Hydrocarbons, C5-C7, n-alkanes, isoalkanes, < 5% n-hexane

Endpoint summary

Description of key information

Taking into account all available data, it can be assumed that hydrocarbons, C5-C6, n-alkanes, isoalkanes, < 5% n-hexane are absorbed rapidly through the lungs and distributed widely in mammalian bodies. As hydrocarbon solvents are highly volatile, inhalation is the primary route of exposure. The source substances are not well absorbed from the intestinal tract and dermal absorption is limited. Absorbed C5-C6 species are metabolized by oxidation to number of compounds. With exception of n-hexane, other C5-C6 species are not metabolised to the neurotoxic metabolite 2,5-hexanedione. Most C5-C6 species are excreted unchanged in exhaled air. Elimination of the metabolites is mainly expected in urine and exhaled air.

Additional information

There are no data available on toxicokinetics of hydrocarbons, C5-C6, n-alkanes, isoalkanes, < 5% n-hexane. However, there are reliable data available considered suitable for read-across using the analogue approach.

The target substance is a hydrocarbon solvent with carbon numbers in the range of C5 to C6. The main constituents of the mixed solvent consist of about 43% of C6 species and about 57% of C5 species. n-Hexane is only present in concentrations < 5% of the total volume.

The source substances chosen for read-across have similar toxicological properties as the target substance. There is only one distinguishing characteristic for n-hexane. n-Hexane has unique toxicological properties due to its ability to be metabolized to the neurotoxic metabolite 2,5-hexanedione. Other C6 species will not be metabolized to 2,5-hexanedione. For this reason, n-hexane and hydrocarbon solvents containing n-hexane at levels greater than 5% represent a worst case scenario.

Taking into account all available data, animal and human toxicity data as well as environmental fate and effects data show that source substances have similar (eco-)toxicological and environmental fate properties as the target substance.

Therefore, read-across is performed based on an analogue approach (for details please refer to the analogue justification which is attached in section 13 of the technical dossier).

In a metabolism study to see whether pentane was metabolized in the intact rat, [1,5-14C]n-pentane was administered to male Sprague-Dawley rats via inhalation in two experiments (Daugherty et al., 1988). Both experiments used an average of 3.44 microcuries of [1,5 -14C]n-pentane plus 1.0 milliliter of 10.1 μmol/mL unlabeled n-pentane gas. In the first experiment, 6 rats were exposed and in the second experiment 4 rats were exposed. Differing amounts of calcium sulfate desiccant were used for each experiment; experiment I used 271 grams calcium sulfate desiccant, and experiment II used 130 grams calcium sulfate desiccant. In a preliminary study that was conducted without animals, n-pentane was detected in the chamber atmosphere after rapidly evacuating the chamber system and resealing the system whenever calcium sulfate was present. This result suggests that the desiccant traps n-pentane but releases it back into the chamber as chamber n-pentane concentration decreases. For experiment 1, radioactivity in whole blood and various tissues was measured after animals were sacrificed once the experiment ended. Urine samples were collected in experiment II, and both experiments collected expired air by measuring the chamber atmosphere and carbon dioxide trap. Approximately 78.9% of total radioactivity administered as radiolabeled [14C] n-pentane was recovered when combining the results of the two experiments. According to the study authors, a proportion of the total 14C activity unaccounted for may be due to the trapping of n-pentane in the desiccant. Tissue and organ results from experiment I showed that the liver, small intestine, and kidneys contained the highest radioactivity per gram of tissue (wet weight). Muscle and liver accounted for the largest proportion of the estimated total of radioactivity expressed as a percentage of the total radioactivity injected into the chamber. Based on these results, the study authors concluded that pentane was metabolized in the intact rat. 

In a second study on the toxicokinetics of n-pentane, F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 min for 5 consecutive days. Doses were as follows: 1 ppm on day 1; 10 ppm on day 2; 100 ppm on day 3; 1000 ppm on day 4; and 5000 ppm on day 5 (Dahl et al., 1988). The study report only presented data for the 100 ppm dose. When pentane was inhaled at 100 ppm, the uptake ranges were 3.6±0.2 and 4.2±0.4 nmol/kg/min/ppm (the mean of two experiments). Additionally, the uptake rate of pentane was greater than that of 2-methylbutane. The study authors concluded that (1) highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; (2) unsaturated compounds are better absorbed than saturated ones; and (3) branched hydrocarbons are less well-absorbed than unbranched ones.

In general,it can be assumed that the toxicokinetics of C5 species are similar (SIDS, 2001). As pentane isomers are highly volatile, inhalation

is the primary route of exposure. C5 species are not well absorbed from the intestinal tract and dermal absorption is limited. Pentanes are well absorbed by inhalation and widely distributed in mammalian bodies. Absorbed pentane isomers are similarly oxidized to the corresponding alcohol with subsequent conjugation primarily as glucuronides. Excretion of the glucuronides is mainly expected in urine and exhaled air. Any unchanged pentane isomers are rapidly eliminated by exhalation. The half-life in rats is approximately 0.13 h. Considering the rapid metabolism and excretion, tissue accumulation is expected to be low.

 

In a study of the metabolism of commercial hexane, n-hexane was metabolized and excreted within 168 h of intravenous bolus administration, inhalation exposure or dermal application. Exhaled breath and urine were the two primary routes for the excretion and its metabolites. n-Hexane was widely distributed to the body tissues but neither n-hexane nor its metabolites were concentrated significantly by any of those tissues. n-Hexane was extensively metabolized and a number of radiolabeled metabolites were excreted in the urine. n-Hexane and its radiolabeled metabolites disappeared from the blood of rats with a half-life of approximately 9-10 h. No significant differences between males and females were noted in the rates and routes of metabolism and excretion. Repeated inhalation exposure had no apparent effect on the rates or routes of excretion of either of the test substances or its metabolites.

In mammals, C6 species are absorbed rapidly through the lungs and distributed widely in the body (EPA, 2005). Hexanes species are not well absorbed from the intestinal tract and dermal absorption is low. C6 species are metabolized by oxidation to a number of compounds in the liver. With the exception of n-hexane, other C6 species are not metabolised to 2,5-hexanedione, which is thought to be the ultimate neurotoxic agent of n-hexane (Frontali et al., 1981). Most C6 species excreted unchanged in exhaled air; some are excreted as metabolites in urine and exhaled air.

References not cited in the IUCLID:

SIDS Initial Assessment Profile (2001) for n-pentane, 2 -methylbutane (isopentane), cyclopentane

Toxicological review of n-hexane (2005), EPA/635/R-03 /012

Frontali et al. (1981) Experimental neurotoxicity and urinary metabolites of the C5 -C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin Toxicol. 18(12):1357 -1367