Dermal and pulmonary absorption of propan-1-ol and propan-2-ol from hand rubs.

Abstract

It has been shown that nontoxic concentrations of ethanol are absorbed after hand hygiene using ethanol-based hand rubs. This study investigated whether absorption of propan-1-ol and propan-2-ol from commercially available hand rubs results in measurable concentrations after use.
The pulmonary and dermal absorption of propanol during hand rubs was investigated. Rubs contained 70% (w/w) propan-1-ol, 63.14% (w/w) propan-2-ol, or 45% (w/w) propan-2-ol in combination with 30% (w/w) propan-1-ol.
Peak median blood levels were 9.15 mg/L for propan-1-ol and 5.3 mg/L for propan-2-ol after hygienic hand rubs and 18.0 mg/L and 10.0 mg/L, respectively, after surgical hand rubs. Under actual surgical conditions, the highest median blood levels were 4.08 mg/L for propan-1-ol and 2.56 mg/L for propan-2-ol. The same procedure performed with prevention of pulmonary exposure through the use of a gas-tight mask resulted in peak median blood levels of 1.16 mg/L of propan-1-ol and 1.74 mg/L of propan-2-ol.
Only minimal amounts of propanols are absorbed through the use of hand rubs. Based on our experimental data, the risk of chronic systemic toxic effects caused by hand rubs is likely negligible. However, our study did not evaluate the consequences of long-term daily and frequent use of hygienic hand rubs.

Full text

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Major article
Dermal and pulmonary absorption of propan-1-ol and propan-2-ol from
hand rubs
Harald Below PhDa,*, Ivo Partecke MDb, Nils-Olaf Huebner MDa, Nora Bieber MDa, Thomas Nicolaia,
Alexander Uschea, Ojan Assadian MD, DTMHa, Elke Below PhDc, Günter Kampf MDa,d,
Wolfram Parzefall PhDe, Claus-Dieter Heidecke MD, PhDb, Dariusz Zuba PhDf, Vincent Bessonneaug,
Thomas Kohlmann PhDh, Axel Kramer MD, PhDa
aInstitute of Hygiene and Environmental Medicine, Ernst Moritz Arndt University, Greifswald, Germany
bDepartment of Surgery, Clinic of General, Visceral, Vascular and Thoracic Surgery, Ernst Moritz Arndt University, Greifswald, Germany
cInstitute of Forensic Science, Ernst Moritz Arndt University, Greifswald, Germany
dBODE Chemie GmbH, Scientific Affairs, Hamburg, Germany
eInstitute of Cancer Research, Medical University of Vienna, Vienna, Austria
fInstitute of Forensic Research, Krakow, Poland
gEnvironmental and Health Research Laboratory, French School of Public Health, Rennes, France
hInstitute for Community Medicine, Ernst Moritz Arndt University, Greifswald, Germany
Key Words:
Alcohol
Blood level
Metabolites
Hand hygiene
Risk assessment
Toxicology
Background: It has been shown that nontoxic concentrations of ethanol are absorbed after hand hygiene
using ethanol-based hand rubs. This study investigated whether absorption of propan-1-ol and propan-
2-ol from commercially available hand rubs results in measurable concentrations after use.
Methods: The pulmonary and dermal absorption of propanol during hand rubs was investigated. Rubs
contained 70% (w/w) propan-1-ol, 63.14% (w/w) propan-2-ol, or 45% (w/w) propan-2-ol in combination
with 30% (w/w) propan-1-ol.
Results: Peak median blood levels were 9.15 mg/L for propan-1-ol and 5.3 mg/L for propan-2-ol after
hygienic hand rubs and 18.0 mg/L and 10.0 mg/L, respectively, after surgical hand rubs. Under actual
surgical conditions, the highest median blood levels were 4.08 mg/L for propan-1-ol and 2.56 mg/L for
propan-2-ol. The same procedure performed with prevention of pulmonary exposure through the use of
a gas-tight mask resulted in peak median blood levels of 1.16 mg/L of propan-1-ol and 1.74 mg/L of
propan-2-ol.
Conclusion: Only minimal amounts of propanols are absorbed through the use of hand rubs. Based on
our experimental data, the risk of chronic systemic toxic effects caused by hand rubs is likely negligible.
However, our study did not evaluate the consequences of long-term daily and frequent use of hygienic
hand rubs.
Copyright ? 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc.
Published by Elsevier Inc. All rights reserved.
Given that hands are the primary vehicle for transmission of
microbial pathogens causing infections, hand hygiene is essential
for infection control in any health care setting,1-10as well as in the
community.11-13Most alcohol-based hand rubs contain ethanol,
propan-1-ol or propan-2-ol, or a combination of these alcohols.1,2,10
In previous studies of hand rubs with ethanol-based formulations,
under extreme test conditions usually not encountered in the
health care setting, 0.5%-2.3% of the applied ethanol was absorbed,
resulting in blood levels of <30 mg/L (0.023%). Although absorption
was found, in practice the use of ethanol-based hand rubs is
considered safe.14,15
* Address correspondence to Harald Below, PhD, Institute of Hygiene and Envi-
ronmental Medicine, Ernst Moritz Arndt University, Walther Rathenau Strasse 49a,
17489 Greifswald, Germany.
E-mail address: below@uni-greifswald.de (H. Below).
I.P. and N.-O.H. contributed equally to this article.
This study was supported by grants from Antiseptica, Pulheim, Germany; Bode
Chemie, Hamburg, Germany; B. Braun Medical, Sempach, Switzerland; Ecolab
Deutschland, Düsseldorf, Germany; Lysoform Dr. Hans Rosemann, Berlin, Germany;
and Schülke & Mayr, Norderstedt, Germany.
