Full text of DOI:10.1093/chromsci/40.9.509

Journal of Chromatographic Science, Vol. 40, October 2002
Analysis of Cigarette Mainstream Smoke for
1,1-Dimethylhydrazine and Vinyl Acetate by
Gas Chromatography–Mass Spectrometry
J. Diekmann*, C. Biefel, and K. Rustemeier
Institut für biologische Forschung (INBIFO†), Fuggerstrasse 3, 51149 Köln, Germany
UDMH is used in the synthesis of polymers, pesticides,
Abstract
pharmaceuticals, and chemotherapeutic agents (5,6). It is,
together with monomethylhydrazine and hydrazine, a widely
used rocket fuel (7). The toxicity of UDMH has been described
in several publications (8–11) and is classified by IARC as a 2B
carcinogen (possibly carcinogenic to humans) (1). Studies on
laboratory animals have demonstrated the carcinogenicity
and tumor-promoting activities of UDMH (12–14); however,
very little information exists in the literature about UDMH in
cigarette smoke, and the information available is unclear.
There are two very similar publications from Hoffmann et al.
(2,3) that report the occurrence of UDMH in cigarette smoke,
but there is no reference for the data, no method, and no yield
given. Another overview (4) of group 2B carcinogens in cig-
arette mainstream smoke does not list UDMH. One publica-
tion describes the occurrence of UDMH in unburned
processed tobacco in which it was found in cigarette-blend,
chewing tobacco, snuff, and Bright tobacco, but not in Burley
tobacco (15). The U.S. Department of Health and Human
Services suggests that if UDMH is found in tobacco, then
smokers may be exposed to it (16). The source for UDMH in
tobacco found by Schmeltz et al. (15) was quite probably the
hydrolysis of the pesticide succinic acid 2,2-dimethylhy-
drazide (daminozide) (17). Daminozide is primarily used as a
plant growth regulator on apples (22) and there is no infor-
mation available citing its extensive use in tobacco plants.
Different analytical techniques are reported in the literature
for the determination of alkylated hydrazines. Because of the
high reactivity of UDMH, all gas chromatographic (GC)
methods require derivatization. GC analysis of underivatized
UDMH will probably result in its adsorption or decomposition
on the column, problems with sample stability in the injec-
tion port, broad peaks, and short column life. An intense
background of many GC–mass spectrometry (MS) applica-
tions to mainstream cigarette smoke in the range of m/z 40
to 100 may also prevent the direct determination of UDMH.
Several derivatization reagents have been used: pentafluo-
robenzaldehyde (15), pentafluorobenzoyl chloride (18), ace-
1,1-Dimethylhydrazine, also known as unsymdimethylhydrazine
(UDMH) and vinyl acetate (VA), are both classified by the
International Agency for Research on Cancer as 2B carcinogens
(possibly carcinogenic to humans) and listed as cigarette smoke
constituents; however, there is little or no quantitative data
available on them. For UDMH in cigarette smoke, neither a yield
nor a method has been published. For VA, the most recent infor-
mation on yields dates back to 1965. To bridge this gap, we have
developed new gas chromatographic–mass spectrometric methods
for both compounds to determine their yields in cigarette smoke.
UDMH is determined by derivatization with 2-nitrobenzaldehyde
in methanol and is not found in cigarette smoke at levels above the
detection limit of 19 ng/cig. In further experiments, when UDMH
is added to the smoke stream or air stream of lit or unlit cigarettes,
the derivative 2-nitrobenzaldehyde-2,2-dimethylhydrazone is
found only in the air stream of the unlit cigarettes. From this, we
conclude that UDMH is either not formed during smoking at all or,
if it is, it reacts immediately and quantitatively with other smoke
constituents (e.g., aldehydes) and is therefore not detectable in
cigarette smoke. VA is determined by trapping in acetone at –78°C
and is found at a concentration of 270 ng/cig for a standard
reference cigarette with a cellulose acetate filter (the reference
cigarette 1R4F). In the literature, VA is reported at concentrations
of 1.6 µg/cig for a cigarette with a cellulose acetate/charcoal filter
and 4 µg/cig for a cigarette with a cellulose acetate filter and for
an unfiltered cigarette.
