Health and Environment Laboratories, Eastman Kodak Company (R.J.B.,
L.G.P, L.A.F., J.C.E.);
BioTox (R.W.K.);
Exxon Biomedical Sciences,
Inc. (C.B.);
Union Carbide Corp. (T.R.T.);
Shell Chemical Co. (M.I.B.);
and
ARCO Chemical Co. (G.A.W.).
Isopropanol (IPA), as a 70% aqueous solution, was applied under
occluded conditions to the shaved backs of male and female Fischer
F-344 rats for a period of 4 hr. Maximum analyzed blood concentrations
of IPA were attained at 4 hr and decreased steadily following removal
of the test material. Blood concentrations were below the limit of
quantification at 8 hr. Acetone (ACE) blood levels rose steadily during
the 4-hr exposures and continued to rise following removal of the test
material, reaching peak analyzed levels at 4.5 hr (male) and 5 hr
(females). ACE blood concentrations were below the limit of
quantification at 24 hr. Basic pharmacokinetic parameters were similar
for male and female rats with mean, first-order elimination half-lives
for IPA and ACE of 0.8 to 0.9 hr and 2.1 to 2.2 hr, respectively.
 |
Introduction |
IPA1
is used as a solvent, as a component of numerous
industrial and consumer products, and in the production of acetone and acetone derivatives (Lington and Bevan, 1994
). Human exposure to IPA
may occur through the manufacture and distribution of this material as
well as from direct exposure to a variety of consumer products
including rubbing alcohol, skin lotions, aerosol products, and deicing
and antifreeze solutions (U.S. Environmental Protection Agency, 1989).
Reported adverse health effects in humans resulting from the current
routine manufacture processes and from the use of IPA are limited to a
few cases of either dermal irritation or sensitization. Poisonings as a
result of intentional ingestion of IPA normally result in a comatose
condition with typical signs or symptoms including pulmonary
difficulty, nausea, vomiting, headache, and central nervous system
depression. Intoxications as a result of sponge bath treatments for the
control of fever have also produced comatose conditions with recoveries
in all cases within 34 hr (Lington and Bevan, 1994).
In animals and humans, IPA is metabolized primarily to ACE by hepatic
alcohol dehydrogenase. Expired air is the major route of excretion
following inhalation, oral, iv, or ip exposures. In animals, the
elimination of IPA from blood is a first-order process at oral doses
less than 1500 mg/kg (Lington and Bevan, 1994). A recent report by
Slauter et al. (1994) of the disposition and
pharmacokinetics of [14C]IPA in male and female
rats and mice following iv, inhalation, or oral exposures indicates a
rapid elimination of label in the expired air (as ACE,
CO2, and IPA). In this latter study, rates and
routes of excretion were similar regardless of sex or route of
administration. The first-order elimination half-lives for IPA in these
studies ranged from 1 to 2 hr and were found to increase with
increasing dose for both rats and mice. In humans, first-order half-lives of 0.8 to 16 hr have been reported for the elimination of
IPA (Lington and Bevan, 1994; Monaghan et al., 1995).
The early literature would suggest that IPA is poorly absorbed through
the skin, resulting in negligible toxicity (Grant, 1923; Boughton,
1944). Thus, reports of deep coma in pediatric cases resulting from the
use of isopropanol sponge bath treatments for fever reduction
were attributed to inhalation exposure (Martinez et
al., 1986). More recent work by Martinez et al. (1986)
in rabbits indicates that dermal absorption of IPA may contribute
significantly to the toxicity of this material and that the delayed
rise in blood acetone levels following dermal exposure may be
responsible for the prolongation of the toxic effects. These workers
report IPA blood concentrations in rabbits as high as 112 mg/dl
following 4-hr combined dermal and inhalation exposures, with control
studies indicating that inhalation exposure alone contributed little to the observed blood levels. Neither total dose absorbed nor absorption rate data were reported by these workers. The current studies were
undertaken to determine the disposition and pharmacokinetics of
[14C]IPA following occluded dermal exposure in
male and female rats. In vivo dermal absorption rates for
IPA were calculated by a comparison of recoveries of radiolabel between
iv and dermal exposures.
| |
Materials and Methods |
Test Materials and Dosing Solutions.
