Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935

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Journal of Photochemistry and Photobiology A:
Chemistry
j our nal home page: www. el sevi er . com/ l ocat e/ j phot ochem
Ultraviolet-photoproduct of acetaminophen: Structure determination
and evaluation of ecotoxicological effect
Kohei Kawabata
a
, Kazumi Sugihara
a,b
, Seigo Sanoh
a
, Shigeyuki Kitamura
c
, Shigeru Ohta
a,
a
Graduate School of Biomedical and Health Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8553, Japan
b
Faculty of Pharmaceutical Sciences, Hiroshima International University,5-1-1 Hirokoshingai, Kure-shi, Hiroshima 737-0112, Japan
c
Department of Health and Pharmaceutical Sciences, Nihon Pharmaceutical University, Komuro 10281, Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan
a r t i c l e i n f o
Article history:
Received 18 June 2012
Received in revised form10 July 2012
Accepted 18 July 2012
Available online 31 August 2012
Keywords:
Acetaminophen
Photodegradation
Ultraviolet irradiation
Photo-Fries rearrangement
Phototoxicity
a b s t r a c t
This study was focused on photodegradation of acetaminophen (AA) exposed to ultraviolet (UV) irradi-
ation at 254 nm delivered by a system similar to that used for sterilization in sewage treatment plants.
The degradation of AA during irradiation for up to 96 h was monitored by means of high-performance
liquid chromatography (HPLC). Based on the mass/charge ratio (m/z) of the protonated ion and the mass
fragmentation pattern in electrospray ionization time-of-ight mass spectrometry (ESI-TOF/MS/MS), the
photoproduct was identied as 1-(2-amino-5-hydroxyphenyl)ethanone (1). Examination of toxicity by
means of a luminescent bacteria test (ISO11348) indicated that AA solution was nontoxic, whereas photo-
exposed AA solution was toxic (EC
50
: 29.46 mg/L). The toxicity of synthetic compound 1 was shown to
account for a substantial part of the toxicity of photo-exposed AA. These results indicate the importance of
investigating not only parent compounds, but also photoproducts the risk assessment of pharmaceuticals
in aquatic environments.
2012 Elsevier B.V. All rights reserved.
1. Introduction
In recent years, pharmaceuticals have emerged as signi-
cant pollutants of aquatic environments. Pharmaceuticals used by
humans and livestock are mainly excreted in urine, either intact or
as metabolite(s), and subsequently enter the aquatic environment.
Although sewage treatment plants (STPs) play an important role in
removing pharmaceuticals from inuent waters, not all pharma-
ceuticals are removed. Indeed, a wide range of pharmaceuticals,
including psychiatric drugs, analgesics, antibiotics, beta-blockers
and hormones, have been found in surface waters, ground waters,
and STP efuents and inuents [27,28,19,6,29]. The concentrations
of pharmaceuticals releasedintoaquatic environment are low, gen-
erally in the range of ng/L to g/L, but nevertheless their potential
impact on ecosystems in aquatic environments cannot be over-
looked.
Many ecotoxicological tests using aquatic organisms, such as
Daphnia magna, Brachinous calyciorus and Oryzias latipes, are
Abbreviations: AA, acetaminophen; UV, ultraviolet; STP, sewage treatment
plant; HPLC, high-performance liquid chromatography; ESI-TOF/MS/MS, elec-
trospray ionization time-of-ight mass spectrometry; EC
50
, median effective
concentration; S.D., standard deviation; PA, p-aminophenol.

Corresponding author. Tel.: +81 82 257 5325; fax: +81 82 257 5329.
E-mail address: sohta@hiroshima-u.ac.jp (S. Ohta).
available for risk assessment of pharmaceuticals in aquatic envi-
ronment [4,10,3].
However, it is important to consider a broad range of factors,
both biotic, such as biodegradation, and abiotic, such as sorption,
photodegradation and hydrolysis, that may affect the persistence,
partitioning andfate of environmental pharmaceuticals. Under lab-
oratory conditions, the concentrations of some pharmaceuticals
were decreased by sorption and biodegradation [30,33,21]. An
activated sludge system, which is one of the treatments used in
STPs, can remove various pharmaceuticals using biodegradation by
bacteria [13].
On the other hand, UV treatment is an efcient method for
disinfecting polluted water. UV irradiation inactivates bacteria by
damaging their DNA. Pharmaceuticals may also be removed as a
result of UVinduced photodegradation. However, it is important to
consider the nature of the photoproducts that may be formed.
