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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is 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.

Data source

Reference
Reference Type:
publication
Title:
Metabolism of ethane and pentane to carbon dioxide by the rat
Author:
Daugherty, M.S., Ludden, T.M., Burk, R.F.
Year:
1988
Bibliographic source:
Drug Metabolism and Disposition. 16(5):666-671

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
Guideline deviations are not expected to interfere with study results
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentane
EC Number:
203-692-4
EC Name:
Pentane
Cas Number:
109-66-0
Molecular formula:
C5H12
IUPAC Name:
pentane
Details on test material:
- Name of test material (as cited in study report): Pentane
- Substance type: C5 aliphatics
- Analytical purity: 99.0%
- Specific activity (if radiolabelling): 10 mCi/mmol
Radiolabelling:
yes
Remarks:
[1,5-14C] pentane

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 357 grams average weight
- Housing: individually housed in a custom-made closed Plexiglass chamber with a removable restraining device to restrict animal movement
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum prior to start of experiment
- Water (e.g. ad libitum): ad libitum prior to start of experiment

Administration / exposure

Route of administration:
inhalation
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglass chamber with oscillating pump to circulate air through carbon dioxide and moisture traps, a 9-litre respirometer to replenish oxygen, a gas washing vessel containing sodium hydroxide to trap evolved carbon dioxide, and a calcium sulfate desiccant to remove moisture.
- Method of holding animals in test chamber: removable restraining device
- Source and rate of air: 9-litre respirometer; 280 mL/minute (rate of oscillating pump)
- Method of conditioning air: calcium sulfate desiccant
- System of generating particulates/aerosols: n-pentane was injected into animal chamber
- Sampling procedure and analytic methods: Chamber sir samples were obtained 5 minutes before and 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 minutes after injection of n-pentane into the chamber. Chamber air pentane concentration was determined by gas chromatography analysis. Chamber air samples were compared to standards that were prepared by serial dilution of gas vessels to obtain a standard curve covering the range of gas concentrations. Chamber air radioactivity was determined by liquid scintillation. Samples (0.5 milliliters) of the solution in the carbon dioxide trap were obtained in duplicate prior to each experiment and once per hour in experiment I and bi-hourly for experiment II. Samples (1.0 milliliters) of the carbon dioxide trap solution were pipetted into scintillation vials and mixed with water and Aquasol-2. Samples were equilibrated in refrigerated scintillation counter at 10 degrees Celsius for 12 hours before counting.
- Treatment of exhaust air: Carbon dioxide trap (250 milliliter gas-washing vessel containing 180 milliliters 3 N sodium hydroxide)
Duration and frequency of treatment / exposure:
Single dose over an 8-hour exposure period
Doses / concentrations
Remarks:
Doses / Concentrations:
An average of 3.44 microcuries of [1,5-14C]pentane plus 1.0 milliliter of 10.1 μmol/mL unlabeled n-pentane gas
No. of animals per sex per dose / concentration:
Experiment I: six male rats per dose (only one dose level used)
Experiment II: four male rats per dose (only one dose level used)
Control animals:
no
Positive control reference chemical:
There was no positive control used.
Details on study design:
There were two experiments conducted with n-pentane. The first experiment used 271 grams of calcium sulfate desiccant was placed inside the chamber; the second experiment used 130 grams of calcium sulfate desiccant was placed inside the chamber. There was no information provided on the rationale behind dose selection or animal assignment.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine (experiment II); blood (experiment I); muscle and fat samples (experiment I); liver kidneys, lung, testes, brain, heart, spleen, and emptied small and large intestines (experiment I)
- Time and frequency of sampling: Urine samples were removed hourly from the urine collection tray; blood, tissues, and organs were collected following the 8-hour experiment.
Statistics:
Statistical methods used were not provided. Means and standard deviations were calculated where appropriate.

Results and discussion

Preliminary studies:
Preliminary studies were conducted without a rat in the chamber. Recovery of n-pentane averaged about 62 percent when 271 grams of calcium sulfate desiccant was added 0.17 to 18 hours post-n-pentane injection. Recovery average 77% when a smaller amount of desiccant was added to the chamber. Also, whenever calcium sulfate was present, n-pentane was detected in the chamber atmosphere after rapidly evacuating the chamber system and resealing the system. This result suggests that the desiccant traps n-pentane but releases back into the chamber as chamber n-pentane concentration decreases.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Absorption results are presented in the table below. Approximately 78.9% of total radioactivity administered as radiolabeled [14 C] 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 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.
Details on distribution in tissues:
Distribution information is not provided in the study report.
Details on excretion:
Urine and exhaled air were measured in this study. However, these endpoints were only measured once and less than 95% of the administered dose was excreted. Therefore, the analysis does not meet OECD's guidelines that recommend measuring excreta at several times after exposure, until about 95% of the administered dose has been excreted or for seven days, whichever comes first.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Recovery of14C activity – Experiment I

Organ or Tissue

14C Activity Recovered (%)

14C Activity in Tissue (nCi/gram wet tissue)

Liver

3.37±0.66

9.11±1.04

Kidney

0.51±0.07

7.11±1.35

Lung

0.27±0.06

5.46±1.00

Testes

0.34±0.05

2.08±0.42

Brain

0.12±0.06

2.65±0.90

Muscle

6.98±2.42

1.29±0.59

Heart

0.12±0.06

2.95±0.95

Small intestine

2.21±0.51

8.81±0.87

Large intestine

0.35±0.14

4.60±1.46

Spleen

0.15±0.02

5.70±1.39

Fat

0.52±0.17

0.94±0.28

Total:

14.92±2.44

 

Recovery of14C activity

(percent of total activity injected, mean ± s.d.)

 

Experiment I (6 rats)

Experiment II (4 rats)

Chamber atmosphere

3.0±0.7

3.9±0.5

Carbon dioxide trap

48.3±2.0

50.5±1.4

Urine

---

7.6±0.8

Tissue

14.9±2.4

---

Whole Blood

2.1±0.8

---

Total Recovery

68.2±3.6

61.9±2.0

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: n-Pentane is metabolized in the intact rat.
n-Pentane is metabolized in the intact rat.
Executive summary:

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. 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 I, 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 total14C activity unaccounted for may be due to the trapping 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 is 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.