IPA (2-propanol, CAS No. 67-63-0) was obtained from Fisher Scientific.
Analysis by GC/MS confirmed the structure and indicated a purity in
excess of 99%. Radiolabeled IPA
(2-propanol-2-14C,
[14C]IPA) was obtained from Sigma as a solution
in isotonic saline. The radiochemical purity of the
[14C]IPA as determined by high pressure liquid
chromatography with radiochemical flow detection was in excess of 99%.
Structural confirmation of the [14C]IPA was
obtained by GC/MS. The concentration of IPA in dosing solutions was
determined by GC/FID on the day prior to use and immediately following
dosing to confirm the concentrations and stabilities of the dosing
solutions. All other chemicals were of reagent grade purity unless
otherwise noted.
Animals.
Male and female Fischer F-344 rats [CDF(F-344)/Crl BR] were obtained
from Charles River Kingston (Stone Ridge, NY) and were from 10 to 12 weeks of age at the time of use. Animal body weights at the time of
dosing ranged from 219 g to 246 g for male rats and 140 g to 163 g for female rats.
Dose Formulations.
Dosing solutions used for dermal applications were 70% (by weight)
IPA. For radiochemical dosing preparations, sufficient amounts of the
stock saline solution of [14C]IPA were placed
into screw-capped vials; unlabeled IPA and either deionized, distilled
water (for dermal dosing) or isotonic saline (for iv dosing) were added
to obtain final solution concentrations. The isotonic saline solution
used for iv dosing was prepared at a concentration of approximately 24 mg/ml.
Dermal Exposure Chambers.
The hair from all test animals was clipped from the thoracic region
immediately posterior to the interscapular area of each animal
approximately 24 hr prior to dose application. All animals were
examined prior to dosing, and any appearing in poor condition or having
abraded skin were not used in the study. On the morning of each study,
chambers fabricated from 3.18-cm-diameter (external) borosilicate glass
tubing were attached to the test animals using a continuous bead of
Permabond 910 (Permabond International Division, Englewood, NJ)
cyanoacrylate glue (Boatman et al., 1993). A circular piece
of polyethylene sheet stock (0.8-mm thickness) was glued to the top of
each chamber as a cover. The surface area of skin enclosed by the cells
was 4.3 cm2, and the aqueous test solution was
observed to completely wet the surface of the skin.
Administration of Test Chemical.
IPA was administered iv as a bolus injection (0.25 ml) into a lateral
tail vein using a 1-ml syringe equipped with a 26-gauge needle. In the
case of iv dosing, a fixed amount of IPA (6 mg/rat) was administered to
each animal to approximate the situation to result following
dermal applications. Aqueous IPA solutions (0.3 ml) were delivered by
syringe to the dermal exposure chambers through a small hole bored in
the cover of each chamber. These holes were covered immediately with a
small piece of polyethylene material glued in place with Permabond 910. Syringe weights were recorded before and after each dose application to
determine the weight of administered dose. Using this procedure, male
rats received a mean dermally applied dose of 0.1800 g of IPA and
female rats a dose of 0.1762 g of IPA.
Dermal Blood-Kinetics Study.
Aqueous IPA was administered to a total of eight test animals (four of
each sex). Excess test material was removed at 4 hr, and the dermal
exposure sites were washed repeatedly with distilled, deionized water
(5 × 1 ml) and dried using cotton swabs. All cells contained
residual test material at 4 hr, and no leakage was apparent. Blood was
sampled at 30 min and at 1, 2, and 4 hr during the 4-hr exposure period
and at 4.5, 5, 6, 8, and 24 hr (after completion of dosing).
Disposition Studies Following IV or Dermal Administration of
[14C]IPA .
