Ultraviolet-photoproduct of acetaminophen: Structure determination and evaluation of ecotoxicological effect

Article abstract of DOI:10.1016/j.jphotochem.2012.07.018

This study was focused on photodegradation of acetaminophen (AA) exposed to ultraviolet (UV) irradiation 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-flight mass spectrometry (ESI-TOF/MS/MS), the photoproduct was identified 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 (EC₅₀: 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.

Full text of DOI:10.1016/j.jphotochem.2012.07.018

Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
Contents lists available at SciVerse ScienceDirect
Journal of Photochemistry and Photobiology A:
Chemistry
journal homepage: www.elsevier.com/locate/jphotochem
Ultraviolet-photoproduct of acetaminophen: Structure determination
and evaluation of ecotoxicological effect
Kohei Kawabataa, Kazumi Sugiharaa,b, Seigo Sanoha, Shigeyuki Kitamurac, Shigeru Ohtaa,∗
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
a b s t r a c t
Article history:
Received 18 June 2012
Received in revised form 10 July 2012
Accepted 18 July 2012
Available online 31 August 2012
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-flight mass spectrometry (ESI-TOF/MS/MS), the
photoproduct was identified 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 (EC50: 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.
Keywords:
Acetaminophen
Photodegradation
Ultraviolet irradiation
Photo-Fries rearrangement
Phototoxicity
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
available for risk assessment of pharmaceuticals in aquatic envi-
ronment [4,10,3].
In recent years, pharmaceuticals have emerged as signifi-
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 influent 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 effluents and influents [27,28,19,6,29]. The concentrations
of pharmaceuticals released into aquatic 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.
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 and fate 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 efficient method for
disinfecting polluted water. UV irradiation inactivates bacteria by
damaging their DNA. Pharmaceuticals may also be removed as a
result of UV induced 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 254 nm [15] and its photoproducts
formed by UV irradiation in the presence of photocatalysts, such
as TiO2 and H2O2, have been identified [1,34,36]. However, the UV
photoproduct(s) of AA in the absence of any photocatalyst have
not been identified and its potential toxicity to aquatic organisms
Many ecotoxicological tests using aquatic organisms, such as
Daphnia magna, Brachinous calyciflorus 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-flight mass spectrometry; EC50
, 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).
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) 29–35
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 254 nm. A mixture of 0.1% acetic acid and
methanol (9:1) was used as an isocratic mobile phase at a flow rate
of 0.5 mL/min. Retention times were 26.6 min (AA) and 25.4 min
(AA photoproduct).
Fig. 1. Structure of acetaminophen.
remains to be investigated. Photodegradation of pharmaceuticals
in the absence of a photocatalyst is an important issue, because such
photodegradation may occur in aquatic environments exposed to
sunlight.
2.4. Identification of photoproduct of AA
Identification 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 (1 nmol/mL) and
reserpine (1 nmol/mL) before analysis. Source/gas parameters of
TOF/MS/MS were as follows: ion source gas 1: 20, ion source gas 2:
0, CurtainGasTM: 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,
collision energy (CE): 20.0, collision gas (CAD): 5.0, ion release 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)ethanone dissolved (0.1 mg/1 mL) 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.
The aim of 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 254 nm was demonstrated, and the
degradation rate was determined by means of high-performance
liquid chromatography (HPLC). Identification of the photoproduct
was carried out using electrospray ionization time-of-flight 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%) from Katayama Chem-
ical Industries (Osaka, Japan), reserpine (purity 99%) from Nacalai
Tesque (Kyoto, Japan), methanol (purity 99%) from Kanto Chemical
(Tokyo, Japan), and acetic acid (purity 99%) from Sigma–Aldrich
(Poole, UK). Milli-Q (18.2 mꢀ/cm) water was prepared by using a
Milli-Q water purification system (Millipore, Billerica, USA).
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 (ARVOTM MX, Perkin Elmer, MA,
USA). Toxic effects were expressed as median effective concentra-
tion (EC50, mg/L). Sample preparation was conducted as follows: AA
(1 mg) was initially dissolved in dimethyl sulfoxide (DMSO, 50 ␮L)
and the solution was diluted further in Milli-Q water (950 ␮L);
thus, the sample solution contained AA 1 mg/mL. Then 22% sodium
chloride solution (NaCl aq, 100 ␮L) was added to give a final 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 (1 mg) was dissolved in Milli-Q water (50 mL), UV irra-
diated for 24 h and concentrated 100 fold by solid-phase extraction.
The residue was used as the sample for the luminescent bacteria
test. Light emission was measured after 15 min of exposure using a
multilabel counter and compared with that of the control sample.
Toxicity was evaluated by calculating the decrease of light emission
of the sample compared to the control.
2.2. Synthetic procedures
The photoproduct, 1-(2-amino-5-hydroxyphenyl)ethanone
(C8H9NO2), was synthesized according to the reported method
to confirm its structure [8]. Yellow powder. 1H NMR (400 MHz,
CD3OD): ð 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 spectrum shows the
base peak [C8H9NO2 + H]+ at a mass/charge ration (m/z) 152.0721
(calculated m/z for C8H10NO2, 152.0711).
2.3. Photodegradation experiments
UV irradiation was carried out at 254 nm in a light cabinet
equipped with a 6 W UVGL-58 Handheld UV lamp (UVP, Upland,
California, USA) and appropriate filters. The irradiation intensity
was 200 ␮W/cm2 at 15 cm from the source, as measured with a digi-
tal radiometer having a 254 nm sensor (UV-37SD, CUSTOM, Tokyo,
Japan). A solution of AA (50 ␮g/50 mL) in Milli-Q water was irra-
diated in glass vessel with the UV lamp (water depth was 3 cm,
distance from the lamp about 15 cm). Irradiation times were 0,
6, 12, 24, 48, 72 and 96 h at 20 ◦C. Control samples were kept
under the same conditions, but covered with aluminum foil to block
the UV irradiation. Irradiated samples were concentrated by solid-
phase extraction using Oasis HLB 3cc cartridges (Waters Corp.,
Milford, USA) in a multi-sample concentration system (Varian Sam-
ple Preparation Vac Elute SPS 24, Lab Extreme, MI, USA). Samples
were eluted with methanol (2 mL), and concentrated under reduced
pressure. The residue was dissolved in methanol (500 ␮L). 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 (5 ␮m, 4.6 × 150 mm, GL Sciences
2.6. Statistical analysis
Results of the luminescent bacteria test (EC50) were expressed
as the mean standard deviation (S.D.). EC50 was calculated using
Probit analysis (Ecotox Statics ver. 2.3; The Japanese Society of Envi-
ronmental Toxicology).
3. Results
3.1. Photodegradation of acetaminophen
AA solution was irradiated with a 6 W UV lamp for 24 h, then
unirradiated AA and the photo-irradiated AA were subjected to

