Cyclopentane

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996-05 to 1997-02

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study is 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.

Objective of study:

toxicokinetics

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

Principles of method if other than guideline:

The study was designed in order to develope a physiological toxicokinetic model and there were several parts conducted (both in vivo and in vitro) to determine the model.

GLP compliance:

yes

Radiolabelling:

not specified

Species:

rat

Strain:

other: CHBB-THOM (SPF)

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Provided by the sponsor
- Weight at study initiation: 200 to 250 grams
- Housing: During acclimation, rats were kept in Macrolon cages, type 3. During experiments, rats were kept in a special all-glass closed inhalation system.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Not specified

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

TYPE OF INHALATION EXPOSURE: Whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Closed all-glass exposure chambers, cyclopentane was injected into the inhalation system

Gas chromatography was used to determine the composition of the gas atmosphere.

Duration and frequency of treatment / exposure:

6 hours

Remarks:

Doses / Concentrations:
10, 30, 100, 300, 1000, 3000, or 10,000 ppm for determination of maximum enrichment of cyclopentane in the body
53, 111, or 1100 ppm for determination of blood levels of cyclopentane

No. of animals per sex per dose / concentration:

2 male rats per dose

Control animals:

no

Positive control reference chemical:

None

Details on study design:

- Dose selection rationale: Dose was selected to gain sufficient data for calculation of kinetic parameters.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, unclear if other measurements were made

METABOLITE CHARACTERISATION STUDIES
- From how many animals: 2
- Method type(s) for identification: GC

Statistics:

Atmosphere samples were taken and for the examined concentration range, calibration curves wr

Preliminary studies:

Metabolism of cyclopentane was found to be saturable with two different metabolic processes distinguished. The steady state curve was shaped like a hockey stick, reaching a maximum value of 0.36 µmol/mL of tissue at 1000 ppm. The alveolar retention of cyclopentane declined with increasing exposure. 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.

Details on absorption:

Absorption was not measured.

Details on distribution in tissues:

Tissue distribution was not measured. However, partition coefficients of cyclopentane in the blood, muscle, liver, and fat were measured and results are provided in Table 1 below. 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.

Details on excretion:

Excretion was not measured.

Metabolites identified:

not specified

Details on metabolites:

As concentrations increased, greater amounts of cyclopentane were exhaled unmetabolized.

Table 1. Partition coefficients of cyclopentane at 37 °C

Tissue:air; liquid:air	Mean	± Standard Deviation	n
Blood	2.6	0.34	15
Muscle	2.7	0.33	3
Liver	2.06 and 2.55		2
Fat	63	4.2	5
Water	0.091	0.005	4
Olive oil	156	3.81	4

Table 2 Measured and predicted steady-state concentrations of cyclopentane in mixed venous blood of male Chbb:THOM rats exposed to vapours of cyclopentane. The model predictions were calculated by the physiological toxicokinetic model.

 

Exposure concentration (ppm)	Measured concentration in blood (mmol/liter)	Predicted concentration in blood (mmol/liter)
53	0.0015±0.0003	0.0018
111	0.0037±0.003	0.0046
1100	0.053±0.007	0.085

 

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results

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.

Executive summary:

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 received a Kilmisch score of 1 and is 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.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study is 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.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

absorption

Principles of method if other than guideline:

The study evaluates the uptake of select hydrocarbons by exposing rat via inhalation for 80 minutes for 5 consecutive days. Vapour uptake was calculated from gas chromatography data. Specifics on the study design and results are presented below.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Lovelace ITRI colony
- Age at study initiation: 12 to 15 weeks of age
- Weight at study initiation: 264 to 339 grams
- Housing: Prior to exposure, animals were housed 2 per cage in polycarbonate cages.
- Diet (e.g. ad libitum): Ad libitum; Lab Blox, Allied Mills, Chicago, IL
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22.2°C
- Humidity (%): 20 to 50%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

With regard to the exposure chamber, the vapour was pumped at 400 mL/minutes from a Teflon supply bag through one sampling loop of a dual -column gas chromatograph, past the nose, through the second sampling loop of the dual column gas chromatograph, and into an exhaust bag. Nose only exposures were conducted using a modified plethysmograph.

Duration and frequency of treatment / exposure:

80 minutes for 5 consecutive days (not counting weekend when no exposures were carried out)

Remarks:

Doses / Concentrations:
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 only presents results for the 100 ppm dose group

No. of animals per sex per dose / concentration:

No data reported.

Control animals:

no

Positive control reference chemical:

A positive control group was not used.

Details on study design:

- Dose selection rationale: No data reported.
- Rationale for animal assignment (if not random): No data reported.

Details on dosing and sampling:

The amount of hydrocarbon vapour absorbed was calculated from the out of gas chromatograph and the flow rate past the rat's nose. Vapour uptake was calculated from the following equation:

uptake (nmol/minute) = flow rate (litre/minute) x vapour concentration (nmol/litre) x ([PAinh(t)/PAinh(cal)] - [PAexh(t)/PAexh(cal)])
where flow rate is the flow rate past the rats' nose; vapour concentration is the supply vapour concentration; PAinh(t) is the chromatogram peak area of inhaled vapour at time t; PAinh(cal) is the chromatogram peak area of inhaled vapour from the pre-exposure calibration; PAexh(t) is the chromatogram peak area of exhaust vapour at time t; PAexh(cal) is the chromatogram peak area of exhaust vapour from the pre-exposure calibration.

