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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Development of a physiologically based pharmacokinetic model for decane, a constituent of jet propellent-8
Author:
Perleberg, U.R., Keys, D.A., Fisher, J.W.
Year:
2004
Bibliographic source:
Inhalation Toxicol.ogy 16(11-12): 771-83

Materials and methods

Objective of study:
distribution
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
Rats were exposed to decane vapors at time-weighted average concentrations of 1200, 781, or 273 ppm in a 32-L leach chamber for 4 h. Time-course samples for 1200 ppm and end-of-exposure samples for 781 and 273 ppm decane exposures were collected from blood, brain, liver, fat, bone marrow, lung, skin, and spleen.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Decane, a 10-carbon n-alkane
Radiolabelling:
not specified

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
Forty-eight male Fischer 344 rats were purchased from Charles Rivers (Raleigh, NC), weighing between 186 g to 240 g (mean body weight = 211 g). All animals were housed in a controlled environment with a 12-h light/dark cycle at 2 1°C. Purina food and water was available at liberty, except during exposures. Rats were given a minimum acclimation period of 2 wk before experiments were begun. All inhalation exposures commenced between 7 and 8 a.m.

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
Gas Uptake Chamber: Initially, decane was evaluated in a newly built gas uptake chamber, without rats to determine if gas uptake could be utilized to obtain information on the metabolism of decane. Slight modifications were made to previously described gas uptake exposure systems. Decane was injected into the system through an injection port (10 uL and 5 uL) at the incoming air stream to the 7-L closed system chamber. However, this method was deemed unsuccessful for the analysis of decane metabolism because the atmospheric loss rate of decane to the glass chamber (without an animal) was too great (Figure 1). Pharmacokinetic studies were then carried out in a Leach chamber, which avoids the problem of decane adherence to the glass by generating a constant concentration within the chamber.

Leach Chamber: The exposure chamber consisted of a 32-L battery jar. Two metal bellows pumps were used to create inhalation exposures. A 40/50 Pyrex bubbler containing decane was mixed with ambient room air to achieve a specified vapor concentration of decane over a four-hour exposure period. Flow rates through the bubbler to obtain decane concentrations of 273 to 1200 ppm ranged from 1 L/min to 4L/min. Ambient airflow was mixed with the bubbler flow rate to give a total flow rate of approximately 8 L/min to the chamber. The atmospheric pressure within the battery jar was monitored by a Magnehelic pressure gauge and maintained between 0 and -1 inches of water by adjusting the flow rate into the chamber. The flow rates of the bubbler and exhaust from the Leach chamber were monitored by Gilmont Instruments flow meters. Chamber atmospheric concentrations were monitored in 10-min intervals over the entire exposure duration using an auto sampling valve mounted on the gas chromatograph. Exhaust was monitored to determine chamber concentration by splitting the exhaust flow so a portion of the exhaust was routed to the gas chromatograph. The flow rate of the split from the exhaust to the gas chromatograph was monitored by a Matheson 600 HAl flow meter, Exposure concentrations were calculated as a time-weighted average (TWA) over the 4-h exposure period. Aerosols generated by the bubbler were removed via a glass wool scrubber. Tedlar bags containing 223 to 1337 ppm decane were sampled by the auto sampler of the gas chromatograph to create a calibration curve for the Leach chamber. All stainless steel tubing was 1/4 inch diameter throughout system, except for the 1/8-inch tubing to the gas chromatograph.
Duration and frequency of treatment / exposure:
4 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
1200, 781, or 273 ppm
No. of animals per sex per dose:
1200 ppm (n = 12 per exposure), 781 ppm (n = 8 per exposure), and 273 ppm (n = 8 per exposure).
Control animals:
no
Positive control:
none
Details on study design:
Fischer 344 rats were exposed for 4 h to concentrations of 1200 ppm (n = 12 per exposure), 781 ppm (n = 8 per exposure), and 273 ppm (n = 8 per exposure). Decane exposure was started immediately after all rats were place into the Leach chamber. The targeted chamber concentration for decane was obtained within 10-15 min after the bubbler containing decane was turned on. Blood, brain, bone marrow, spleen, liver, lung, perirenal fat, and skin tissues were collected for the 1200 ppm decane exposure immediately after the 4-h exposure up to 24 h post exposure, while only end-of-exposure tissue samples were collected for 781 and 273 ppm decane exposures. Rats for the end-of-exposure sampling were removed from the Leach chamber within 30s after turning off the decane exposure, but maintaining air flow to the Leach chamber. Rats were killed by CO2 intoxication within 2-3 min after removal from the Leach chamber; tissue samples were quickly collected (30 s to 2 min) and placed into 2 mL pre-weighed screw-cap vials (National Scientific Co., Scottsdale, AZ) to be weighed. All samples collected were approximately 0.2 g (except bone marrow, 0.02 mg). Bone marrow was collected last (about 3-4 min after killing the rat) by scrapping the inside of femur bones. Skin samples were collected from the abdomen after clipping the hair. Tissue collection techniques for this study were similar to techniques used by Fisher and colleagues with trichloroethylene, a very volatile chemical (Greenberg et al., 1999). Although some inherent experimental error occurs when collecting tissues for analysis of volatile chemicals such as decane, the experimental error was minimized by taking tissues as quickly as possible by trained necropsy personnel and then placing the tissues in sealed vials.