Introduction
1,1-Dimethylhydrazine, also known as unsymdimethylhy-
drazine (UDMH) and vinyl acetate (VA), are both classified by
the International Agency for Research on Cancer (IARC) as 2B
carcinogens (possibly carcinogenic to humans) and listed as
cigarette smoke constituents (1–4).
* Author to whom correspondence should be addressed: email joerg.diekmann@pmintl.com.
† INBIFO is a Philip Morris research laboratory.
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher’s permission.
509

Journal of Chromatographic Science, Vol. 40, October 2002
tone (19,20), salicylaldehyde (21), and 2- and 4-nitroben-
zaldehyde (22–25). We selected the 2-nitrobenzaldehyde
derivatization method because it is easy to perform as well as
fast, highly sensitive, selective, and quantitative. Saxton et al.
(22), Majumdar et al. (23), and Brinkmann et al. (24) deter-
mined UDMH as a degradation product of daminozide.
Inverse derivatizations are also cited in the literature.
McDaniel and Howard (26) derivatized aldehydes, ketones,
and carboxylic acids with UDMH, and VandenHeuvel and
Horning (27) derivatized steroid ketones with UDMH.
Because of the data reported by Hoffmann et al. (2,3), UDMH
may be important when cigarette smoke is evaluated for its
toxicological impact; therefore, a method was needed to be
developed for the determination of UDMH in cigarette smoke.
The starting point for the method development for VA
determination was the following: as opposed to its polymer,
the monomer VA was used in the commercial production of
polymers such as polyvinyl acetate (PVA) and copolymers
such as ethylene-vinyl acetate in wood, paper, paint, and
packaging and in the tobacco industry (28) as, for example,
sideseam adhesives in the cigarette paper. Therefore, we eval-
uated the possibility that VA may be produced during com-
bustion. The toxicity of VA has been described by Bogdanffy et
al. (29) and classified by IARC as a 2B carcinogen (1,4).
Studies on laboratory animals have demonstrated the car-
cinogenicity and tumor-promoting activities of VA (29,30). In
1965, Newsome et al. (31) detected VA in cigarette smoke at
concentrations from 0.5 µg/puff (for a cigarette with a cellu-
lose acetate filter and for an unfiltered cigarette) to 0.2
µg/puff (for a cigarette with a cellulose acetate/charcoal
filter). Assuming that a cigarette has approximately 8 puffs,
the values are approximately 4 µg/cig (unfiltered) and 1.6
µg/cig (charcoal filtered). It must be mentioned that the cig-
arette smoke was not generated under International Organi-
zation for Standardization (ISO) standard conditions and that
the method used for quantitation was a GC–flame ionization
detection (FID) method that, compared with the chromato-
graphic possibilities of today, shows poor separation. Norman
(32) reported a value of 4 µg/cig for VA, giving no reference
for the data and no method for the determination of VA but
citing Newsome et al. (31), one of his earlier coworkers.
Guerin (33) reported 400 ng/cig citing the Norman article
(32). This may have been a printer’s error or a citation error;
however, both values were cited in IARC (34). The overview of
class 2B carcinogens in cigarette smoke by Smith et al. (4)
also cited the Newsome et al. article (31). Headspace sampling
(HS) techniques are mentioned in several publications for the
determination of volatile VA. For example, Wang et al. (35)
detected VA in coffee, and Kunigami et al. (36) described the
analysis of VA in adhesive formulations. One publication from
Watson and Ashley (37) analyzed acetates, including VA, in
cigarette tobacco by HS–solid-phase microextraction, but no
VA was detected (detection limit of 1.1 ng/cig). Because the
most recent method for the determination of VA in cigarette
smoke was a GC–FID method published in 1965 by Newsome
et al. (31) and no more recent data were found in the litera-
ture, we decided to develop a method for the determination of
VA in cigarette smoke.
Experimental
Materials
The test cigarettes were the University of Kentucky (Lex-
ington, KY) reference cigarette 1R4F. This reference cigarette
is one of a series of reference cigarettes developed for research
purposes in a joint effort by the National Cancer Institute of the
National Institute of Health (Bethesda, MD), the Agriculture
Research Service of the U.S. Department of Agriculture (USDA)
(Washington, D.C.), and the University of Kentucky Tobacco
and Health Research Institute (Lexington, KY). The reference
cigarette 1R4F was designed in 1983 with the following spec-
ifications: 83.5-mm length, 25-mm circumference, 35-mm
butt length, 11-mg total particular matter (TPM), and 0.8-mg
nicotine/cig. The cigarettes were stored and conditioned
according to ISO standard 3402 (38).