Acetaminophen (AA) [paracetamol, para-acetylaminophenol]
(Fig. 1) is widely used as an analgesic and antipyretic drug all
over the world. It is ranked as one of the top 25 prescriptions in
the UK [14]. AA has been detected in discharges from hospitals
and STPs, and in regional discharges [20], and its acute toxicity to
aquatic organisms was investigated [16]. It was shown to be pho-
todegraded by UV irradiation at 254nm[15] and its photoproducts
formed by UV irradiation in the presence of photocatalysts, such
as TiO
2
and H
2
O
2
, have been identied [1,34,36]. However, the UV
photoproduct(s) of AA in the absence of any photocatalyst have
not been identied and its potential toxicity to aquatic organisms
1010-6030/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jphotochem.2012.07.018
30 K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935
Fig. 1. Structure of acetaminophen.
remains to be investigated. Photodegradation of pharmaceuticals
intheabsenceof aphotocatalyst is animportant issue, becausesuch
photodegradation may occur in aquatic environments exposed to
sunlight.
The aimof this research is to investigate the photodegradation
of AA and also to identify the photoproduct and evaluate its tox-
icity to aquatic organisms. In this work, photodegradation of AA
exposed to UV irradiation at 254nm was demonstrated, and the
degradation rate was determined by means of high-performance
liquid chromatography (HPLC). Identication of the photoproduct
was carried out using electrospray ionization time-of-ight mass
spectrometry (ESI-TOF/MS/MS), and the toxicity of AA and its pho-
toproduct was examined by employing the luminescent bacteria
test, ISO11348.
2. Materials and methods
2.1. Materials
Materials were purchased from the following sources:
acetaminophen (purity 98%), dimethyl sulfoxide (purity 99%)
and sodium chloride (purity 99%) from Wako Pure Chemicals
(Osaka, Japan), p-aminophenol (purity 98%) fromKatayama Chem-
ical Industries (Osaka, Japan), reserpine (purity 99%) from Nacalai
Tesque (Kyoto, Japan), methanol (purity 99%) fromKanto Chemical
(Tokyo, Japan), and acetic acid (purity 99%) from SigmaAldrich
(Poole, UK). Milli-Q (18.2m/cm) water was prepared by using a
Milli-Q water purication system(Millipore, Billerica, USA).
2.2. Synthetic procedures
The photoproduct, 1-(2-amino-5-hydroxyphenyl)ethanone
(C
8
H
9
NO
2
), was synthesized according to the reported method
to conrm its structure [8]. Yellow powder.
1
H NMR (400MHz,
CD
3
OD): 2.55 (s, Me), 6.65 (d, J =8.8, H-C(3)), 6.85 (dd, J =8.8,
2.8, H-C(4)), 7.16 (d, J =2.8, H-C(6)). The mass spectrumshows the
base peak [C
8
H
9
NO
2
+H]
+
at a mass/charge ration (m/z) 152.0721
(calculated m/z for C
8
H
10
NO
2
, 152.0711).
2.3. Photodegradation experiments
UV irradiation was carried out at 254nm in a light cabinet
equipped with a 6W UVGL-58 Handheld UV lamp (UVP, Upland,
California, USA) and appropriate lters. The irradiation intensity
was 200W/cm
2
at 15cmfromthesource, as measuredwithadigi-
tal radiometer having a 254nmsensor (UV-37SD, CUSTOM, Tokyo,
Japan). A solution of AA (50g/50mL) in Milli-Q water was irra-
diated in glass vessel with the UV lamp (water depth was 3cm,
distance from the lamp about 15cm). Irradiation times were 0,
6, 12, 24, 48, 72 and 96h at 20

C. Control samples were kept

under the same conditions, but coveredwithaluminumfoil toblock
the UV irradiation. Irradiated samples were concentrated by solid-
phase extraction using Oasis HLB 3cc cartridges (Waters Corp.,
Milford, USA) ina multi-sample concentrationsystem(VarianSam-
ple Preparation Vac Elute SPS 24, Lab Extreme, MI, USA). Samples
wereelutedwithmethanol (2mL), andconcentratedunder reduced
pressure. The residue was dissolved in methanol (500L). The
decrease of AA and generation of photoproduct were monitored
with a HPLC (L-7110, HITACHI, Tokyo, Japan) system equipped
with an Inertsil ODS-3 column (5m, 4.6150mm, GL Sciences
Inc., Tokyo, Japan), a UV detector (L-7440, HITACHI, Tokyo, Japan),
and a Chromato-Integrator (D-2500, HITACHI, Tokyo, Japan). The
UV detector was set at 254nm. A mixture of 0.1% acetic acid and
methanol (9:1) was used as an isocratic mobile phase at a owrate
of 0.5mL/min. Retention times were 26.6min (AA) and 25.4min
(AA photoproduct).