Conflict of interest: G.K. is a paid employee of Bode Chemie, Hamburg,
Germany. The other authors have no conflicts of interest to disclose.
Contents lists available at ScienceDirect
American Journal of Infection Control
journal homepage: www.ajicjournal.org
American Journal of
Infection Control
0196-6553/$36.00 - Copyright ? 2012 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.ajic.2011.03.009
American Journal of Infection Control 40 (2012) 250-7

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Comparable blood levels were found for propan-2-ol; in a study
using a commercial hand rub applied every 10 minutes over a
4-hourperiod,subjects’blood levels ofpropan-2-ol rangedfrom0.5
to 1.8 mg/L.16Leeper et al17reported that after extensive epidermal
application of 273 g of propan-2-ol, only 0.9% was absorbed within
10 hours. In contrast, Brown et al18found negligible blood levels of
propan-2-ol in subjects who applied a hygienic hand rub 30 times
in a 1-hour period. Propanol-2-ol also was not detec\table in the
breath of these subjects. However, the Brown et al study used
a method that is approximately 30-fold less sensitive than the
method used in the study of Turner et al16and in the present study.
The dermal and inhalation absorption of propan-2-ol is sup-
ported by case reports on intoxication.19-22After preoperative skin
antisepsis in pediatric surgery, serum levels of up to 12.2 mg/L
(mean, 5.0 ? 3.37 mg/L) were documented by Wittmann et al.23
Compared with propan-2-ol, the data on absorption of propan-
1-ol is even scantier. On isolated human epidermis, the following
constants of permeability have been determined: 800 cm/hour for
ethanol, 1,200 cm/hour for propan-1-ol, and 1,350 cm/hour for
propan-2-ol.24,25Peschel et al26demonstrated that after modified
surgical hand rubs with propanol-containing products with and
without the ingestion of alcoholic beverages, propan-2-ol and
propan-1-ol levels could disturb the analysis of congeners.
Measured propan-1-ol levels were generally 0.2-1.8 mg/L, with
levels pf 8.8 mg/L and 14 mg/L measured in 2 subjects.
The aim of the present experimental study was to determine the
absorbed amounts of propan-2-ol and propan-1-ol from the use of
commercially available hand rubs. The primary goal is to assess the
toxicological risk from the absorption data. We tested 3 hand rubs
containing propan-1-ol alone, propan-2-ol alone, and both in
combination under the same worst-case conditions as in our
previous study examining ethanol absorption,14as well as under
clinical conditions with and without pulmonary exposure.
METHODS
Study design and setting
All 3 experiments had a controlled blinded design and were
approved by the Ethics Committee of the Board of Physicians of
Mecklenburg-Pomerania, University of Greifswald (BB 07/09). In
experiment 1, under a worst-case model of excessive hygienic or
surgical hand rubs, hand rub application was performed in a 37 m3
room with 2 open windows and an open door, without controlled
air exchange during applications. Between hand rub applications,
participants were placed in a second room in which the use of
alcohol-based hand rubs was not permitted. Blood samples were
collected in another separate room.
Experiment 2 involved surgical hand rubs, including a hygienic
hand rub on entering the surgical theatre. Absorption was deter-
mined during the routine surgical program, which included 3
interventions of approximately 90 minutes each. Blood samples
were collected in the doctors’ lounge in the surgical suite.
Experiment 3 was performed in the same manner as in exper-
iment 2, but pulmonaryexposurewas prevented through the use of
a gas-tight mask (X-plore 4390 with A2 filter; Draeger, Lübeck,
Germany) during hand rub application and while the surgeon was
in the wash room.
Participants
Twelve participants (6 males, 6 females) participated in exper-
iment 1, 10 surgeons (6 males, 4 females) participated in experi-
ment 2, and 10 participants (6 males, 4 females) participated in
experiment 3. For all experiments, inclusion criteria were age at
least 18 years and the ability to perform a standardized application
according to European Standard EN 1500:1997.27Exclusion criteria
were defined as visible skin lesions on hands or arms, skin disease,
alimentary intake of ethanol, and use of cosmetics in any form
within 24 hours before the start of a test and on the day of the test.
Furthermore, individuals with diabetes mellitus, pregnant or
lactating women, and individuals who participated in a clinical
experiment within 30 days before the start of the study also were
excluded. To exclude potential oral alcohol consumption by
participants, we also determined the ethanol levels of all partici-
pants during the 3 experiments. Written consent was obtained
from all participants.
Hand rubs
Three commercially available hand rubs were tested: hand rub
P1 (Skinman Sensitive, 70% w/w propan-1-ol; Ecolab, Düsseldorf,
Germany), hand rub P2 (Manorapid ready for use, 63.14% w/w
propan-2-ol; Antiseptica, Pulheim, Germany), and hand rub P1P2
(Sterillium Classic Pure, 45% w/w propan-2-ol in combination with
30% w/w propan-1-ol and 0.2% w/w mecetronium etilsulfate; Bode
Chemie, Hamburg, Germany). All hand rubs were applied in both
hygienic and surgical hand rubs. The hand rubs did not contain any
fragrance or dye but a mixture of skin care components.
Hand rub application
In experiment 1, both hygienic hand rubs and surgical hand rubs
were performed with P1P2 and P2, because at the time that this
experiment was conducted, a hand rub containing only propan-
1-ol was not commercially available. Hands were washed with
nonmedicated neutral soap and dried thoroughly immediately
before the start of the experiment. Foreach hygienic hand rub, 4 mL
of hand rub was applied in the test room to both hands and rubbed
in for 30 seconds according to the standard rub-in procedure
described in EN 1500:1997.27After waiting for 1 minute outside the
test room, this procedure was repeated. A total of 20 hygienic hand
rubs were performed, resulting in a total exposure time of 10
minutes over a 30-minute period.