Reagents and chemicals
UDMH, 2-nitrobenzaldehyde, VA, acetaldehyde, and propi-
onaldehyde were purchased from Aldrich, Fluka, and Sigma
(Deisenhofen, Germany) and were labeled as 98% or 99% pure.
VA-d6 (99% pure) was obtained from CDN Isotopes (Dr. Ehren-
storfer, Augsburg, Germany). Methanol (Lichrosolv) and ace-
tone (p.A.) were purchased from Merck (Darmstadt, Germany).
Preparation of standards and derivatization reagent
A stock solution of UDMH was prepared in methanol at a
concentration of 1.55 mg/mL. From this stock solution, stan-
dard solutions were prepared for external calibration and to
verify the linearity of the derivatization. Acetaldehyde and pro-
pionaldehyde were prepared in methanol at concentrations of
20 µL/mL or were used as pure solutions. The derivatization
reagent was prepared with 2-nitrobenzaldehyde dissolved in
methanol at concentrations of approximately 100 mg/mL.
Stock solutions of VA and VA-d6 were prepared in acetone at
concentrations of 8.59 and 7.04 mg/mL. From these stock
solutions, standard solutions were prepared for an internal
standard calibration. A stock solution of 4.1 mg/mL was pre-
pared for control samples of VA.
Smoke generation, sample collection, and derivatization
of UDMH
Mainstream smoke was generated in basic conformity with
ISO 3308 (39). The cigarettes were electrically lighted and
smoked on a 20-port rotary smoking machine with a 35- 0.5-
mL puff volume and a 2.0- 0.1-s puff duration every minute.
The cigarette mainstream smoke was collected under condi-
tions adapted from a published method (40). UDMH was col-
lected in only one (the first) wash bottle (midget
microimpinger), whereas VA was collected in 3 wash bottles
connected in series (Figure 1). The first wash bottle contained
approximately 6 g of glass beads, and the second and the third
wash bottles each contained approximately 5 g of glass beads.
For the determination of UDMH, the first wash bottle con-
tained 5 mL methanol and 2 mL derivatization reagent, and no
glass fiber filter was used. For the determination of VA, the first
wash bottle contained 7 mL acetone, and the second and third
510

Journal of Chromatographic Science, Vol. 40, October 2002
wash bottles each contained approximately 6 mL acetone. Prior
to sampling, the wash bottles were cooled to –78°C with a
mixture of isopropanol and dry ice. After sampling was com-
pleted, the wash bottles were thawed and the contents funneled
into a volumetric flask. The wash bottles were rinsed with sol-
vent and the volumetric flask was filled to the 10-mL mark for
UDMH and the 25-mL mark for VA. One milliliter of the sample
was added to an autosampler vial. The UDMH sample was
heated for 30 min at 30°C. The internal standard VA-d6 was
added to the VA sample.
In some experiments for the determination of UDMH, the
cigarettes were not lit (“dry puffs”); instead, fresh air was drawn
through the cigarettes, and the sample collection was per-
formed in the same way as with the lit cigarettes.
40°C, held for 3 min and heated at 50°C to 200°C, and then held
for 1 min (total GC run time 7.20 min).
MS parameters and data analysis
Mass spectra from standard solutions of the hydrazones were
acquired in full-scan mode (mass range of 50 to 400). For the
quantitation of 2-NDH, selected masses were acquired in
single-ion monitoring (SIM) mode; 2-NDH was quantitated by
its molecular ion (M)+ m/z 193 and the ion at m/z 74 was used
for confirmation. An additional criterion for the determination
of 2-NDH was the retention time of 9.5 min ( 0.05 min).
Acetaldehyde 1,1-dimethylhydrazone was detected with the
(M)+ ion at m/z 86 and propionaldehyde 1,1-dimethylhydrazone
with the (M)+ ion at m/z 100 in SIM mode.
VA and VA-d6 were detected and quantitated in SIM mode
with the masses of the molecular ions (m/z 86 and 92). Qual-
ifier ions for confirmation could not be used because of matrix
effects.