K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
31
Table 1
EC50 (mg/L) values of solutions of acetaminophen, acetaminophen irradiated with
UV for 24 h and compound 1 in the luminescent bacteria test. Values are given as
mean standard deviation.
Compounds
P. phosphoreum
Acetaminophen
N.D.
Photo-exposed acetaminophen
Compound 1
29.46 0.75
75.04 12.74
n = 3; values in mean S.D.; N.D., no detectable toxicity.
photoproduct at m/z of 152.0715 (Fig. 4), which corresponds to
C8H10NO2 (calculated m/z for C8H10NO2, 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 (C8H9NO2). 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 1 showed the same protonated ion at m/z
152.0721 and the same fragmentation pattern as the photoproduct
(Fig. 6).
Fig. 2. HPLC analysis of acetaminophen (a) and acetaminophen irradiated UV
(200 ␮W/cm2/s) for 24 h (b).
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 EC50 of AA could not be
calculated (Table 1). In contrast, UV-irradiated AA solution showed
marked toxicity (EC50: 29.46 mg/L). Synthetic 1 also showed toxic-
ity in this test (EC50: 75.04 mg/L, Table 1).
HPLC analysis to evaluate photodegradation of AA and generation
of the AA photoproduct (Fig. 2). Retention times were 26.6 min (AA)
and 25.4 min (photoproduct). After UV irradiation for 24 h, 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 24 h irradiation, while both
AA and the photoproduct had each decreased to less than 20% after
96 h irradiation (Fig. 3). The control was unchanged, confirming that
UV irradiation is required for photodegradation of AA.
4. Discussion
Our results indicate that AA is photodegraded upon exposure to
UV irradiation at 254 nm. Although both AA and the photoproduct
were degraded during UV irradiation for 96 h (Fig. 2), there was
no indication that a further photoproduct was generated from the
initially formed photoproduct.
3.2. Structure determination of the photoproduct
The photoproduct was shown to have the structure 1 from the
results of ESI-TOF/MS/MS. The putative photodegradation pathway
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 H2O2 via photo-generated hydroxyl and other
radicals [1]. However, compound 1 was not generated, or at least
was not identified, in those experiments.
Photo-Fries rearrangement is one of the photodegradation path-
ways of Propachlor, which is used as a herbicide in Greece and other
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 effluents 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 effluents in the range of ng/L to
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 spectrum showed the protonated ion of the
120
100
80
60
40
20
0
AA
Photoproduct
Control
0
12
24
36
48
60
72
84
96
Irradiation time (hr)
Fig. 3. Remaining amounts (%) of acetaminophen and its photoproduct after UV
irradiation for up to 96 h. Acetaminophen (ꢀ) and photoproduct (ꢁ) were monitored
by HPLC. Acetaminophen which was not exposed to UV served as the control (ꢂ).

