Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
-reliability scoring based on 1984 guideline.
Deviations:
yes
Remarks:
-deviations included source or origin of the test article and acclimatization period were not reported and information was not reported at all time-points for each individual rat
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Isopropyl chloride (IPC)
- Physical state: Reported as a "volatile solvent"
- Analytical purity: 97%
- Impurities (identity and concentrations): isopropanol 2%, diisopropylether 0.6%, low chain hydrocarbons 0.3%, and water 0.08%
- Storage condition of test material: Stored in glass bottles at approximately 4°C
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga, Germany
- Age at study initiation: Not reported
- Weight at study initiation: 349 ± 65 g
- Fasting period before study: Not reported
- Housing: Housed individually in polycarbonate cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Fortified autoclaved pellet diet from lid racks; ad libitum (diet was not available during exposure period)
- Water (e.g. ad libitum): Heat-treated tap water from water bottles; ad libitum (water was not available during exposure period)
- Acclimation period: Not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 12 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: head only

Male Sprague Dawley rats received single head-only exposures to IPC vapor for 6 h with weekly repetitions.

For exposure, the liquid test substance was vaporized at defined rates (approximately 35°C) diluted with fresh, filtered, and conditioned air to obtain the target concentrations, and passed continuously through the exposure chambers (flow rate being approximately 160 L/min). The concentrations of the test substance in the exposure chambers were monitored continuously by a flame ionization detector (FID) during exposure. The FID was calibrated by “offline” capillary gas chromatography analysis of samples collected using adsorption tubes. The mean IPC concentrations in the exposure chambers were 248, 419, and 1007 ppm (deviations from the mean values were less than 5%).
Duration and frequency of treatment / exposure:
6-hour single exposure with weekly repetitions (some animals were included in more than 1 dose group; no explanation was provided)
Doses / concentrations
Remarks:
Doses / Concentrations:
Target exposure concentrations = 250, 500, and 1000 ppm.
Actual mean concentrations = 248, 419, and 1007 ppm.
No. of animals per sex per dose:
4 to 6 animals/group
Control animals:
no
Positive control:
None used.
Details on study design:
- Dose selection rationale: The authors reported that in previous inhalation studies, the toxicity of IPC at concentrations between 200 and 1000 ppm has been studied.
- Rationale for animal assignment (if not random): Not reported

Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: On each exposure day, blood samples were taken from a minimum of 4 rats at the following time-points: 1 sample before the start of exposure, 2 samples within 1 h after start of exposure, 1 sample within the last half hour before the end of exposure, and 2 samples within 1 h after the end of exposure. The IPC concentration in blood was determined by gas chromatography.

Statistics:
The parameters for IPC absorption were least square fitted using the Levenberg-Marquardt method (Press et al., 1989) from the IPC concentration in each blood sample according to a 3-parameter exponential regression model.

Due to the fact that no statistical difference was seen between the elimination constant during exposure and after end of exposure, the values for the IPC concentrations during and after exposure were pooled, and an additional evaluation (2-parameter model) was performed according to an exponential regression equation.

Analysis of variance followed by Duncan test was performed for equilibrium concentrations determined in blood.

Results and discussion

Preliminary studies:
The authors reported that in previous inhalation studies, the toxicity of IPC at concentrations between 200 and 1000 ppm was studied (Leuschner, 1990; Gage, 1970; Dow Chemical Company, 1958; INBIFO P0542/1811, 1993). This study investigated the biokinetics of inhaled IPC in the above-mentioned concentration range.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The elimination constants during exposure as well as those after exposure were between 0.04 and 0.07 per min. No concentration-related differences or trends were observed. The biological half-life of IPC in rats was approximately 15 min. The data indicates that a residual accumulation of IPC in blood can be excluded. The blood equilbrium concentrations measured following IPC exposures to 248, 419, and 1007 ppm were 3.7, 4.5, and 9.3 μg/mL, respectively. No other details on absorption were reported.
Details on distribution in tissues:
Not investigated.
Transfer into organs
Observation:
other: not applicable
Details on excretion:
Not investigated.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
other: blood equilbrium concentration was 3.7 μg/mL at 248 ppm
Test no.:
#1
Toxicokinetic parameters:
other: blood equilbrium concentration was 4.5 μg/mL at 419 ppm
Test no.:
#1
Toxicokinetic parameters:
other: blood equilbrium concentration was 9.3 μg/mL at 1007 ppm
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: approximately 15 minutes

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not investigated.

Applicant's summary and conclusion

Conclusions:
The blood equilbrium concentrations measured following IPC exposures to 248, 419, and 1007 ppm were 3.7, 4.5, and 9.3 μg/mL, respectively. The elimination constants during exposure as well as those after exposure were between 0.04 and 0.07 per min. No concentration-related differences or trends were observed. The biological half-life of IPC in rats was approximately 15 minutes. Based on the findings, the authors reported that a residual accumulation of IPC in blood can be excluded.