For data analysis, the chromatogram peak areas were deter-
mined automatically by the HP ChemStation Integrator
program in the HP Enhanced ChemStation Version
B.03.00 software.
Standard addition experiments for the determination
of UDMH
UDMH was added to the smoke stream through a glass con-
nector placed between the smoking machine and the wash
bottles (Figure 1). After the second, fourth, fifth, and seventh
puffs of the smoking machine, 10 µL of a standard solution of
UDMH containing 1.55 mg/mL was added to the smoke (total
62 µg UDMH). After each addition, the hole was closed. In
some experiments, a hairdryer was used to heat the glass con-
nector to insure that all the added UDMH (boiling point
63.9°C) vaporized. In a separate experiment, 5 µL of a standard
solution of UDMH (concentration of 1.55 mg/mL) was added to
cigarette filters (7.7 µg/filter). The cigarettes were then
smoked, and after smoking, the filters were cleaned of tobacco.
The filters were extracted with a solution of 8 mL methanol and
2 mL derivatization reagent by shaking for 10 min. An aliquot
of the solution was removed and heated for 30 min at 30°C for
derivatization.
Calibration and validation data
Calibration and validation data for the determination of
UDMH
A 12-point calibration curve for 2-NDH with a concentration
range of 0.077 to 15.47 µg/mL was produced as an external cal-
ibration and to verify the linearity of the derivatization. The cal-
ibration curve was linear (correlation coefficient [r2]= 0.999) and
all of the results were within 8% of expected. The concentration
of 2-NDH at 0.08 µg/mL was found to be the quantitation limit
with a signal-to-noise (S/N) ratio of 10:1, and the concentration
of 0.03 µg/mL was found to be the detection limit (S/N = 3:1).
Assuming that 10 cigarettes would be smoked and the smoke
trapped in a 7-mL derivatization reagent in methanol, the detec-
tion limit would be 19 ng/cig. The stability of 2-NDH in the
matrix of 10 cigarettes smoked and trapped in methanol was
GC–MS instrumentation
A Hewlett Packard (HP) 6890 GC equipped with an HP 6890
Series autosampler was coupled with an HP5973 mass-selective
detector (230°C transfer line temperature) operating in electron
impact (70 eV) mode. The MS quadrupole
and source heaters were maintained at
106°C and 200°C, respectively. The GC
worked in splitless mode and was fitted
with an SGE BP 624 column with a 0.32-
mm i.d. and 1.8-µm film thickness. Helium
carrier gas was maintained at 2.6 mL/min.
For the determination of 2-nitrobenzalde-
hyde–2,2-dimethylhydrazone (2-NDH), the
GC oven was heated to 100°C and held for
2 min, then increased to 230°C at
30°C/min, and held for 6 min (total GC
run time 12.33 min). For the determina-
tion of acetaldehyde 1,1-dimethylhydra-
zone
and
propionaldehyde
1,1-dimethylhydrazone, the GC oven was
held at 50°C for 2 min, then increased to
230°C at 10°C/min, and held for 3 min
(total GC run time 23 min). For the deter-
mination of VA, the GC oven was started at
Figure 1. A collection of gas-phase cigarette mainstream smoke: (1) glass fiber filter was not used for
the UDMH determination and (2) only the first wash bottle was used for the UDMH determination
511

Journal of Chromatographic Science, Vol. 40, October 2002
determined by the following procedure: a standard solution of
UDMH and 2-nitrobenzaldehyde was added to the
microimpingers filled with methanol. One control sample was
removed for measuring. Then, ten cigarettes were smoked, and
the smoke was trapped in the microimpingers. Samples were
taken out immediately and again 6 h after smoking. There was
no loss of 2-NDH in either sample. In one sample, which was
removed 72 h after sample trapping, there was a 28% decrease
in 2-NDH. Based on these results, all experiments (sample col-
lection, extraction, derivatization, and measurement) were car-
ried out within 6 h. The decrease in concentration may have
been the result of stability problems with hydrazones in the
presence of light and an acetic acid catalyst (5,20).
smoke components (e.g., with aliphatic aldehydes or ketones).
Bark and Prachuabpaibul (41) and McDaniel and Howard (26)
reported that aliphatic aldehydes react quantitatively with
UDMH, and Smith et al. (42) obtained good yields for the reac-
tion of aliphatic steric unhindered ketones with UDMH.
