Hydrocarbons, C6-C7, n-alkanes, isoalkanes, cyclics, >5% n-hexane

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
See toxicokinetics, metabolism and distribution.
Short description of key information on absorption rate: 
Under dermal in vitro test conditions, n-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to n-heptane simultaneously reduced skin barrier function. Similar properties are expected for hydrocarbons, C6-C7, n-alkanes, isoalkanes, > 5% n-hexane.
Due to the experimental setup, e. g. undepletable reservoir of test substance and therefore absence of any evaporation, the dermal penetration factors reported by Fasano and McDougal (2008) are very conservative. In contrast, when using a diffusion cell, which is a more realistic setup for volatile subsances like hydrocarbon solvents, dermal penetration rates of 0.1 µg/cm2/h and 0.0005 µg/cm2/h were obtained for heptane and octane, respectively (Tsuruta, 1982).

Additional information

There are no toxicokinetic data available on hydrocarbons, C6-C7, n-alkanes, iso-alkanes, cyclics, > 5% n-hexane. However, there are reliable data available for other category members. Thus, read-across was conducted based on a category-approach.

The inhaled uptake of n-heptane vapors was explored by Dahl et al. (1988) in male rats exposed for 5 consecutive days, 80 min/day with escalation of vapor concentration daily (from 1 ppm up to 5000 ppm). During the exposures, respiratory and gas chromatographic data were collected at 1 min intervals. For n-heptane, only data from one exposure at 100 ppm were available. Uptake of inhaled n-heptane vapor was 4.5 ± 0.3 nmol/kg/min/ppm (n = 10). The value is given for uptake during minutes 60 to 70 from the start of exposure of the experiment. Taking into account all data of the report, a number of trends relating uptake to chemicals properties were observed. Among these, highly volatile hydrocarbons are less well-absorbed than less volatile hydrocarbons; unsaturated compounds are better absorbed than saturated ones; and branched hydrocarbons are less well-absorbed than unbranched ones. These trends can be used to predict relative uptake rates within classes of hydrocarbons.

In a subsequent study, differences in biological fate of inhaled nephrotoxic iso-octane and non-nephrotoxic n-octane were explored by Dahl (1989) in rats exposed to 14C-labeled vapor by nose-only inhalation at concentrations of 0, 1.0, and 350 ppm for a single 2 hour exposure. Radioactivity of exhalant, urine, and feces was measured for 70 hours post-exposure after which residual radioactivity in the carcasses was determined. Inhaled uptake of n-octane was greater than iso-octane uptake at both concentrations. The uptake rate at the low concentration for n-octane was twice that of the high concentration (6.1 and 3.4 nmol/kg/min/ppm, respectively).

The major route of elimination of 14C was carbon dioxide. For n-octane absorbed at low concentration, the amount of inhaled 14C in the carcass at 70 hours post-exposure was nearly 5% of total inhaled, a significantly higher level than that remaining after high concentration exposure (approx. 2%). The fraction of inhaled n-octane exhaled unchanged was 4.5 and 6.5% of high and low exposure levels, respectively. Half of n-octane 14C retained at the end of the 2 hour exposure was eliminated within 5-10 hours post-exposure and stopped after 30 hours when 75-85% of activity was eliminated. The rate of excretion of n-octane was markedly affected by the concentration of inhaled vapor. The ratio of 14CO2 to 14C in urine was 5:1 after inhalation at the low concentration but 1:1 after inhalation at the high concentration.

The excretion pattern of n-octane, fairly evenly distributed between 14CO2 and kidney by 15 hours, and the rapid elimination differed from that of iso-octane for which excretion was primarily through the kidney at a slower rate.

Toxicokinetic properties of n-heptane were investigated in rats during inhalation of 100 ppm of the hydrocarbon for 3 days, 12 hours/day (Zahlsen et al., 1992). The concentration of n-heptane was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. n-Heptane was found in moderate concentrations in the kidneys and only in marginal concentrations in blood, brain and liver. In perirenal fat, concentrations were the highest, however, decreasing with lasting exposure. This is in contrast to other n-alkanes, which showed increasing concentrations.

Partition coefficients of n-heptane were determined in human blood and tissues by Perbellini et al. (1985). The solubility of n-heptane was tested in blood, saline, olive oil and in the most important human tissues (lung, kidney, liver, brain, muscle, heart, and fat). The solubility of n-heptane in saline was low and very high in olive oil, displaying a partition coefficient of 452 (20.0 SD). The partition coefficients were therefore high in fat and fatty tissues compared to the other examined tissues.

Based on read-across from structurally related substances within a category approach, C₇-C₉alkanes are readily absorbed and distributed through the body. n-Alkanes are readily metabolized and excreted in urine and expired as CO₂. iso-Alkanes are less readily metabolized to a range of metabolites that are excreted in the urine. Tissue/blood ratios are greater than unity, especially for iso-alkanes, but on prolonged administration, metabolizing enzymes appear to be induced and ratios decrease. For n-alkanes, there appears to be a very low rate of metabolism to potentially neurotoxic gamma diketones, and no such metabolism for the iso-alkanes.

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.

Discussion on absorption rate:

There are no dermal absorption data available onhydrocarbons, C6-C7, n-alkanes, iso-alkanes, cyclics > 5% n-hexane. However, there are reliable data available for another category member. Thus, read-across was conducted based on a category-approach.

Fasano and McDougal (2008) described the procedures for determination of a permeability coefficient (Kp) and two short-term dermal absorption rates at 10 and 60 min. The flux values for n-heptane and the 10 and 60 min short-term absorption values (the quantity of chemical remaining in the skin plus that portion that had penetrated the skin was detected in the receptor fluid) were 63.2 µg/cm2/h, 113 µg/cm2/h (for the 10 min flux) and 22.1 µg/cm2/h (for the 60 min flux). Therefore, the 10 min flux value for n-heptane (based on both the amount in the skin and the receptor solution) was greater than the flux measured in a similar manner over 60 min.

Skin integrity measurements were taken before and after each experiment. A ratio of post- to pre-test impedance of "1" indicates that the skin barrier did not change over the course of the experiment. In the Kp experiments, skin exposed to n-heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to n-heptane. The barrier properties for the skin in the short-term experiments were given as the ratios of 0.90 for 10 min and 0.88 for 60 min. At the end of the Kp experiment, the portion of n-heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of n-heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of n-heptane following a 10 min exposure. The portion of n-heptane in the donor solution (wash) was 6.84% at 10 min. The greater portion of the applied dose remaining in the skin at 10 min suggests that partitioning into the skin from the donor solution is the driver of penetration with this brief exposure. After the 60 min experiments, there was also a larger percentage of n-heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of n-heptane detected in the receptor solution illustrates and confirms the movement of the chemical from the skin into the receptor solution. Under the test conditions, n-heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to n-heptane simultaneously reduced skin barrier function.