The surgical hand rub experiments were started 7 days after the
hygienic hand rub experiments. Here, 4 mL of hand rubwas applied
tothe hands and rubbed on the hands and forearms. This procedure
was repeated 5 times, with the hands and forearms kept covered
with the hand rub for the recommended application time of 3
minutes.28After a 5-minute wait outside the test room, the
procedure was repeated. A total of 10 surgical hand rubs were
performed, resulting in a total exposure time of 30 minutes over an
80-minute period. For hygienic and surgical hand rubs, each hand
rub was tested individually on one of 2 consecutive test days. At the
end of each test day, a skin care cream (Neutrogena; Johnson &
Johnson, Düsseldorf, Germany) was applied to the treated skin
areas.
For experiments 2 and 3, when entering the surgical theater,
a hygienic hand rub was performed. This hygienic hand rub was
performed for 30 seconds with the same hand rub as used for the
surgical hand rub. Then, 10 minutes later, a surgical hand rub with
an application time of 1.5 minutes was performed before each of 3
consecutive 90-minute surgical interventions. The exact volume of
the product applied for both the hygienic hand rub and the 3
surgical hand rubs was noted and used to calculate the absorption
rate. After the hand rub application and air-drying, surgical gloves
and gowns were donned.
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Blood sampling
In all experiments, skin antisepsis was performed with an
alcohol-free skin antiseptic (7.5% povidone-iodine solution, Brau-
nol; B Braun, Melsungen, Germany) before blood sampling with
a peripheral intravascular catheter (Inside-W, 18 GA; BD, Sandy,
UT). Baseline samples were obtained before the first hand rub. In
experiment 1, samples were obtained at 2.5, 5,10, 20, 30, 60, and 90
minutes after the last hygienic hand rub or at 5, 10, 20, 30, 60, 90,
and 120 minutes after the last surgical hand rub. In experiments 2
and 3, blood samples were collected before the hygienic hand rub
and 3 times at 90-minute intervals (after each surgical procedure),
as well as at 60 and 90 minutes after the third surgical procedure.
Blood samples were stored at 4?C before analysis and were
analyzed within 12 hours.
Chemical analysis
Chemical analysis was performed using gas chromatography in
a modification of the method described by Roemhild et al,14,29
which uses head-space injection (CombiPal-Autosampler; CTC
Analytics, Zwingen, Switzerland) with flame-ionization detection
(5890 series II gas chromatograph; Hewlett Packard, Waldbronn,
Germany). In brief,1 mL of sample or 1 mL of standard and 0.5 g of
anhydrous Na2SO4 were filled in 1.5-mL head space vials and
incubated for 45 minutes at 75?C. Then 2.5 mL was injected (time
interval, 0.5 minute). A DB 624 column (60 m ? 0.32 mm ? 1.8 mm;
J&W Scientific, Folsom, CA) was used for separation. The chro-
moatographic conditions were an injector temperature of 150?C,
a detector temperature of 250?C, a column temperature program of
40?C for 8 minutes, followed by a ramp of 3?C/minute to 120?C (0
minutes) and then 30?C/minute to 230?C (5 minutes). Nitrogen
(5.0) served as the carrier gas at a rate of 1.45 mL/minute (21.9 cm/s).
For each measurement, calibration was performed according to the
method of the external standard with 3 calibration points (Medi-
drug BGS-S, levels 1-3; Medichem, Steinenbronn, Germany) and
custom-made standards in water. The latter were used for control
standards and propionaldehyde, which is not included in the
commercially available standards. This calibration standard was
produced based on the weight of the original contents of the
substances followed by dilution to the calibration level. The
method’s detection limits were 0.13 mg/L for propan-1-ol, 0.03 mg/L
for propan-2-ol, 0.14 mg/L for ethanol, 0.01 mg/L for acetone, and
0.02 mg/L for propionaldehyde.
For all measurements, quality controls were performed using
certified reference material (Medidrug BGS 2/05 S-Plus; Medi-
chem). Parallel selected samples were analyzed in the chemical
laboratory of the Institute of Forensic Medicine, University of
Greifswald.
Data calculation and statistical analysis
Blood concentrations are expressed as median and 25% and 75%
percentiles. Concentrations below the detection limit were set to 0.
The amount of absorbed alcohol was calculated separately for each
participant based on the method of Wittmann et al.14,23In brief, the
median amount absorbed is the product of the maximum blood
level, body weight, and a sex-dependent factor (0.6 for women; 0.7
for men). The proportion of absorbed alcohol was calculated from
the amount of alcohol initially applied and the percentage of that
amount absorbed. P values were calculated for differences in blood
concentrations in each experiment using Wilcoxon’s rank-sum test
and for differences between experiments 2 and 3 using the Mann-
Whitney U test for unpaired samples. All analyses were done using
SPSS version 11.5.1 (SPSS, Munich, Germany).
RESULTS
Quality control
The results of the certified reference material analysis (n ¼ 9;
propanols and acetone) and the comparison of the results of
parallel samples analyzed by the chemical laboratory at the Insti-
tute of Forensic Medicine were within the limits of analytical
deviation and fulfilled the requirements of an interlaboratory test.
Baseline blood concentrations
For each parameter, a total of 107 baseline values were deter-
mined during the 3 experiments. For propan-1-ol, 91 of 107
samples (85 %) were below the detection limit (median and 25th
and 75th percentiles, <0.13 mg/L). For propan-2-ol 6, 7 of 107
samples (62.6%) were below the detection limit (median and 25th
percentile, <0.03 mg/L; 75th percentile, 0.16 mg/L). For propio-
naldehyde, 80 samples (74.8%) had concentrations below the
detection limit (median, 0.03 mg/L; 25th percentile, <0.02 mg/L;
75th percentile, 0.07 mg/L). Acetone was detectable in all 107
samples (median, 2.10 mg/L; 25th percentile, 1.57 mg/L; 75th
percentile, 3.08 mg/L). The ethanol baseline values were below the
detection limit in most cases (n ¼ 86; 80.4%), or at most 0.55 mg/L.