With regard to the possibility that UDMH may have
remained on the cellulose acetate of the cigarette filter, we
performed the following experiments: we added UDMH to the
cigarette filters and “smoked” the cigarettes lit and unlit. The
extracts from the filters showed that UDMH disappears in
smoke from the lit cigarettes, whereas it could be extracted
from the filter of the unlit cigarettes. We assumed that during
smoking, any UDMH that may be formed reacts with other
smoke constituents (e.g., aldehydes). To explore this hypoth-
esis, we bubbled the cigarette mainstream constituents
acetaldehyde and propionaldehyde through a methanolic solu-
tion of UDMH. Although it was easy to identify the corre-
sponding acetaldehyde 1,1-dimethylhydrazone and
propionaldehyde 1,1-dimethylhydrazone by their mass spectra,
attempts to analyze cigarette smoke extract for the hydrazones
were not successful.
Calibration and validation data for the determination of VA
An 18-point calibration curve for VA with a concentration
range of 0.02 to 85.9 µg/mL was linear (r2 = 1.0) and all of the
results were within 2.2% of expected. The concentration of
VA at 0.02 µg/mL was found to be the quantitation limit (S/N
= 10:1). Assuming that 10 cigarettes would be smoked and
the smoke trapped in 25 mL acetone, the quantitation limit
would be 8 ng/cig. The precision of an intraday (n = 5) deter-
mination of samples from 10 1R4F cigarettes was 2.5%. The
trapping efficiency was 82% in the first trap, 16% in the second
trap, 2% in the third trap, and the concentration of VA in a
fourth wash bottle, connected in series to the other three, was
below the detection limit.
Concentration of VA in the cigarette smoke from the
reference cigarette 1R4F
Smoke was generated from 10 1R4F cigarettes, and the
smoke constituents were trapped in 3 microimpingers con-
nected in series at –78°C filled with acetone. A concentration
of 270 ng/cig was found.
Results
Conclusion
UDMH in cigarette smoke from the reference
cigarette 1R4F
We have developed reliable methods for the determination of
UDMH and VA in cigarette smoke and found that UDMH is not
detectable in cigarette smoke at levels above 19 ng/cig with the
analytical method described. Through standard addition exper-
iments, we found that UDMH is not stable in cigarette smoke,
which means that if UDMH is initially formed during smoking,
its reaction with other smoke constituents is immediate and
quantitative. It is worth noting that UDMH may be a precursor
of N-nitrosodimethylamine (NDMA), a class 2A carcinogen
that occurs in cigarette smoke up to 1.62 µg/cig (43), and that
oxidative processes on UDMH can tend to produce NDMA
(44,45); however, this has not been shown to take place in cig-
arette smoke.
Smoke was generated from 10 1R4F cigarettes, and the
smoke constituents were trapped in a microimpinger at –78°C
filled with methanol and the derivatization reagent. After
derivatization, the liquid trap was analyzed for 2-NDH (Table I).
No 2-NDH was found. In addition, approximately 62 µg UDMH
was added to the smoke via the spiking port (Figure 1), but the
derivative 2-NDH was still not found, even when only one cig-
arette was smoked.
In contrast, when UDMH was added to the “airstream” of
unlit cigarettes, the derivative was found (Table I). We assume
that UDMH does not reach the trap, because it reacts with
The VA yield in cigarette smoke was 270 ng/cig for the ref-
erence cigarette 1R4F. The method can be used, for example, to
investigate the influence of PVA-based adhesives used in ciga-
rette production on cigarette smoke composition.
Table I. Detection of 2-NDH in Liquid Traps Before and
After UDMH was Added to the Smoke or Airstream of
Lit or Unlit Cigarettes
2-NDH found
above the detection
limit (19 ng/cig)
No. of
cigarettes
UDMH added to
smoke/airstream
Cigarettes
Acknowledgments
Lit
Lit
Lit
10
10
1
no
yes
yes
yes
no
no
no
yes
The authors wish to thank M. Douda for sample generation
and analysis, J. Oey for his assistance with compiling refer-
ences, H. Voelkel for the preparation of Figure 1, and L. Conroy
for editing the manuscript.
Unlit
10
512

Journal of Chromatographic Science, Vol. 40, October 2002
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