Groups of three male or female rats were administered
[14C]IPA iv in isotonic saline at a
nominal concentration of 24 mg/g (6 mg/rat). Alternatively,
similar-sized groups of rats were dosed dermally with
[14C]IPA (0.3 ml/rat) as described for the
dermal blood-kinetics study. All dosed rats were placed immediately
into individual, all-glass metabolism chambers (Metabowl, Jencons Ltd.,
Hemel Hempstead, Herts, England). After 4 hr, rats receiving the dermal
dose were removed briefly from the chambers, unabsorbed liquid at the
exposure sites was rapidly recovered, and the sites were washed
repeatedly with distilled, deionized water (5 × 1 ml) and dried
with cotton swabs. All washings and swabs (as well as the plastic
covers from the exposure chambers) were saved for subsequent
radioactivity analysis by LSS. Following recovery of the residual dose,
animals were immediately returned to the metabolism chambers for the
duration of the study. Urine and cage wash samples, expired volatile
organics (trapped with silica gel), and expired
CO2 (trapped in 2.5 M sodium hydroxide) were
collected at 8, 24, and 48 hr following dose administration and
analyzed for radioactivity by LSS. Feces were collected at 24 and 48 hr
and were homogenized with deionized, distilled water. An aliquot of
this mixture was combusted (Packard Model 306 Sample Oxidizer, Packard
Instruments Company, Downers Grove, IL) and analyzed for radioactivity
by LSS.
Washing Efficiency Studies with
[14C]IPA.
Groups of three male or female rats were administered
[14C]IPA dermally as described above for
the disposition studies. After approximately 5 min, the dose was
removed from the chambers, and unabsorbed liquid at the exposure sites
was recovered. Animals were then placed into all-glass metabolism
chambers, and urine and cage wash samples, expired volatile organics,
expired CO2, and feces were collected and
analyzed for a period of 24 hr following administration of the dose.
Blood Analyses.
Blood was sampled by retro-orbital sinus puncture (approximately 0.2 ml) or was collected at study termination (24 hr) by exsanguination
via the posterior vena cava. Blood samples were kept on ice
or were refrigerated prior to analysis. All blood samples were
processed on the day of collection by a modification of the method of
Smith (1984). Processing consisted of brief centrifugation (1000g, 5 min, 5°C) to separate plasma. Weighed plasma
samples (approximately 50 mg) were treated with 50 µl each of 0.2 M
sodium tungstate, 0.2 M cupric sulfate, and an internal standard
solution (1 mM n-propanol) and were briefly centrifuged
(16,000g, 5 min, 5°C) a second time to remove precipitated
plasma protein. The clear supernatants from this procedure were
analyzed by GC/MS using an adaptation of the methods of Smith (1984)
and of Chueng and Lin (1987) to quantitate levels of acetone and
isopropanol. Standards were prepared by spiking whole blood from a
control animal with known amounts of ACE and IPA; these standards were processed in the same manner as were test samples. As a result, analyzed concentrations of IPA and ACE in plasma could be directly related to concentrations in whole blood. Treated plasma samples were
analyzed by GC/MS using the following conditions: instrument, Hewlett-Packard 5890 GC with 5970 MSD; column, DB-1701 (J & W Scientific, Folsom, CA), 30 M × 0.25 mm (0.2-mm film thickness); head pressure, 5 psi; oven, 30°C (isothermal, 6-min run time); injector, split (flow = 30 ml/min); injection temperature,
280°C; injection volume, 1 µl; mode (MSD), single ion monitoring
(ions: 43.10, 45.10, and 31.10 AMU). Figure
1 contains representative chromatograms.
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|
Fig. 1.
Representative GC/MS analysis of
(A) plasma from a male rat spiked with 0.28 µmol/g of IPA
and ACE and (B) plasma from an untreated rat.
Components detected include IPA (2.6 min) and ACE (2.5 min). The
internal standard, n-propanol, had a retention time of
3.6 to 3.7 min.
|
|
Calculation of Pharmacokinetic Parameters.