Blood levels and absorbed propanols and metabolites in
experiment 1
In the worst-case model, the calculated applied amounts for
hygienic hand rubs were 44.25 g of propan-2-ol for P2, 30.64 g of
propan-2-ol for P1P2, and 20.42 g of propan-1-ol for P1P2. Expo-
sures for surgical hand rubs were 110.62 g of propan-2-ol for P2,
76.6 g of propan-2-ol for P1P2, and 51.05 g of propan-1-ol for P1P2
(Table 1).
In experiment 1, after the hygienic hand rubs, the highest
median concentrations of propan-2-ol was 5.3 mg/L (0.0042%) with
P2 and 4.9 mg/L (0.0038%) with P1P2, and the highest median
concentrations of propan-1-ol was 9.15 mg/L (0.0088%) with P1P2.
Propan-1-ol reached its highest median concentration at 30
minutes after the last application (P1P2), and propan-2-ol reached
its highest median concentration at 60 min after the last applica-
tion (P2 and P1P2) (Table 1). In the worst-case model, the median
blood concentrations after surgical hand rubs were higher: 5.8 mg/
L (0.0046%) with P2 and 10.0 mg/L (0.0079%) with P1P2 for propan-
2-ol (Table 3), and 18 mg/L (0.0173%) for propan1-ol with P1P2.
Propan-1-ol reached its highest median concentration after 30
minutes (P1P2), and propan-2-ol did so after 30 minutes with P1P2
and after 60 minutes with P2 (Table 1).
The median amounts of absorbed propan-2-ol were 310 mg
(0.7%) with P2 and 310 mg (1.0%) with P1P2; the median amount of
absorbed propan-1-ol was 600 mg (2.9%) with P1P2 (hygienic hand
rub). For the surgical hand rubs, the median amount of absorbed
propan-2-ol was 472 mg (0.4%) with P2 and 569 mg (0.7%) with
P1P2, and that of absorbed propan-1-ol was 918 mg (1.8%) with
P1P2 (Table 1).
Acetone, the main metabolite of propan-2-ol, reached its
maximum concentration at 60 minutes after the last application,
6.2 mg/L for P2 and 4.5 mg/L for P1P2 (hygienic hand rub). After the
surgical hand rubs, the maximal median concentrations were 5.4
mg/L for P2 and 4.95 mg/L for P1P2, at 60 minutes and 90 minutes,
respectively, after the last application (Table 3).
Independent of the type of hand rub used, the concentration of
propionaldehyde as a metabolite of propan-1-ol did not change
significantly (Table 1).
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252

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Blood levels and absorbed propanols and metabolites in experiments
2 and 3
During the 1 hygienic hand rub and the 3 subsequent surgical
hand rubs, surgeons were exposed to a mean total of 33 mL of hand
rub, corresponding to a mean total propan-2-ol exposure of 18.25 g
for P2 and 12.64 g for P1P2 and a mean propan-1-ol exposure of
20.1 g for P1 and 8.43 g for P1P2 (Table 2).
In experiment 2, the highest median blood level of propan-1-ol
was 4.08 mg/L (0.0039%; P1), and that of propan-2-ol was 2.56 mg/L
(0.0025%; P1P2) (Table 3). Excluding pulmonary adsorption in
experiment 3 resulted in lower median concentrations than were
recordedin experiment 2, with 1.16 mg/L propan-1-ol (0.0011%; P1)
and 1.74 mg/L propan-2-ol (0.0017%; P2) (Table 3).
In experiment 2, the highest median absorbed amounts of
propan-1-ol and propan-2-ol were 271 mg (1.3%; P1) and 92.7 mg
(0.5%; P2), respectively (Table 2). The combination of propanols
(P1P2) influenced absorption; thus, we found 124 mg (1.5%)
propan-1-ol and 137 mg (1.1%) propan-2-ol. In experiment 3, the
highest median absorbed amounts of propan-1-ol and propan-2-ol
were 109 mg (0.5%) for P1,151 mg (0.8%) for P2, and 97.6 mg (1.2%)
and 129 mg (1.0%), respectively, for P1P2. The decline in the
absorbed amount of propan-1-ol (from 271 mg to 109 mg) is
significant (P ¼.023), whereas the increase in the absorbed amount
of propan-2-ol (from 92.7 mg to 151 mg) is salient but not signifi-
cant (Table 2).
The relative absorbed amount of propan-1-ol (1.2%-2.9%) was
approximately 3 times higher than that of propan-2-ol (0.4%-1.1%).
Absorption of propan-2-ol was approximately twice as high after
application of the mixture of the 2 propanols as after application of
propan-2-ol alone (Tables 1 and 2).
The differences in acetone levels between experiment 2 and
experiment 3 are noteworthy. In experiment 2, there was
a significant increase in the blood concentration of acetone,
with a maximum of 10.22 mg/L; in contrast, these were no
significant changes in acetone blood levels in experiment 3
(Table 3). In experiments 2 and 3, blood levels of propionalde-
hyde did not increase significantly from baseline values (data
not shown).
