Cyclopentane

Basic toxicokinetics

Administrative data

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Objective of study:

toxicokinetics

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Cyclopentane

EC Number:

206-016-6

EC Name:

Cyclopentane

Cas Number:

287-92-3

Molecular formula:

C5H10

IUPAC Name:

cyclopentane

Details on test material:

- Name of test material (as cited in study report): cyclopentane
- Substance type: C5 aliphatics
- Physical state: liquid
- Analytical purity: 95.6%
- Lot/batch No.: A
- Storage condition of test material: room temperature

Radiolabelling:

not specified

Test animals

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

Administration / exposure

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

Doses / concentrations

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

Results and discussion

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.

Toxicokinetic / pharmacokinetic studies

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.

Metabolite characterisation studies

Metabolites identified:

not specified

Details on metabolites:

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

Any other information on results incl. tables

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

 

Applicant's summary and conclusion

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.