Data were normalized twice: once for the mass of rats and to the concentration of inhaled vapour; the second to allow for direct comparison between uptakes rats obtained at different concentrations within the concentration range where little saturation effect was observed for many compounds. The following equation was used for normalization uptake:

Normalized uptake (nmol/min/kg/ppm) = uptake (nmol/minute)/(rat mass (kg) x vapour concentration (ppm))

The data were averaged over 10 minute intervals between 11 and 70 minutes of exposure. The report only discusses the interval from 60 to 70 minutes.

Statistics:

Probabilities were derived from the t test for comparison of the uptake rats of branched and straight-chain hydrocarbon vapours in rats.

Preliminary studies:

A preliminary study was not conducted.

Details on absorption:

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).

Details on distribution in tissues:

No data reported.

Details on excretion:

No data reported.

Metabolites identified:

not specified

Details on metabolites:

No data reported.

The number of animals used per compound per experiment is not reported. Abbreviated information on test methods and results was available because the study is a published article.

Conclusions:

Interpretation of results: no data

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.

Executive summary:

In a toxicokinetic study, 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 on day 4; and 5000 ppm on day 5. 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 isopentane. 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 is 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.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

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.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

absorption

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

Radiolabelling:

yes

Remarks:

[1,5-14C] pentane

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

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

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.

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.

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.

Metabolites identified:

not measured

Recovery of^14C 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 of^14C 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

Conclusions:

Interpretation of results: 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.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

This study is 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.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Objective of study:

absorption

Principles of method if other than guideline:

The study evaluates the uptake of select hydrocarbons by exposing rat via inhalation for 80 minutes for 5 consecutive days. Vapour uptake was calculated from gas chromatography data. Specifics on the study design and results are presented below.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Lovelace ITRI colony
- Age at study initiation: 12 to 15 weeks of age
- Weight at study initiation: 264 to 339 grams
- Housing: Prior to exposure, animals were housed 2 per cage in polycarbonate cages.
- Diet (e.g. ad libitum): Ad libitum; Lab Blox, Allied Mills, Chicago, IL
- Water (e.g. ad libitum): Ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22.2°C
- Humidity (%): 20 to 50%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

With regard to the exposure chamber, the vapour was pumped at 400 mL/minutes from a Teflon supply bag through one sampling loop of a dual -column gas chromatograph, past the nose, through the second sampling loop of the dual column gas chromatograph, and into an exhaust bag. Nose only exposures were conducted using a modified plethysmograph.

Duration and frequency of treatment / exposure:

80 minutes for 5 consecutive days (not counting weekend when no exposures were carried out)

Remarks:

Doses / Concentrations:
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 only presents results for the 10 ppm dose group

No. of animals per sex per dose / concentration:

No data reported.

Control animals:

no

Positive control reference chemical:

A positive control group was not used.

Details on study design:

- Dose selection rationale: No data reported.
- Rationale for animal assignment (if not random): No data reported.

Details on dosing and sampling:

The amount of hydrocarbon vapour absorbed was calculated from the out of gas chromatograph and the flow rate past the rat's nose. Vapour uptake was calculated from the following equation:

uptake (nmol/minute) = flow rate (litre/minute) x vapour concentration (nmol/litre) x ([PAinh(t)/PAinh(cal)] - [PAexh(t)/PAexh(cal)])
where flow rate is the flow rate past the rats' nose; vapour concentration is the supply vapour concentration; PAinh(t) is the chromatogram peak area of inhaled vapour at time t; PAinh(cal) is the chromatogram peak area of inhaled vapour from the pre-exposure calibration; PAexh(t) is the chromatogram peak area of exhaust vapour at time t; PAexh(cal) is the chromatogram peak area of exhaust vapour from the pre-exposure calibration.

Data were normalized twice: once for the mass of rats and to the concentration of inhaled vapour; the second to allow for direct comparison between uptakes rats obtained at different concentrations within the concentration range where little saturation effect was observed for many compounds. The following equation was used for normalization uptake:

Normalized uptake (nmol/min/kg/ppm) = uptake (nmol/minute)/(rat mass (kg) x vapour concentration (ppm))

The data were averaged over 10 minute intervals between 11 and 70 minutes of exposure. The report only discusses the interval from 60 to 70 minutes.

Statistics:

Probabilities were derived from the t test for comparison of the uptake rats of branched and straight-chain hydrocarbon vapours in rats.

Preliminary studies:

A preliminary study was not conducted.

Details on absorption:

When 2-methylbutane 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).

Details on distribution in tissues:

No data reported.

Details on excretion:

No data reported.

Details on metabolites:

No data reported.

The number of animals used per compound per experiment is not reported. Abbreviated information on test methods and results was available because the study is a published article.

Conclusions:

Interpretation of results: no data

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.

Executive summary:

In a toxicokinetic study, 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 is 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.

Description of key information

Short description of key information on bioaccumulation potential result:

One key study (OECD 417) was identified on the inhalation kinetics of cyclopentane in the rat. 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 read-across 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 read-across 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

One key 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 read-across 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 read-across 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.