Hydrocarbons, C5, n-alkanes, isoalkanes

Endpoint summary

Description of key information

Toxicokinetic studies were identified for cyclopentane, n-pentane, and 2-methylbutane.  For cyclopentane, an inhalation kinetic study (OECD 417) was identified in the rat.  In this study, a bioaccumulation factor of 2.5 was calculated for lower concentrations and increased to about 9.1 at 1000 ppm with a maximum value of 11.5, which is the thermodynamic partition coefficient of whole body to air.
Two studies were identified on the toxicokinetics of n-pentane. In one study (OECD 417), rats were exposed to rabiolabeled n-pentane via inhalation. Tissue and organ results from experiment 1 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. In the other study (non-guideline), F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 minutes for 5 consecutive days. 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). One toxicokinetics study was identified for 2-methylbutane. In this study (non-guideline), F344 rats were exposed to a variety of hydrocarbon vapours, including pentane, via inhalation for 80 minutes for 5 consecutive days.

Additional information

Toxicokinetic studies were identified for cyclopentane, n-pentane, and 2-methylbutane. One study on the inhalation kinetics of cyclopentane in the rat was identified (Filser, 1997). This study was conducted in two parts. The first study was conducted to quantify the toxicokinetic parameters of inhaled cyclopentane, while the second part of the study was conducted to develop a physiological toxicokinetic model that would enable the study of toxicokinetic process occurring in the rat when exposed to cyclopentane vapours. In the first study, two male rats were exposed to cyclopentane at concentrations of 10, 30, 100, 300, 1000, 3000, or 10,000 parts per million (ppm) via inhalation in a closed exposure system. Metabolism of cyclopentane was found to be saturable with two different metabolic processes distinguished. One metabolic process had low affinity and high capacity while the other had high affinity and low capacity. The authors’ assumption that cyclopentane metabolism was oxidative, was supported by the findings that biotransformation of cyclopentane was almost completely inhibited for the whole 6 hour exposure duration when the rats were administered dithiocarb, a P-450 inhibitor. The study authors reported that the rate of metabolism was dose related with a proportional increase in metabolism up to 100 ppm concentration following which metabolism became saturated at about 1000 ppm. The bioaccumulation factor was 2.5 at the lower concentrations and increased to about 9.1 at 1000 ppm with a maximum value of 11.5, which is the thermodynamic partition coefficient of whole body to air. The steady state in the rat was estimated by multiplying the bioaccumulation factor with the exposure concentration. The steady state curve was shaped like a hockey stick, which reached a value of 0.36 µmol/mL of tissue at 1000 ppm. The alveolar retention of cyclopentane declined from 35% (observed with concentrations <20 ppm) to 5.4% at 1000 ppm and was related to an exposure dependent increase in the exhalation of unmetabolized cyclopentane. At concentrations <20 ppm 20% of the cyclopentane was exhaled unmetabolized compared to 88% at 1000 ppm and 99% at 10,000 ppm. In the second part of the study, the authors used the results presented above to develop a physiological toxicokinetic model. This model permitted a better understanding of the toxicokinetic processes occurring in rats exposed to cyclopentane vapors. It enabled the prediction of not only the average cyclopentane concentration in the whole body, but also concentrations in select organs and tissues (lung, arterial and venous blood, live, muscle, fat and richly perfused tissues). According to the model demand, distribution coefficients of 2.6, 2.7, 2.3, and 63 were determined for the blood: air, muscle: air, liver: air, and fat: air, respectively. The model was validated by comparing simulated concentration-time curves of the test chemical in the atmosphere of closed exposure systems and of predicted cyclopentane concentrations in blood of exposed animals. Steady-state concentrations of 0.0015, 0.0037, and 0.053 µmol/mL were determined in the mixed venous blood entering the right ventricle in rats exposed to 53, 111, or 1100 ppm, respectively. Based on the physiological toxicokinetic model performance the authors concluded that the model predictions were in agreement with the experimental data. This study was classified as reliable without restrictions because it is indicated in the study protocol that the study was conducted according to GLP or equivalent and the study appears to be well conducted and provides important information on the inhalation kinetics of cyclopentane.

 

Two studies were identified on the toxicokinetics of n-pentane. 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 mice were exposed and in the second experiment 4 mice 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 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. This study received a Klimisch score of 2 and was classified as reliable with restrictions because while there is no statement regarding whether this study was conducted according to GLP or equivalent, the full study protocol was provided, including test materials and methods.

 

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 minutes 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 presents 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. This study received a Klimisch score of 2 and was classified as reliable with restrictions because although the study did not follow an OECD guideline and it was not stated whether the study was GLP compliant, the study appears to be scientifically sound and there is an adequate level of detail.

 

One toxicokinetic study was available on 2-methylbutane (Dahl et al., 1988).  F344 rats were exposed to a variety of hydrocarbon vapours, including 2-methylbutane, via inhalation for 80 minutes for 5 consecutive days. Doses were as follows: 1 ppm on day 1; 10 ppm on day 2; 100 ppm on day 3; 1000 on day 4; and 5000 ppm on day 5. The study report only presents data for the 10 ppm dose. When pentane was inhaled at 10 ppm, the uptake ranges were 1.6±0.2 and 1.5±0.2 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. This study received a Klimisch score of 2 and was classified as reliable with restrictions because although the study did not follow an OECD guideline and it was not stated whether the study was GLP compliant, the study appears to be scientifically sound and there is an adequate level of detail.