A linear equation of the form shown in eq. 1 was fitted to the mean
analyzed concentrations of IPA in male and female rat blood obtained
during the 4-hr dermal exposures.
|
(1)
|
In eq. 1, Ct is the blood
concentration of IPA at time t (see fig. 4).
A mono-exponential equation of the form shown in eq. 2 was fitted to
the mean IPA blood concentrations from the 4-, 4.5-, and 5-hr sampling
times (male rats) or from the 4-, 4.5-, 5-, and 6-hr sampling times
(female rats) following the 4-hr dermal exposures (see fig. 5).
|
(2)
|
In eq. 2, k0 is the first-order
elimination rate constant. The half-life of IPA was calculated as shown
in eq. 3.
|
(3)
|
A di-exponential function of the form shown in eq. 4 was fitted
to the mean analyzed concentrations of ACE in male and female rat blood
following dermal exposures.
|
(4)
|
In eq. 4, Ct represents the
measured blood concentration of ACE in male and female rats from 4 hr
(end of dermal exposures) to 8 hr. The terminal elimination rate
constant for ACE is represented by the term
ka. The terminal half-life of ACE in rat
blood was calculated from ka according to
eq. 3.
Calculation of Dermal Absorption Rates.
Two methods were used to calculate the in vivo rate of
dermal absorption of [14C-IPA] in rats. In the
first method, total recovered radioactivity following an iv
administration was applied as a normalization factor to recoveries
following dermal administration. Thus, following dermal exposures to
[14C]IPA, the amount of absorbed radioactivity
was assumed to equal the total radioactivity recovered from urine,
feces, chamber rinses, expired
14CO2, and volatile
organics. These total recovery values were corrected to 100% by
dividing the total by the fraction of administered radioactivity
recovered following iv administration. Alternatively, expired
14CO2 (from NaOH traps)
following iv administration was used as a dosimeter for absorbed
radioactivity. In this procedure, total radioactivity as expired
14CO2 following dermal
administration was corrected to 100% by dividing the total by the
fraction of radioactivity recovered as
14CO2 following iv
administration.
In the case of male rats, an absorption rate
(mg/cm2/hr) for IPA was calculated as shown in
the following example (calculation based on total recovered
radioactivity): % absorbed dose (table 3) = 91.20% (total recovered) 
84.43% (recovered dose) = 6.77%. Corrected recovered dose = 6.77% 
0.8311 (table 2) = 8.15%. Thus, mg IPA absorbed/hr = [180.0 mg (administered IPA) × 0.0815] 4 hr = 3.66 mg
IPA/hr. 
absorption rate (mg/cm2/hr) = 3.66 mg
IPA/hr 4.3 cm2 = 0.85 mg/cm2/hr (table. 4).
Absorption rates for female rats were calculated similarly.
Permeability coefficients (Kp) were
derived from the absorption rates by dividing by the concentration of
IPA in the administered aqueous solution (568.5 mg IPA/g solution).
Regression and Statistical Analyses.
The program SAS/STAT (Version 6.02, SAS Institute, Inc., Cary, NC) was
used to perform all regression analyses and statistical comparisons.
Unless otherwise stated, all results represent the mean ± 1 SD
for either three or four animals. The asymptotic standard errors for
fitted parameters are reported. IPA and ACE blood concentrations were
analyzed for both gender-related and time-related statistical differences. If necessary, data were transformed into ranks for nonparametric analyses. An appropriate repeated measures' analysis of
variance model was used to detect significant differences (
level of
0.05).
| |
Results and Discussion |
Dermal Blood-Kinetics Study.
Mean concentrations of IPA and ACE in blood from male and female F-344
rats are summarized in figs. 2 and
3. Concentrations of IPA reached
quantifiable levels by 1 hr and increased steadily through 4 hr,
reaching maximum concentrations of 0.19 µmol/g (for males) and 0.24 µmol/g (for females) at 4 hr. Concentrations of ACE reached
quantifiable levels by 30 min and continued to rise during the 4-hr
exposure period reaching concentrations of 0.67 µmol/g (for males)
and 0.78 µmol/g (for females) at 4 hr. ACE concentrations continued
to rise subsequent to exposure, attaining significantly
(p < 0.05) higher observed peak levels in
females vs. males at the 5-, 6-, and 8-hr sampling points.
