Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, according to accepted guidelines.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
-reliability scoring based on 1984 guideline
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Isopropanol (isopropyl alcohol, 2-propanol)
- Analytical purity: >99.8% (non-radiolabelled) and >98% (radiolabelled)
- Lot/batch No.: 6077-1 (non-radiolabelled) and 6226-15 (radiolabelled)
- Radiochemical purity (if radiolabelling): 99.3% (low dose) and 99.5% (high dose)
- Specific activity (if radiolabelling): 2.99 μCi/mg (low dose) and 0.3240 μCi/mg (high dose)
- Locations of the label (if radiolabelling): [2-14C]isopropanol
- Expiration date of radiochemical substance (if radiolabelling): not reported
Radiolabelling:
yes
Remarks:
[2-14C]isopropanol

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC)
- Age at study initiation: 7 to 9 weeks old
- Weight at study initiation: 98 to 225 g
500 ppm group: mean bw at the time of dosing = 122 g (females) and 163 g (males)
5000 ppm group: mean bw at the time of dosing = 125 g (females) and 188 g (males)
- Fasting period before study: not reported
- Housing: Housed in specially designed, polycarbonate restrainers
- Individual metabolism cages: Animals were housed in restrainers.
- Diet (e.g. ad libitum): Certified Purina Rodent Chow (5002), ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: Rats were quarantined in polycarbonate cages for at least 7 days prior to initiation of each study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C (72 ± 3°F)
- Humidity (%): 50 ± 20%
- Air changes (per hr): 10 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: nose only

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose only exposure system
- Method of holding animals in test chamber: polycarbonate restrainers
- Source and rate of air: During the exposure of a group of 10 animals, the total inlet flow rate was approximately 5 L/min. The total flow was uniformly divided into 10 equal portions of approximately 500 mL/min each. This rate provided a sufficient supply of fresh isopropanol atmosphere to each rat to prevent rebreathing of expired air.
- Method of conditioning air: Conditioned air was provided to the isopropanol vapor generator and then to the individual nose ports using a Gast Model 0531 rotary, vane-type, oiless pump in parallel with a 10 L ballast that was maintained at a constant positive pressure of approximately 5 psi (to remove pressure fluctuations). The flow to the vapor generation section of the inhalation system was regulated and the flow-rate automatically logged to computer disk using a mass-flow controller (MKS instruments).
- System of generating particulates/aerosols: not applicable
- Composition of vehicle (if applicable): not applicable
- Concentration of test material in vehicle (if applicable): not applicable
- Method of particle size determination: not applicable
- Treatment of exhaust air: The isopropanol atmosphere that was not inhaled by the rat and the expired air from the rat were withdrawn from each nose port at a rate so that a small positive pressure was maintained in the nose chamber. Return flow was controlled by a mass-flow controller (MKS instruments).

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not applicable
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not applicable
Duration and frequency of treatment / exposure:
Single exposure for 6 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
500 (low dose) and 5000 ppm (high dose) (actual concentrations were averaged to be 476 and 4960 ppm, respectively)
No. of animals per sex per dose:
4 animals/sex/group
Control animals:
no
Positive control:
None.
Details on study design:
- Dose selection rationale: A dose-range finding study was performed prior to the initiation of the study (see preliminary studies section below).
Details on dosing and sampling:
PHARMACOKINETIC STUDY (absorption, distribution, and excretion)
- Tissues and body fluids sampled: urine, feces, blood, breath, and tissues
- Time and frequency of sampling: Urine and feces were collected at 8, 24, 48, and 72 hours following exposure. Timed blood samples were collected at intervals during and after exposure. Following final excreta collection, selected tissues were obtained and analyzed for total radioactivity.
Statistics:
Statistical analysis was not performed.