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not specified

Any other information on results incl. tables

Sensitivity analysis for selected decane model parameters at 200 ppm evaluated during exposure (3 h) and postexposure (5-25 h)

  Arterial Blood Concentration    Lung Tissue Concentration   Brain Tissue Concentration
Model parameter 3h 5h 7h   3h 5h 7h   3h 5h 15h 25h
PWB 0.98 2.54 1.98   0.98 2.54 1.98   0.95 1.01 1.12 1.48
PB 0 -0.05 0.03   0 -0.05 0.03   0.36 0.72 3.32 4.06
PL 0 0.9 0.02   0 0.9 0.02   -0.02 0.02 0.02 0.02
PLU 0 0.04 0   1 1.04 1   0 0 0 0
PAF -0.01 0.47 0.66   -0.01 0.47 0.66   -0.01 -0.01 0.05 0.4
PAB 0 0.2 0.1   0 0.2 0.1   0.63 0.28 -2.28 -3.01
PABM -0.01 0.53 0.75   -0.01 0.53 0.75   -0.01 0 0 -0.09
PASK 0 0.62 0.62   0 0.62 0.62   0 0 0.02 -0.01
QPC 0.02 -1.53 -0.98   0.02 -1.53 -0.98   0.05 -0.01 -0.12 -0.48
Body Weight 0.01 -0.89 -1.21   0.01 -0.89 -1.21   -0.62 -0.26 2.24 2.84
VBC 0 -0.12 0.03   0 0.12 0.03   -0.64 -0.28 2.31 3.06

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no data
PBPK results - The blood/air partition coefficient value was sensitive for predicting blood, brain, and lung decane concentrations. The lung/blood partition coefficient value was sensitive for predicting lung decane concentration. The blood and lung decane concentrations were sensitive to the bone marrow permeability area cross product, ventilation rate, and body weight. The model-predicted brain concentrations of decane were sensitive to the body weight brain/blood partition coefficient value, the permeability-area cross product for the brain, and the volume of the brain.
Executive summary:

Decane is one of the highest vapor phase constituents of jet propellent-8 (JP-8), was selected to represent the semi-volatile fraction for the initial development of a physiologically based pharmacokinetic (PBPK) model for JP-8. Rats were exposed to decane vapors at time-weighted average concentrations of 1200, 781, or 273 ppm in a 32-L leach chamber for 4 h. Time-course samples for 1200 ppm and end-of-exposure samples for 781 and 273 ppm decane exposures were collected from blood, brain, liver, fat, bone marrow, lung, skin, and spleen. The pharmacokinetics of decane could not be described by flow-limited assumptions and measured in vitro tissue/air partition coefficients. A refined PBPK model for decane was then developed using flow-limited (liver and lung) and diffusion-limited (brain, bone marrow, fat, skin, and spleen) equations to describe the uptake and clearance of decane in the blood and tissues. Partition coefficient values for blood/air and tissue/blood were estimated by fitting end-of-exposure pharmacokinetic data and assumed to reflect the available decane for rapid exchange with blood. PBPK model predictions were adequate in describing the tissues and blood kinetics. For model validation, the refined PBPK model for decane had mixed successes at predicting tissue and blood concentrations for lower concentrations of decane vapor, suggesting that further improvements in the model may be necessary to extrapolate to lower concentrations.

The blood/air partition coefficient value was sensitive for predicting blood, brain, and lung decane concentrations. The lung/blood partition coefficient value was sensitive for predicting lung decane concentration. The blood and lung decane concentrations were sensitive to the bone marrow permeability area cross product, ventilation rate, and body weight. The model-predicted brain concentrations of decane were sensitive to the body weight brain/blood partition coefficient value, the permeability-area cross product for the brain, and the volume of the brain.