DISCUSSION
The literature contains little information on absorption of
propanols after application of hand rubs. In contrast to some
authors who found certain levels of absorption,16,26,30others
detected no propanol in the blood after application of hand
rubs16,18
or skin disinfection.15
perform a 2-step experiment. The first step was a worst-case
model to clarify whether any absorption occurred, and if so, to
what extent (experiment 1). In the second step, absorption was
determined under clinically relevant conditions (experiment 2),
and also excluding the possibility of pulmonary absorption
(experiment 3). For this purpose, we used a highly sensitive
analytical method.14,29
The criteria for selecting the hand rubs used were commercial
availability, a pure formulation of propan-1-ol or propan-2-ol,
and of the combination of the 2 propanols. Only one hand rub
containing propan-1-ol was commercially available. To select the
pure propan-2-ol and the combined product, we compiled a list
of the 10 most-used hand rubs in Germany and chose 2 by
lottery.
Consequently, we opted to
Table 2
Applied and median absorbed amounts and proportion of propanols after surgical hand rub with P1, P2 and P1P2 in experiment 2 (dermal and pulmonary absorption) and
experiment 3 (dermal absorption only)
Hand rubSubstance Absorption Amount applied, g
Amount absorbed, mg (% of absorbed alcohol)
Median, mg 25th percentile, mg75th percentile, mg
P1 Propan-1-ol Dermal and pulmonary
Dermal only
Dermal and pulmonary
Dermal only
Dermal and pulmonary
20.1
20.1
18.25
18.25
8.43
12.64
8.43
12.64
271 (1.3)
109 (0.5)
92.7 (0.5)
151 (0.8)
124 (1.5)
137 (1.1)
97.6 (1.2)
129 (1.0)
125 (0.6)
55.2 (0.3)
72.4 (0.4)
87.4 (0.5)
67.1 (0.8)
87.4 (0.7)
45.3 (0.5)
64.1 (0.5)
492 (2.4)
174 (0.9)
156 (0.9)
177 (1.0)
182 (2.2)
181 (1.4)
124 (1.5)
159 (1.3)
P2 Propan-2-ol
P1P2Propan-1-ol
Propan-2-ol
Propan-1-ol
Propan-2-ol
Dermal only
Table 1
Median maximum blood concentrations of propanols and their metabolites, applied and median absorbed amounts, and proportion of propanols after 20 hygienic or 10
surgical hand rubs with formulation P2 or P1P2 from 12 participants in the worst-case model (experiment 1)
Experiment
Hand
rub Substance
Median maximum blood concentration
Amount
applied, g
Amount absorbed, mg (% of absorbed alcohol)
Time after exposure,
minutes
Median (25th; 75th percentiles),
mg/L
P
Median
25th
percentile
75th
percentile
1, HHR P2 Propan-2-ol
Acetone
Propan-1-ol
Propan-2-ol
Acetone
Propionaldehyde
Propan-2-ol
Acetone
Propan-1-ol
Propan-2-ol
Acetone
Propionaldehyde
60
60
30
60
60
10
60
60
30
30
90
60
5.3 (3.2; 10.5)
6.2 (3.5; 11.9)
9.15 (4.87; 13.1)
4.9 (3.1; 6.6)
4.5 (2.5; 5.6)
0.15 (0.1; 0.3)
5.8 (3.27; 7.47)
5.4 (4.17; 7.02)
18.0 (10.55; 25.1)
10.0 (5,85; 12.9)
4.95 (3.02; 6.1)
0.2 (0.1; 0.2)
.001
.007
.001
<.001
<.001
.002
.001
.002
<.001
<.001
<.001
.016
44.25 310 (0.7)225 (0.5)416 (0.9)
P1P2 20.42
30.64
600 (2.9)
310 (1.0)
410 (12.0)
229 (0.7)
1,043 (5.1)
479 (1.6)
1, SHRP2110.62 472 (0.4)321 (0.3) 575 (0.5)
P1P251.05
76.6
918 (1.8)
569 (0.7)
703 (1.4)
364 (0.5)
1,220 (2.4)
746 (1.0)
HHR, hygienic hand rub; SHR, surgical hand rub.
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Table 3
Experiments 2 and 3 (dermal and pulmonary absorption vs dermal absorption only), median blood concentrations (mg/L) of propanols and acetone before and after surgical hand rubs with P1, P2, and P1P2
Hand rubSubstance AbsorptionBefore first application
After application
First OPSecond OP Third OP60 minutes after last OP 90 minutes after last OP
P1 Propan-1-ol Dermal and pulmonary
<0.13 (<0.13)*
2.77 (1.90-3.62)
P ¼ .005
0.86 (0.54-1.21)
P ¼ .005
0.60 (0.45-0.82)
P ¼ .005
0.06 (<0.03-0.07)
P ¼ .686
4.21 (3.29-5.44)
P ¼ .074
2.03 (1.54-2.54)
P ¼ .333
<0.13 (<0.13)
<0.13 (<0.13)
0.92 (0.68-1.43)
P ¼ .005
0.85 (0.36-1.25)
P ¼ .005
4.08 (3.36-5.91)