2.4. Identication of photoproduct of AA
Identication of the AA photoproduct was carried out using
ESI-TOF/MS/MS (Qstar

XL, Applied Biosystems, CA, USA). The AA

photoproduct was isolated from photo-exposed AA solution by
means of HPLC and injected into the ESI-TOF/MS/MS by NanoSpray
Infusion. Analysis was conducted in the positive ion mode. Cal-
ibration was carried out with p-aminophenol (1nmol/mL) and
reserpine (1nmol/mL) before analysis. Source/gas parameters of
TOF/MS/MS were as follows: ion source gas 1: 20, ion source gas 2:
0, CurtainGas
TM
: 25, ionspray voltage (positive): 5500. TOF/MS/MS
parameters were as follows: declustering potential (DP): 60.0,
focusing potential (FP): 280.0, declustering potential 2 (DP2): 10.0,
collisionenergy(CE): 20.0, collisiongas (CAD): 5.0, ionrelease delay
(IRD): 11.0, ion release width (IRW): 10.0. Scan type was both
TOFMS mode, which is used for measuring the MS, and product
ion scan mode, which is used for measuring the MS/MS. Synthetic
1-(2-amino-5-hydroxyphenyl)ethanonedissolved(0.1mg/1mL) in
a solution of 0.1% acetic acid and methanol (9:1) was also ana-
lyzed by ESI-TOF/MS/MS under the same conditions used for the
AA photoproduct.
2.5. Luminescent bacteria test
The luminescent bacteria test was carried out according to
ISO11348. This method is based on measuring the light emission
decrease of luminescent bacteria (Photobacterium phosphoreum),
which is related to the level of toxic stress. Luminescence was mea-
sured with a multilabel counter (ARVO
TM
MX, Perkin Elmer, MA,
USA). Toxic effects were expressed as median effective concentra-
tion(EC
50
, mg/L). Samplepreparationwas conductedas follows: AA
(1mg) was initially dissolved in dimethyl sulfoxide (DMSO, 50L)
and the solution was diluted further in Milli-Q water (950L);
thus, the sample solution contained AA 1mg/mL. Then 22% sodium
chloride solution (NaCl aq, 100L) was added to give a nal NaCl
concentration of 2%. This sample was diluted 2, 4, 8, 16, 32, 64 and
128 times with 2% NaCl aq for use. Control samples that did not
contain AA were also prepared. Photo-exposed AA was prepared as
follows: AA (1mg) was dissolved in Milli-Q water (50mL), UV irra-
diatedfor 24handconcentrated100foldby solid-phase extraction.
The residue was used as the sample for the luminescent bacteria
test. Light emission was measured after 15min of exposure using a
multilabel counter and compared with that of the control sample.
Toxicity was evaluatedby calculating the decrease of light emission
of the sample compared to the control.
2.6. Statistical analysis
Results of the luminescent bacteria test (EC
50
) were expressed
as the meanstandard deviation (S.D.). EC
50
was calculated using
Probit analysis (EcotoxStatics ver. 2.3; TheJapaneseSocietyof Envi-
ronmental Toxicology).
3. Results
3.1. Photodegradation of acetaminophen
AA solution was irradiated with a 6W UV lamp for 24h, then
unirradiated AA and the photo-irradiated AA were subjected to
K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935 31
Fig. 2. HPLC analysis of acetaminophen (a) and acetaminophen irradiated UV
(200W/cm
2
/s) for 24h (b).
HPLC analysis to evaluate photodegradation of AA and generation
of the AAphotoproduct (Fig. 2). Retentiontimes were 26.6min(AA)
and25.4min (photoproduct). After UVirradiationfor 24h, the peak
of AA was decreased and a peak of the photoproduct had appeared.
