Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

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, heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to heptane simultaneously reduced skin barrier function.
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 et al., 1982).

Key value for chemical safety assessment

Additional information

The uptake of inhaled Normal-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 Normal-Heptane, only data from one exposure at 100 ppm were available. Uptake of inhaled 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.

Toxicokinetic properties of Normal-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 Normal-Heptane was measured by head space gas chromatography in blood, brain, liver, kidneys and perirenal fat. Normal-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 Normal-Heptane were determined in human blood and tissues by Perbellini et al. (1985). The solubility of 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 Normal-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.

Alkanes that are metabolized to gamma diketones can produce peripheral neuropathy in experimental animals and man. Perbellini et al. (1986) have demonstrated that C7-C9 n-alkanes do not generate neurotoxic metabolites or produce them in quantities too low to produce neurotoxic effects. Exposure of male rats to 1800 ppm Normal-Heptane for 6 hours only produced the major urinary metabolites 2-heptanol and 3-heptanol. 2,5-Heptanedione, a potentially neurotoxic metabolite was only present in a low concentration (4.4 µg/24 hours) in the urine, approximately 0.8% of urinary metabolites. Other metabolites included 2- or 3-heptanone and gamma valerolactone. At the end of exposure, the amount of 2-heptanol in blood and tissue (liver, muscle, kidney, and nervous tissue) was between 0.2 and 2.0 mg/L. The concentration of the parent compound Normal-Heptane was 5.7 mg/L in blood and 10 to 25.6 mg/L in tissues. 24 hours after the end of exposure, no quantifiable amounts were present in blood or tissue, demonstrating rapid clearance of Normal-Heptane and its metabolites.

 

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.

Discussion on absorption rate:

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 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 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 Normal-Heptane had a damage ratio of 0.57, confirming that approx. 43% of the skin barrier function was lost due to exposure to 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 Normal-Heptane in the skin (0.01%) was less than the portion in the receptor solution (0.12%). The portion of Normal-Heptane in the donor solution (wash) was 95.4%. In contrast to the Kp experiment, the skin (0.14%) retained a larger percentage of Normal-Heptane following a 10 min exposure. The portion of Normal-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 heptane in the receptor solution (0.12%) than in the skin (0.06%). The increased proportion of Normal-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, Normal-Heptane was able to penetrate the skin. During prolonged exposure, the penetration of the skin was aggravated, since the exposure to heptane simultaneously reduced skin barrier function.