IPA concentrations fell below quantifiable levels at the 6-hr sampling
time for males and at the 8-hr sampling time for females. Mean measured
concentrations of IPA for male and female rats did not significantly
differ at any measured time point (p 
0.05).
The concentration of ACE in blood had fallen to a level of 0.30 µmol/g (for males) and 0.55 µmol/g (for females) at 8 hr and was
not quantifiable by 24 hr.
Summarized in table 1 are calculated
first-order elimination rate constants and half-lives for IPA and ACE
in rat blood. For IPA, the elimination rate constants were 0.90 hr-1 and 0.74 hr-1,
respectively, for male and female rats. These values correspond to
half-lives for IPA in blood of 0.77 hr and 0.93 hr, respectively. For
ACE, the terminal elimination rate constants were 0.32 hr-1 and 0.33 hr-1,
respectively, for male and female rats. These values correspond to
half-lives for ACE in blood of 2.2 hr and 2.1 hr, respectively.
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TABLE 1
Calculated first-order elimination rate constants (k0 or
ka) and half-lives (t1/2) for IPA and ACE based on
measured blood concentrations following a 4-hr dermal exposure to a
70% aqueous solution of IPA
|
|
IPA blood concentrations were found to increase linearly over the 4-hr
exposures with no apparent approach to an equilibrium or plateau value
(fig. 4). This result is surprising in
view of the rapid elimination half-life (<1 hr) for this material in
the rat (Slauter et al., 1994). Based on an assumption of
simple first-order elimination from a single compartment, such rapid
elimination would suggest that IPA blood concentrations should have
approached an equilibrium or plateau value by 2.5 to 3 hr. The current
experimental findings can be explained if the absorption rate is
assumed to increase during the 4-hr exposures. The most likely cause of
this increasing rate of absorption is an increase in the hydration state of the stratum corneum. Such hydration does occur slowly over the
course of 2 to 3 days with human skin in vitro (Scheulplein and Morgan, 1967). In this respect, the epidermis or stratum corneum has been shown to be the principle barrier to penetration of alcohols in human skin (Scheulplein and Blank, 1973). Scheulplein (1964) reports
that measured in vitro values of
kp for n-pentanol increase by a
factor of approximately 2 over a period of 3 days after exposure to a
dilute aqueous solution of the alcohol. It is proposed that hydration
results in the creation of "pores" or "holes" in the stratum
corneum through which increased absorption occurs. Occlusion has also
been shown to greatly increase dermal absorption rates by increasing
the hydration state of the skin. This has been demonstrated after
topical steroid applications and can result in increased fluxes of 10- to 100-fold with occlusion (Vickers, 1963). Alternatively, the alcohol
itself may contribute to the increased permeability. This latter
possibility has been demonstrated with a series of drug compounds
tested in vitro with human skin using either an aqueous
buffer or a 1:1 (v:v) mixture of ethanol and water as the receptor
solutions (Kasting et al., 1987). Ethanol increased the
average rates of penetration by a factor of 1.7 in this system.
Following the removal of excess test material at 4 hr, loss of IPA from
blood proceeded rapidly with similar elimination rates calculated for
male and female rats (see fig. 5 and
table 1). The results from the current studies agree well with similar
published data from studies in animals and humans. For example, Slauter et al. (1994) report half-lives for IPA in male and female
F-344 rats ranging generally from 1 to 2 hr following iv, oral, or
inhalation exposures. These workers report increasing half-lives with
increasing doses of IPA, suggesting saturation of the alcohol
dehydrogenase enzyme (Lington and Bevan, 1994). Monaghan et
al. (1995) report elimination rate constants for IPA in humans
ranging from 0.72 to 0.85 hr-1 following oral
administration of 70% IPA at a dose of 0.6 ml/kg. Elimination rate
constants from this latter study correspond to half-lives of 0.81 to
0.97 hr.