Results and discussion

Preliminary studies:
A dose-range finding study was performed prior to the initiation of the study. After exposure to 3100 ppm, the animals exhibited some loss of balance, but did not show any body weight depression or loss of appetite. After exposure to 770 and 230 ppm essentially no dose-related symptoms were observed. It was suggested that a high dose for the definitive studies be chosen near 6700 ppm, no lower than 3100 ppm, and a low dose be chosen in the 230 ppm to 770 ppm range.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The concentration of radiolabel in the blood increased rapidly following the initiation of inhalation exposure at either concentration. The concentration of radiolabel appeared to still be rising at the end of the exposure to 500 ppm but appeared to have plateaued by the end of the exposure to 5000 ppm IPA. The peak levels attained by the end of the exposure to 5000 ppm were almost exactly 10 times the levels attained following inhalation of 500 ppm. This indicates that absorption is not dose dependent in this range of concentrations. Radiolabel was found to disappear rapidly from the blood following cessation of inhalation exposure. Parent IPA appeared in the blood quickly following the start of exposure to either of the concentrations of IPA vapor studied. Parent IPA concentration in the blood was found to decrease very fast following cessation of the 500 ppm exposure. IPA concentration in the blood dropped more slowly following the end of exposure to 5000 ppm IPA than following the 500 ppm exposure.
Details on distribution in tissues:
In general, IPA and its radiolabeled metabolites were widely distributed among the tissues following nose only inhalation exposure to nominal concentrations of 500 and 5000 ppm. Tissue to blood ratio (TBR) values observed in the tissues of male and female rats following exposure to 500 ppm indicate that even though tissue distribution was broad, clearance from the tissue compartment was uniform and nearly complete. No evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue with the possible exception of adipose tissue, kidney, liver, and ovarian tissue, which had moderately elevated TBR values. Following inhalation of 5000 ppm, elevated TBR values in adipose.tissue, liver kidney and ovary were observed. Approximately 5% of the absorbed dose was found in the residual carcass 72 h following the low Inhalation whereas less than 1.5% was found in the carcass of animals that had been exposed to 5000 ppm 168 h following the start of inhalation exposure.
Details on excretion:
Following nose only inhalation of IPA at the wide range of concentrations studied the breath is, by far, the predominant route of excretion of radiolabel by both sexes. The excretion of the absorbed dose was rapid, with greater than 90% of the absorbed radiolabel being excreted from the breath, urine, and feces within 72 h of the beginning of the inhalation exposure. Exhalation in the breath accounted for a total of about 83% of the absorbed dose at the low exposure level while it accounted for just under 88% following the high exposure level. Even though total excretion of radiolabel in the breath was practically the same following either inhalation exposure, the distribution of radiolabel that appeared in the breath was dramatically different. Following exposure to 500 ppm males and females exhaled an average of 49% of the absorbed radiolabel as carbon dioxide in the breath. Following exposure to 5000 ppm, only 22% of the radiolabel present in the exhaled breath was found to be 14CO2. While the exhaled breath was the major route of excretion following both exposure levels, urine was a minor route of elimination of radiolabel and excretion in the feces was negligible.

In general no significant differences were observed between male and female animals within the same study in the rates and routes of elimination of radiolabel absorbed during inhalation exposure. On a relative basis the radiolabel absorbed during the low exposure was excreted somewhat more slowly than occurred following the high exposure.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 0.8 hrs (males) and 0.9 hrs (females) (blood; dose of 500 ppm)
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 2.1 hrs (males) and 1.8 hrs (females) (blood; dose of 5000 ppm)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 116 μg-eq/g (males) and 125 μg/g (females) at 6 hrs (blood; dose of 500 ppm)
Test no.:
#1
Toxicokinetic parameters:
Cmax: 1258 μg-eq/g (males) and 1449 μg/g (females) at 6 hrs (blood; dose of 5000 ppm)

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Following exposure to 500 ppm IPA nearly all of the radiolabel present as volatile compounds in the exhaled breath was accounted for by acetone. This was not the case following exposure to 5000 ppm IPA where an average of approximately 80% of the radiolabeled volatile compounds in the breath was identified as acetone with the balance being accounted for by IPA. A third radiolabeled metabolite (accounting for less than 5% of the total dose) was found when the urine was analyzed by HPLC; this urinary metabolite was identified as isopropyl glucuronic acid.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results