P ¼ .005
2.40 (1.96-2.93)
P ¼ .017
2.14 (1.18-3.00)
P ¼ .005
0.53 (0.27-0.94)
P ¼ .008
2.56 (1.29-3.02)
P ¼ .005
0.64 (0.49-1.22)
P ¼ .007
6.42 (3.80-7.82)
P ¼ .005
2.34 (1.79-2.68)
P ¼ .959
4.08 (1.50-6.75)
P ¼ .005
0.85 (0.51-2.17)
P ¼ .005
0.90 (0.58-0.99)
P ¼ .008
0.06 (<0.03-0.07)
P ¼ .752
6.34 (4.60-8.88)
P ¼ .007
1.99 (1.58-2.54)
P ¼ .333
<0.13 (<0.13)
<0.13 (<0.13)
1.50 (0.87-1.86)
P ¼ .005
1.54 (0.87-2.66)
P ¼ .005
6.72 (5.07-7.93)
P ¼ .005
3.62 (2.26-4.62)
P ¼ .386
1.21 (0.72-3.28)
P ¼ .007
0.50 (0.18-2.20)
P ¼ .012
1.96 (1.26-3.09)
P ¼ .005
0.89 (0.63-1.90)
P ¼ .005
8.54 (5.94-12.09)
P ¼ .005
3.06 (2.18-3.66)
P ¼ .333
3.25 (0.59-7.47)
P ¼ .005
1.16 (0.38-2.39)
P ¼ .005
0.55 (0.44-1.24)
P ¼ .005
0.07 (<0.03-0.14)
P ¼ .183
9.15 (5.64-12.78)
P ¼ .008
2.21 (1.71-2.73)
P ¼ .646
<0.13 (<0.13)
<0.13 (<0.13)
1.70 (1.16-2.22)
P ¼ .005
0.95 (0.57-1.69)
P ¼ .005
9.02 (6.74-10.42)
P ¼ .005
4.16 (2.91-5.54)
P ¼ .053
0.51 (0.3-2.07)
P ¼ .059
0.68 (0.29-1.66)
P ¼ .012
1.39 (0.91-2.29)
P ¼ .005
1.24 (0.50-2.20)
P ¼ .013
8.14 (6.56-11.69)
P ¼ .005
4.17 (3.18-5.59)
P ¼ .028
0.95 (0.73-1.89)
P ¼ .007
0.64 (0.15-1.03)
P ¼ .012
0.46 (0.33-0.54)
P ¼ .005
0.06 (<0.03-0.07)
P ¼ .344
8.21 (4.12-16.96)
P ¼ .005
2.13 (1.78-2.79)
P ¼ .575
<0.13 (<0.13)
<0.13 (<0.13)
1.00 (0.74-1.58)
P ¼ .005
1.74 (1.38-2.73)
P ¼ .005
8.25 (6.38-9.59)
P ¼ .005
4.10 (2.58-5.29)
P ¼ .059
0.3 (0.17-0.87)
P ¼ .441
0.18 (<0.13-0.56)
P¼0.028
0.82 (0.68-1.66)
P ¼ .008
0.70 (0.43-1.20)
P ¼ .007
8.81 (7.03-10.50)
P ¼ .005
4.45 (3.01-6.43)
P ¼ .022
0.54 (0.32-1.20)
P ¼ .017
<0.13 (<0.13-0.24)
P ¼ .068
0.36 (0.24-0.48)
P ¼ .037
0.06 (<0.03-0.11)
P ¼ .482
6.98 (4.70-13.51)
P ¼ .005
1.98 (1.48-2.25)
P ¼ .333
<0.13 (<0.13)
<0.13 (<0.13)
0.85 (0.50-1.10)
P ¼ .005
1.35 (0.54-2.36)
P ¼ .005
7.93 (5.22-10.07)
P ¼ .005
4.43 (2.68-5.40)
P ¼ .114
0.43 (0.25-0.87)
P ¼ .515
0.08 (<0.13-0.27)
P ¼ .042
1.36 (0.96-1.63)
P ¼ .005
0.61 (0.39-1.19)
P ¼ .012
10.22 (6.80-11.93)
P ¼ .005
3.96 (3.33-4.12)
P ¼ .017
Dermal only
<0.13 (<0.13-0.00)*
Propan-2-olDermal and pulmonary 0.21 (0.13-0.23)
Dermal only
<0.03 (<0.03-0.07)
AcetoneDermal and pulmonary1.85 (1.69-3.60)
Dermal only2.32 (1.87-3.09)
P2 Propan-1-ol Dermal and pulmonary
Dermal only
Dermal and pulmonary
<0.13 (<0.13)
<0.13 (<0.13)
0.13 (0.06-0.24) Propan-2-ol
Dermal only0.06 (<0.03-0.07)
Acetone Dermal and pulmonary2.15 (1.49-2.51)
Dermal only 2.90 (2.38-3.63)
P1P2
Propan-1-olDermal and pulmonary
<0.13 (<0.13-0.15)
Dermal only
<0.13 (<0.13)
Propan-2-ol Dermal and pulmonary0.22 (0.04-0.399)
Dermal only
<0.03 (<0.03-0.06)
Acetone Dermal and pulmonary2.51 (1.70-3.59)
Dermal only
2.40 (1.75-2.68)
*The values are median alcohol concentration (25th and 75th percentiles) from 10 participants (total exposure to 33 mL; total contact time, 5 minutes).
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Baseline values
The ethanol baseline values indicate that the participants
abstained from ethanol before and during our experiments. The
proportion of propan-1-ol values below the limit of detection is in
line with reports in the literature and suggests a physiological,
endogenous low-level blood concentration. Small amounts of
propan-1-ol in the blood could not be explained by intake of
alcoholic beverages.31A strong indication that propan-1-ol may be
formed under physiological conditions is the finding that after
participants drank propan-1-ol-free alcoholic beverages, their
propan-1-ol levels rose to detectable levels (up to 0.2 mg/L).26,31
Because ADH preferentially metabolizes ethanol, the metabolism
of propan-1-ol is competitively inhibited by ethanol, which may
result in an increase of measurable concentrations of propan-1-ol.
The main reason that propan-1-ol is notrecognized as physiological
is likely its detection limit, which is 5-fold higher than that of
propan-2-ol (0.13 mg/L vs 0.03 mg/L).