As shown in figs. 2 and 3, ACE concentrations in blood increased
steadily during 4-hr dermal exposures to IPA. Peak, measured ACE blood
concentrations occurred subsequent to the removal of excess test
material at 4 hr, and similar terminal blood elimination half-lives for
ACE were obtained for both male and female rats (see fig.
6 and table 1). Plaa et al.
(1982) report elimination half-lives for ACE in male Sprague-Dawley
rats ranging from 2.4 hr to 7.2 hr following oral administration.
Saturation of elimination is apparent at higher doses, resulting in
increased half-lives. Monaghan et al. (1995) report
elimination rate constants for ACE in humans ranging from 0.035 to 0.048 hr-1, corresponding to half-lives of 14 to 20 hr. Given similar rates of IPA dermal absorption and ACE
elimination for male and female rats, the higher blood concentrations
of ACE attained by female rats in the current studies are presumably
due to the lower body weights of this gender.
Disposition of Radioactivity Following IV Administration of
[14C]IPA.
Following iv administration of [14C]IPA in rats
at a nominal dose of 6 mg/rat, 50 to 55% of the administered
dose was eliminated as CO2 by 48 hr (table
2). Volatile organics accounted for 21 to
26% of the recovered radioactivity in these studies. Small additional
amounts of radioactivity were also recovered in urine and corresponded
to 6.0% (for males) and 5.1% (for females) of the cumulative total.
Cage washes and feces accounted for <1% of recovered radioactivity.
Slauter et al. (1994) report CO2
recoveries of 29 to 30% in male and female rats following a 300 mg/kg
iv dose with combined recoveries of IPA and ACE (expired breath)
accounting for the majority of the remainder (54 to 55%). The
decreased yields of CO2 in these latter studies
suggest saturation of the metabolic pathways leading from acetone to
CO2. In this regard, Plaa et al.
(1982) reported saturation of ACE elimination in rats at blood concentrations in excess of 300 to 400 mg/liter.
Disposition of Radioactivity Following Dermal Administration of
[14C]IPA.
The majority (84 to 86%) of dermally administered
[14C]IPA (70% aqueous solution) was
recovered from the dermal exposure sites at 4 hr (table
3). Expired CO2 and
volatile organics accounted for the majority of the additionally
recovered radioactivity from these studies with only small amounts
found in feces and urine. Total radioactivity recovered following the
4-hr dermal exposures were 91 to 92%. Radioactivity unaccounted for in
these studies (8 to 9%) was presumably lost because of volatilization
as a consequence of the experimental procedure. This was confirmed in
separate dermal studies in which total radioactivity recovered
following brief (5-min) exposures indicated losses on the order of 13 to 14% (data not shown).
Dermal Absorption Rates and Permeability Constants for IPA.
Summarized in table 4 are the calculated
rates of dermal absorption for IPA and the corresponding permeability
constants derived from these. Calculated absorption rates based on
recovered CO2 were 0.78 ± 0.03 mg/cm2/hr and 0.77 ± 0.13 mg/cm2/hr for male and female rats, respectively.
The corresponding permeability constants based on these values were
1.37 × 10-3 (males) and 1.35 × 10-3 (females). Similar absorption rate values of
0.85 ± 0.04 mg/cm2/hr and 0.78 ± 0.16 mg/cm2/hr, respectively, for male and female rats
were obtained using total recovery of radioactivity as the basis for
the calculation. Permeability constants derived from these latter
absorption rates were 1.50 × 10-3 (males)
and 1.37 × 10-3 (females).
