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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Data obtained from peer-reviewed publication. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.

Data source

Reference
Reference Type:
publication
Title:
Disposition and Pharmacokinetics of Isopropanol in F-344 Rats and B6C3F1 Mice
Author:
Slauter, R.W., Coleman, D.P., Gaudette, N.F., Mckee, R.H., Masten, L.W., Gardiner, T.H., Strother, D.E., Tyler, T.R. and Jeffcoat, A.R.
Year:
1994
Bibliographic source:
Fundam. Appl. Toxicol. 23, 407-420 (1994)

Materials and methods

Objective of study:
excretion
metabolism
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
no
GLP compliance:
not specified

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)
- Locations of the label (if radiolabelling): [2-14C]isopropanol
Radiolabelling:
yes

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
- Fasting period before study: not reported
- Housing: Individually in metabolism cages
- 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:
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: The IPA atmosphere was mixed in a 500-ml mixing chamber and filtered prior to division into 10 equal portions of approximately 500 mL/min each.
- Method of conditioning air: Conditioned air was provided to the isopropanol vapor generator and then to the individual nose ports using a rotary, vane-type, oiless pump in parallel with a 10 L ballast that was maintained at a 5 psi. The flow to the vapor generation section of the inhalation system was regulated using a mass-flow controller (MKS instruments).
- 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.
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: not reported
- Rationale for animal assignment (if not random): not reported
Details on dosing and sampling:
PHARMACOKINETIC STUDY (absorption, distribution, and excretion)
- Tissues and body fluids sampled: urine, feces, blood, breath, and selected tissues (not specified in the publication)
- Time and frequency of sampling: Urine and feces were collected at selected times 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.

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, volatile breath trap samples
- Time and frequency of sampling: composite 0-24 and 24-48 hr
- From how many animals: pooled samples of four rats
- Method type(s) for identification: HPLC, NMR

Results and discussion

Preliminary studies:
not reported
Main ADME resultsopen allclose all
Type:
absorption
Results:
rapid absorption
Type:
distribution
Results:
widely distributed without any accumulation
Type:
metabolism
Results:
major metabolites were acetone and carbon dioxide
Type:
excretion
Results:
the predominant elimination pathway is exhaled breath

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.
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. No evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue with the possible exception of kidney and liver, which had slightly elevated concentrations of radiolabel relative to the blood.
Details on excretion:
Following nose only inhalation of IPA 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.
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.:
#2
Toxicokinetic parameters:
half-life 1st: 2.1 hrs (males) and 1.8 hrs (females) (blood; dose of 5000 ppm)
Test no.:
#3
Toxicokinetic parameters:
AUC: 111.0±10.8 (males) and 152.1±5.8 (females) (blood; dose of 500 ppm)
Test no.:
#4
Toxicokinetic parameters:
AUC: 4648±149 (males) and 5436±583 (females) (blood; dose of 5000 ppm)
Test no.:
#5
Toxicokinetic parameters:
Cmax: 28 µg eq/g (males) and 36 µg eq/g (females) (blood; dose of 500 ppm)
Test no.:
#6
Toxicokinetic parameters:
Cmax: 800 µg eq/g (males) and 951 µg eq/g (females) (blood; dose of 5000 ppm)

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Acetone was found to be the primary radiolabeled metabolite of IPA. In the exhaled breath acetone accounted for 75-100% of the radiolabeled organic volatile compounds being exhaled. The balance of the exhaled radioactivity was accounted for by CO2 and IPA itself. 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.

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Pharmacokinetics of propan-2-ol (IPA) was studied in rats. Animals were exposed by inhalation for 6 hours to IPA vapor. Total exhalation of radiolabel (as CO2, acetone, propan-2-ol) was 83%-87% of the administered dose. Urine and feces accounted for excretion approximately 7% and 1%, respectively. No single tissue contained greater than 1.6% of recovered dose.
Executive summary:

This study is from read-across substance. The study was regarded reliable with restrictions since the study is similar to OECD 417 guideline study, but the publication contains insufficient information on study methods and study results.

Rats were exposed by inhalation route to IPA vapor at concentration of 500 and 5000ppm for 6 hrs. At 500ppm concentration total exhalation of radiolabel was 83% of the dose with radiolabeled CO2 accounting for 53% in males and 46% in females. Exhalation of radioabeled volatile organics (IPA and acetone) by male rats was 29% and by females was 38%. Urine and feces accounted for excretion of approximately 7% and 1% of the absorbed dose, respectively. No single tissue contained greater than 1,6% of recovered dose in either sex. Carcass contained an average of 5% of the dose. Peak blood levels of IPA were similar for males and females, averaging 28 and 36 µg eq/g blood, respectively. At 5000 ppm total exhalation of radiolabel was 87% of the absorbed dose with an average of 21% of as CO2 and an average of 66% as organic volatiles. Male rats excreted 7,0% and females 8,0% of the absorbed dose in the urine. Less than 1% of absorbed dose was eliminated in the feces. No tissue retained more than 0,5% of the absorbed dose. Carcass contained an average of approximately 1,5% of the dose. Peak blood levels of IPA averaged 800 µg eq/g for males and 951µg eq/g blood for females.

No bioaccumulation or biopersistence potential of IPA was observed in the study.

As the target substance hydrolyses immediately (half-life < 3minutes) the intrinsic properties are related to this main organic degradation product (IPA) of the target substance.