Because the photoproduct was eluted faster than AA, it is expected
to have higher polarity than AA. No other photoproduct of AA was
detected in this experiment. AA decreased to 50% and the photo-
product amounted to about 30% after 24h irradiation, while both
AA and the photoproduct had each decreased to less than 20% after
96hirradiation(Fig. 3). Thecontrol was unchanged, conrmingthat
UV irradiation is required for photodegradation of AA.
3.2. Structure determination of the photoproduct
Structure determination of the photoproduct was carried
out by ESI-TOF/MS/MS. The results of toxicity testing (Table 1)
indicated that the photoproduct is more toxic than AA. In ESI-
TOF/MS/MS, the mass spectrumshowed the protonated ion of the
0
20
40
60
80
100
120
0 12 24 36 48 60 72 84 96
C

/

C
0
(
%
)
Irradiation time (hr)
AA
Photoproduct
Control
Fig. 3. Remaining amounts (%) of acetaminophen and its photoproduct after UV
irradiation for up to 96h. Acetaminophen () and photoproduct () were monitored
by HPLC. Acetaminophen which was not exposed to UV served as the control ().
Table 1
EC
50
(mg/L) values of solutions of acetaminophen, acetaminophen irradiated with
UV for 24h and compound 1 in the luminescent bacteria test. Values are given as
meanstandard deviation.
Compounds P. phosphoreum
Acetaminophen N.D.
Photo-exposed acetaminophen 29.460.75
Compound 1 75.0412.74
n=3; values in meanS.D.; N.D., no detectable toxicity.
photoproduct at m/z of 152.0715 (Fig. 4), which corresponds to
C
8
H
10
NO
2
(calculatedm/z for C
8
H
10
NO
2
, 152.0711). It is possible
that the photoproduct is generated by UV-induced intra-molecular
rearrangement reaction of AA, because AA and the photoproduct
have the same molecular formula (C
8
H
9
NO
2
). Fragment ions of the
protonated ion of the photoproduct were detected at m/z 134.0696
and 110.0607, which correspond to characteristic loss of hydroxyl
group and acyl group (Fig. 4). The main fragmentation pathway
was loss of the acyl group, because the fragment ion peak at m/z
110.0607 was the largest. The results indicated that the photo-
product is 1-(2-amino-5-hydroxyphenyl)ethanone (1) (Fig. 5). In
ESI-TOF/MS/MS, synthetic 1showedthesameprotonatedionat m/z
152.0721 and the same fragmentation pattern as the photoproduct
(Fig. 6).
3.3. Toxicity evaluation using luminescent bacteria test
The effects of AA solution and photo-exposed AA solution on
aquatic organisms were investigated by means of luminescent
bacteria test. AA had no effect, and so the EC
50
of AA could not be
calculated (Table 1). In contrast, UV-irradiated AA solution showed
marked toxicity (EC
50
: 29.46mg/L). Synthetic 1 also showed toxic-
ity in this test (EC
50
: 75.04mg/L, Table 1).
4. Discussion
Our results indicate that AA is photodegraded upon exposure to
UV irradiation at 254nm. Although both AA and the photoproduct
were degraded during UV irradiation for 96h (Fig. 2), there was
no indication that a further photoproduct was generated fromthe
initially formed photoproduct.
The photoproduct was shown to have the structure 1 from the
results of ESI-TOF/MS/MS. The putative photodegradationpathway
of AA is shown in Fig. 7. Compound 1 is considered to be formed
through the photo-Fries rearrangement of AA, i.e., the amide bond
of AA is cleaved by UV irradiation and the generated acyl group
radical attacks at the ortho position, resulting in transfer of the acyl
group to the ortho position.
There have been previous reports of photodegradation of AA
[34,36,2], but only in the presence of photocatalysts. For example,
AA was transformed into many photoproducts by UV irradiation
in the presence of H
2
O
2
via photo-generated hydroxyl and other
radicals [1]. However, compound 1 was not generated, or at least
was not identied, in those experiments.
Photo-Fries rearrangement is one of the photodegradationpath-
ways of Propachlor, whichis usedas a herbicide inGreece andother
European countries [18]. Therefore, involvement of photo-Fries
rearrangement in the formation of compound 1 from AA seems
reasonable.
Moreover, this photodegradation reaction may occur in the
aquatic environment. For example, various pharmaceuticals have
been found to be present in efuents from STPs, at which water
treatment included primary settling and an activated sludge pro-
cess, and appeared to be photodegraded on exposure to sunlight
[2]. AA has been detected in STP efuents in the range of ng/L to
32 K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935
Fig. 4. ESI-mass spectrum(positive ion mode) of the photoproduct (a) and fragmentation pattern of the protonated ion (b) in ESI-TOF/MS/MS.
g/L concentration [27], so residual AA fromactivated sludge sys-
tems may be transformed into the photoproduct by UV irradiation
during sterilization treatment, so it is necessary to investigate the
presence of it.