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TABLE 4
Comparison of dermal absorption rates and permeability constants for
IPA in male and female F-344 rats following a 4-hr exposure to a 70%
aqueous solution of [14C]IPA
|
|
The results from the current studies provide the first measured values
for the in vivo permeability of IPA. Similar in
vivo results for IPA and most other low molecular weight alcohols
are lacking. However, DiVincenzo and Hamilton (1979) report a dermal absorption rate of 0.53 mg/cm2/hr for
n-butanol in the beagle dog when applied as a dilute
solution, a result which compares favorably to the values of 0.77 to
0.85 mg/cm2/hr obtained for IPA in the current
studies (table 4). Although suitable
in vivo results are lacking, it is also appropriate to compare our data with published in vitro results. In this
regard, permeability measurements obtained in vitro provide
reliable estimates of in vivo values (Barber et
al., 1992; Bronaugh et al., 1982a) with differences
typically less than a factor of 5 for any specific test chemical. Also,
measured differences between in vivo and in vitro
results are generally least for water-soluble materials having moderate
to rapid rates of dermal absorption (Bronaugh et al.,
1982a). In our studies, permeability values were found to be
similar for male and female rats and to compare favorably with
published in vitro values for low molecular weight alcohols (table 5). Additionally, although rat
skin has been found to be more permeable than human skin in
vitro, these differences are generally low (Bronaugh et
al., 1982b). In this regard, Morris et al. (1995)
report a value of 2.39 × 10-3 cm/hr for the
permeability coefficient of IPA through full-thickness rat (F-344) skin
using 70% aqueous IPA as the test material. These workers also report
similar permeabilities for IPA with either full-thickness mouse or
human skin (3.37 × 10-3 and 3.00 × 10-3 cm/hr, respectively).
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TABLE 5
Comparison of permeability constants for IPA as determined in the
current study with values from Scheulplein and Blank (1973) for a
series of normal alcohols determined in vitro with
full-thickness human epidermis
|
|
Summarized in table 5 are a number of permeability coefficients
for primary alcohols determined in vitro with human
epidermis (Scheulplein and Blank, 1973). IPA results from the current
studies agree most closely with those of its isomer,
n-propanol. Based on the rating scale developed by Marzulli
and co-workers (1969), IPA would receive a skin penetrant rating of
"fast" based on the results of these studies.
| |
Conclusions |
Permeabilty coefficients for IPA through male and female rat skin
were calculated in the current studies based on the total absorption of
[14C]IPA over the 4-hr exposure periods. IPA
was applied under occluded conditions using a completely sealed
exposure chamber to approximate the infinite dose situation in which
absorption is limited only by the rate of penetration through the skin.
Concentrations of IPA in blood during the 4-hr exposures increased
linearly and failed to approach plateau levels, suggesting that
absorption was in fact increasing during the 4-hr exposure periods.
Permeability values determined in the current studies should provide an
upper limit on the rate of penetration of IPA through human skin. Thus,
absorption rates for low molecular weight alcohols measured in
vitro through human skin are increased when applied as an aqueous
solution (Scheulplein and Blank, 1973). This latter effect has been
attributed to increased hydration and swelling of the stratum corneum,
thus allowing more rapid penetration of the polar alcohols (Scheulplein
and Blank, 1973). In addition, occlusion has been shown to
significantly increase the rate of penetration of both methanol and
ethanol through full-thickness guinea pig skin in vitro
(Gummer and Maibach, 1986). It is anticipated that actual human
exposures to IPA under typical use conditions involving brief dermal
contact without occlusion would result in total absorbed doses
significantly less than those predicted from the current study.
This work was funded by the Isopropanol Panel of the Chemical
Manufacturers Association.
Abbreviations used are:
IPA, isopropanol;
ACE, acetone;
GC/MS, gas chromatography/mass spectrometry;
GC/FID, gas
chromatography/flame ionization detection;
LSS, liquid scintillation
spectrophotometry.
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Abstract
Introduction
G and
Lock S
(1982)
Isopropanol and acetone potentiation of carbon tetrachloride-induced hepatotoxicity: Single versus repetitive pretreatment in rats.
J Toxicol Environ Health
9:
235-250[Medline]. 
)
and ACE (
) in blood from male rats treated dermally (occluded)
with 70% aqueous solutions of IPA for 4 hr.