Endogenous propan-2-ol blood levels reported in the literature
vary greatly, ranging from 0.01 to 10 mg/L.23,31,32Our results are in
the lower range of this range (<0.03-0.25 mg/L; <0.000024%-
0.0002%). A possible reason for the presence of physiological
propan-2-ol could be the reduction of acetone in certain metabolic
situations, such as hunger and illness.32,33
Zuba et al34reported that acetone, acetaldehyde, methanol,
propan-2-ol, and propan-1-ol are commonly found in the blood of
alcoholic patients. The origin of these substances is related mainly
to their presence in alcoholic beverages as impurities (congeners),
whichlead tosteady-state concentrations
consumption and ultimately to metabolic changes in the body. The
peak concentration of propan-2-ol was 75.6 mg/L, and that of
propan-1-ol was 13.5 mg/L.34
after prolonged
Relationship between applied and absorbed amounts
We found a clear, direct correlation between the amounts
applied and the amounts absorbed (Tables 1 and 2). In all 3
experiments, systemic uptake was seen, with the greatest absorp-
tion occurring in the worst-case model. In experiment 1, the
increase in concentrations of propanols and their metabolites was
significant at all time points studied. In experiments 2 and 3,
dermal absorption also was significant at most time points, but was
markedly lower than that seen in experiment 1 (Tables 1-3).
The proportion of median absorbed propanols ranged from 0.4%
to 2.9% (mean, 1.1%). The use of P1P2 was apparently associated
with a slightly increased relative absorption rate.
Risk assessment of absorbed amounts
Propan-1-ol
During clinical exposure, both propanols were absorbed in
measurable concentrations. The median absorbed amount of
propan-1-ol was 271 mg (Table 2). The highest median propan-1-ol
concentration was 4.08 mg/L (experiment 2; Table 3). Blood levels
after rubs with P1 reached about half the values attained after
drinking alcoholic beverages containing propan-1-ol.34
In contrast to propan-2-ol, propan-1-ol is not fully accepted as
a physiological compound. However, certain foods and beverages
contain detectable amounts of propan-1-ol, for example, 6-73 mg/L
in beer, 3-8 mg/L in malt beer, 12-68 mg/L in wine, 5-217 mg/L in
fruit wine, and 94-5,773 mg/L in fruit brandy.35The amount
absorbed depends on the kind of beverage consumed. Although
propan-1-ol is not usually detected in vodka and other distilled
spirits, subjects have measurable concentrations after drinking
these beverages.31Typical serum propan-1-ol concentrations after
bolus intake (over 1-1.5 hours) with resulting blood ethanol levels
of approximately 1.0%-1.3% were up to 0.05 mg/L for vodka, 0.30
mg/L for beer, 0.20 for wines, 0.40 for brandy, and 2.5 mg/L for fruit
brandy.36Because we found higher blood levels of propan-1-ol
after hand rubs compared with levels reported after drinking
alcoholic beverages, the risk of toxicity must be carefully consid-
ered. However, although data on the high dose range for propan-1-
ol toxicity have been reported,37such data are lacking on the low
dose range (see below), which is of interest here. Our data from
experiments 2 and 3 show no significant increase in concentrations
of propionaldehyde, the main metabolite of propan-1-ol; in no case
did the blood propionaldehyde level exceed 0.1 mg/L. Thus, we
conclude that propan-1-ol toxicity due to the metabolite propio-
naldehyde is highly unlikely.
As a consequence of the European Union assessment, it is
necessary to limit propan-1-ol; in scenarios with short-term and
repeated exposures,38exposure should be reduced. In the case of
hand rubs, this can be achieved only by decreasing inhalation
exposure, that is, by increasing room ventilation.
Propan-2-ol
The median absorbed amount of propan-2-ol during clinical
exposure was 137 mg (experiment 2; Table 2) at a concentration of
2.56 mg/L (Table 3). In contrast to propan-1-ol, an acceptable daily
intake of 2.4 mg/kg (144 mg/60 kg) has been determined for
propan-2-ol.39However, the risk of hand rubs should not be eval-
uated based on an acceptable daily intake, which expresses the
limit for life-long intake via food and includes a safety factor of at
least 100. Hand rubs are applied mainly by health care profes-
sionals, and the possible health risk depends on the actual expo-
sure. Under our exaggerated experimental conditions, it is possible
that the acceptable daily intake of propan-2-ol could be reached.
This indicates that the safety factor of 100 may be somewhat
uncertain, but does not imply a significant toxic risk.
When used in combination with ethanol drinking, propan-2-ol
and propan-1-ol have similar elimination rate constants (0.14 ?
0.07 g kg?1h?1vs 0.14 ? 0.12 g kg?1h?1). Their elimination rate is in
the same range as that of ethanol in social drinkers (0.15 g/kg/h).
They both have a high biological half-life, 5.1 ? 4.3 hours for
propan-1-ol and 4.8 ? 2.4 hours for propan-2-ol.34
Previous case reports on acute intoxication suggest that propan-
2-ol blood levels <50 mg/L are harmless. Onlylevels >500 mg/L are
associatedwithmildintoxication.Patientswithabloodlevel?1,500
mg/L are deeply comatose.19-22,40In 2 reported cases of oral intoxi-
cationwith propan-2-ol, blood levels reached 3,150 mg/L and 4,200
mg/L,whichwouldbelethalwithoutintensivemedicalcare.41These
dataaredifficulttocomparewithlow-levelchronicexposuresuchas
occurs from the use of hand rubs, and it is not possible to reliably
determine a threshold for toxic effects after chronic exposure.
The German MAK (threshold limit value) Commission has set
a propan-2-ol inhalation exposure limit of 200 ppm (500 mg/m3) in
the workplace; in the United States, theOccupational Safety and
Health Administrationhas set this limit at 400 ppm.42Application
of 10 mL of hand rub (8 g) could achieve this value temporarily in
a 20-m3room without ventilation. Thus, potential health risks by
pulmonary absorption should be minimized by appropriate
ventilation.
