein, 1970. Absorption of aliphatic hydrocarbons by rats. Biochim Biophys Acta 219(2):437-46, 1970.

Boogaard, P, 2007. Toxicokinetic assessment of gastrointestinal absorption of hydrocarbons with carbon number greater than 35 with specific relevance to Residues (Fischer-Tropsch), C40-70, branched and linear, Unpublished report, Shell Health, 22 November 2007.

Brown, BA, Diembeck, W, Hoppe, U, Elias, PM, 1995. Fate of topical hydrocarbons in the skin. J. Soc. Cosmet. Chem., 46, 1-9, January/February 1995.

Halliday, JS, Mackerer, CR, Twerdok, LE and Sipes IG, 2002. Comparative pharmacokinetic and disposition studies of [1-[14C}=1-eicosanylcyclohexane, a surrogate mineral hydrocarbon, in female Fischer-344 and Sprague-Dawley rats, Drug Metab Dispos 30(12): 1470-7, 2002.

Illing 2006, [unpublished report Naphtha (Fischer-Tropsch), light, C4-C10 – branched and linear: Summary of toxicological information relevant to Annex VIIa notification endpoints, 2006].

Kim, D., Andersen, M., and Nylander-French, 2006. Dermal absorption and penetration of jet fuel components in humans. Toxicology Letters. 165: 11-21.

Lester, 1979. Normal paraffins in living matter – occurrence, metabolism and pathology, Prog Food Nutr Sci 3(1-2): 1-66, 1979.

Low, KL, Shymanski, PM, Kommineni, C, Naro, PA, Mackerer, CR, 1992. Oral absorption and pharmacokinetic studies of radiolabelled normal paraffinic, isoparaffinic and cycloparaffinic surrogates in white oil in Fischer 344 rats, Toxicology Forum, Special meeting on mineral hydrocarbons, Green College, Oxford UK, Sep 21-23, 1992.

Morgan, RG, and Hoffman, AF, Use of 3H-labeled triether, a nonabsorbable oil-phase marker, to estimate fat absorption in rats with cholestyramine-induced steatorrhea, J Lipid Res 11(3): 231-6, 1970.