(a) (b)
Fig. 5. Structure of the photoproduct (a) and proposed fragmentation pattern in
ESI-TOF/MS/MS (b).
The results of the luminescent bacteria test indicated that AA
would not be toxic to aquatic organisms, its photoproduct was
toxic. Compound 1 has a similar structure to p-aminophenol (PA)
which is oxidative metabolized into aminophenoxy radical and
benzoquinonimine [17]. There is a report that PA showed toxic-
ity since formed benzoquinonimine bound covalently to cellular
macromolecules [17]. It is possible that compound 1 showed tox-
icity in the luminescent bacteria test as same mechanisms (Fig. 8).
Also, AA shows toxicity to hepatocyte on account of the generation
of N-acetyl-p-benzoquinonimine bycytochrome P450andcovalent
binding to some proteins [12], but AA had no effects on the aquatic
organisms. PA is 5 to 10 times more potent than AA as a nephro-
toxicant in F344 rats [24], and the inhibition of AA deacetylation
by preventing the formation of PA greatly reduced renal toxicity
suggesting that renal toxicity of AA is due to PA at least in part
[25]. Fromthese reports, it is tempting to speculate that compound
K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935 33
Fig. 6. ESI-mass spectrum(positive ion mode) of synthetic 1 (a) and fragmentation pattern of the protonated ion (b) in ESI-TOF/MS/MS.
1 has a same mechanism on account of the similarity of chemical
structure to PA.
However, the toxic concentration range of the photoproduct is
of mg/L order, being considerably higher than the concentrations
at which AA has been detected in aquatic environments (g/L-
ng/L). Nevertheless, this result illustrates the potential importance
of investigating the toxicity of not only parent compounds, but
also potential photoproducts as a part of the environmental risk
assessment of pharmaceuticals.
In the present experiments, photo-exposed AAsolution showed
toxicity in the luminescent bacteria test, but EC
50
was lower than
of synthetic 1 (Table 1). Therefore, although compound 1 is the
only photoproduct of AA identied here, and clearly a substantial
contributor to the increase of toxicity of after UV irradiation of AA,
it is possible that other photoproduct(s) not detected in this work
might have contributed to the increase of toxicity.
There are several reports indicating that the toxicity of pharma-
ceuticals to aquatic organisms can be altered by UVirradiation. The
beta-adrenergic antagonist propranolol was reported to be trans-
formed into less toxic compounds by UV irradiation [22], while
the antibiotic sulfamethoxazole was transformed into more toxic
compounds [31].
There are many reports of photoproduct formation from
pharmaceuticals in response to UV irradiation, although the inu-
ence of these reactions on ecotoxicity has generally not been
examined. For example, the calcium-channel blocker barnidipine,
widely used to treat hypertension and angina, is photodegraded
by UV irradiation [9]. The diuretic drug furosemide is photo-
transformedintothe dimer [5], whichhas mutagenic potential [11].
Photodegradation of analgesic dipyrone [7], ibuprofen and keto-
profen [23], antibiotic oxytetracycline [35], and beta-adrenergic
antagonist propranolol [32] has also been reported. Further, in
34 K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 2935
Fig. 7. Proposed pathway of photodegradation of acetaminophen to compound 1.
Fig. 8. Suggested toxic mechanismof compound 1.
case of carbamazepine, uoxetine and diclofenac, various photo-
products are generated through complex photodagradation [26],
in contrast to the case of AA, where a single product is generated
via a simple pathway. Clearly the outcome of photodegradation is
dependent on many factors, chemical structure, the kinds of func-
tional groups and the wavelength of UV exposure.
In conclusion, we have shown that UV irradiation increases the
ecotoxicity of AA. Given the wide range of pharmaceuticals that
may be released into the aqueous environment, our results empha-
size the importance of taking intoaccount the potential inuence of
photodegradationinevaluating the ecotoxicity of pharmaceuticals.
Acknowledgements
This study was supported by the Grants-in-Aid for Scientic
Research of Japanese Society for the Promotion of Science (JSPS
20590122).
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jphotochem.
2012.07.018.
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