Metabolic aspects
For propan-1-ol, we found a low but statistically significant
increase in the main metabolite, propionaldehyde, only in the
worst-case model. Surprisingly, we found increased propan-2-ol
levels after application of P1, which contains only propan-1-ol
(experiment 2; Table 3). In experiment 2, participants had the
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255

Page 7

greatest increase in acetone levels of any experiments. The partic-
ipants did not eat during the experiment, and abstinence increased
their acetone blood levels. In experiment 3, during which the
participants were permitted to eat between the surgical proce-
dures, acetone levels increased only moderately, and, accordingly,
no propan-2-ol was detected (Table 3).
Propan-2-ol is oxidized to acetone, which is subsequently
degraded to acetate and formiate.43Acetone is a physiological
metabolite generated during ketogenesis from fatty acid break-
down44; as such, acetone was detectable at baseline levels (0.8-5.9
mg/L) on all experimental days. The great variations observed
correspond with levels reported in the literature ranging from 0.01
mg/L to 10 mg/L.23,31,45Elevated urinary acetone is a possible
markerof exposureto propan-2-ol. Conversely, propan-2-ol maybe
produced from acetone by reductive metabolism in the presence of
sufficient nicotinamide adenine dinucleotide and nicotinamide
adenine dinucleotide phosphate.46Thus, elevated levels of acetone
may lead to an increase in propan-2-ol blood concentration.31,43
This metabolic pathway may explain the appearance of propan-2-
ol in our participants after application of P1 alone. Some authors
have suggested that both propan-2-ol and acetone should be
considered when evaluating physical stress.47The “endogenous”
level of propan-2-ol depends mainly on diet and disease states. The
propan-2-ol level is elevated in alcoholics, but this may be
a consequence of the “special” diet (ie, starvation, low-calorie food),
not alcohol per se, during prolonged consumption of alcoholic
beverages, resulting in metabolic disturbances. In addition, the
largeexcess of nicotinamide adenine dinucleotide phosphate favors
reduction processes.
Dermal absorption without inhalation exposure
During routine hand rub application, it is practically impossible
to avoid inhalation exposure. Until now, the proportion of inhala-
tion absorption was generally unknown. By preventing pulmonary
absorption, the absorbed amount of propan-1-ol was significantly
lower than the combined dermal and pulmonary absorption (109
mg vs 271 mg; P ¼.023) (Table 2). After eliminating one value from
a participant with inexplicably high absorption, the difference
remained (P ¼ .041).
This tendency was not seen with propan-2-ol. Application of
P1P2 resulted in no significant change in the absorption of either
propan-2-ol or propan-ol-1. Here and with application of P2 alone,
the differences were not significant. Our results support the
suspicion that propan-2-ol is dermally absorbed to a greater extent
than propan-1-ol, which might be attributed to the higher dermal
permeability coefficient of propan-2-ol (1,350 cm/hour vs 1,200
cm/hour).24,25Unlike propan-2-ol, a large proportion of propan-1-
ol is absorbed through the lungs, although propan-2-ol has slightly
higher volatility (8 10?6atm.m3/mol at 25?C vs 7.4 10?6atm.m3/
mol at 25?C). Propan-1-ol from P1P2 is apparently absorbed pref-
erably via dermal contact. Thisobservation maybe explained bythe
lower volatility of P1P2 due to the mixture of 45% propan-2-ol and
30% propan-1-ol, compared with P1 which is 70% propan-1-ol. In
addition, the high proportion of propan-2-ol could increase the
dermal absorption of propan-1-ol. We found no uniform tendency
of absorption in experiments 2 and 3, possibly due to differences in
skin integrity (eg, microlesions). The small sample size (n ¼ 10)
makes it difficult to draw conclusions regarding the predominant
exposure pathway. In addition, individual genetic variability in
metabolic enzymes might play a role in determining the internal
dose of alcohols, although investigating this was beyond the scope
of this study.
Compared with propanolols, ethanol has lower dermal absorp-
tion24,25and less toxicity, and it is more easily metabolized by ADH.
Thus, ethanol-based preparations may be preferable in wards with
a high frequency of hygienic hand rub use. Yet the differing dermal
absorption and metabolization of alcohols is certainly not the only
relevant factor in product selection in wards with a high frequency
of hand rub use. The spectrum of antimicrobial activity, efficacy,
dermal tolerance, and possible impact on compliance in hand
hygiene also should be taken into account. Irrespective of the type
of alcohol in a hand rub, it seems advisable to increase air exchange
in the room to prevent unnecessary pulmonary absorption.
This study has several limitations. The number of participants
was relatively low. Dermal absorption is influenced by the integrity
of the skin (undetectable microlesions) and may vary among the
participants and also on different days, implying that small differ-
ences between pulmonary and dermal absorption are difficult to
recognize. The chosen exposure was a 1-day application, which
represents a common frequency of hand rubs in a surgical theater.
We did notevaluate the consequences of dailychronic and frequent
hygienic hand rubs. We also did not assess the risks to health care
workers who are metabolically deficient in aldehyde dehydroge-
nase, a condition that could present an increased risk of toxicity.
In conclusion, in the present study, propanols were absorbed at
such low levels that no acute toxic symptoms could be observed
and were not expected to arise in our participants. The study
revealed that on average, only 0.4%-2.9% of the administered
amounts of propanols were absorbed; these substances were
metabolized quickly, and their concentrations rapidly decreased to
physiological levels. They were rapidly eliminated after the end of
exposure and did not accumulate, as also demonstrated by the
nonaccumulation of propionaldehyde or acetone in experiments 2
and 3. Because long-term exposure to propanols through the
application of hand rubs has yet to be investigated, and given the
lack of toxicologic data, further studies are needed. In cases of
alcohol dehydrogenase and/or aldehyde dehydrogenase malfunc-
tion, a different risk assessment should be conducted.
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