32
K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
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 from activated 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.
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 by cytochrome P450 and covalent
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]. From these reports, it is tempting to speculate that compound
(a)
(b)
Fig. 5. Structure of the photoproduct (a) and proposed fragmentation pattern in
ESI-TOF/MS/MS (b).

K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
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.
There are several reports indicating that the toxicity of pharma-
ceuticals to aquatic organisms can be altered by UV irradiation. 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 influ-
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-
transformed into the dimer [5], which has 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
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 AA solution showed
toxicity in the luminescent bacteria test, but EC50 was lower than
of synthetic 1 (Table 1). Therefore, although compound 1 is the
only photoproduct of AA identified 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.

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K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
[7] M.J. Gomez, C. Sirtori, M. Mezuca, A.R. Fernandez-Alba, A. Aguera, Pho-
todegradation study of three dipyrone metabolites in various water systems:
identification and toxicity of their photodegradation products, Water Research
42 (2008) 2698–2706.
[8] W. Guo, W. Liu, L. Zhu, Y. Zhang, P. Cheng, G. Dong, C. Zhuang, J. Yao, C. Sheng,
Z. Miao, W. Zhang, Topoisomerase I-mediated antiproliferative activity of 10-
substituted and 12-substituted homocamptothecins, Chemistry & Biodiversity
8 (2011) 1539–1549.
[9] G. Ioele, F. Oliverio, I. Andreu, M. De Luca, M.A. Miranda, G. Ragno, Different
photodegradation behavior of barnidipine under natural and forced irradia-
tion, Journal of Photochemistry and Photobiology A: Chemistry 215 (2010)
205–213.
[10] M. Isidori, M. Lavorgna, A. Nardelli, L. Pascarella, A. Parrella, Toxic and geno-
toxic evaluation of six antibiotics on non-target organisms, Science of the Total
Environment 346 (2005) 87–98.
[11] M. Isidori, A. Nardelli, A. Parrella, L. Pascarella, L. Previtera, A multispecies study
to assess the toxic and genotoxic effect of pharmaceuticals: furosemide and its
photoproduct, Chemosphere 63 (2006) 785–793.
[12] L.P. James, P.R. Mayeux, J.A. Hinson, Acetaminophen-induced hepatoxicity,
Drug Metabolism and Disposition: The Biological Fate of Chemicals 31 (2003)
1499–1505.
[13] A. Jelic, M. Gros, A. Ginebreda, R. Cespedes-Sanchez, F. Ventura, M. Petrovic,
D. Barcelo, Occurrence, partition and removal of pharmaceuticals in sewage
water and sludge during wastewater treatment, Water Research 45 (2011)
1165–1176.
Fig. 7. Proposed pathway of photodegradation of acetaminophen to compound 1.
[14] O.A.H. Jones, N. Voulvoulis, J.N. Lester, Aquatic environmental assessment of
the top 25 English prescription pharmaceuticals, Water Research 36 (2002)
5013–5022.
[15] I. Kim, H. Tanaka, Photodegradation characteristics of PPCPs in water with UV
treatment, Environment International 35 (2009) 793–802.
[16] Y. Kim, K. Choi, J. Jung, S. Park, P.G. Kim, J. Park, Aquatic toxicity of
acetaminophen, carbamazepine, cimetidine, diltiazem and six major sulfona-
mides, and their potential ecological risks in Korea, Environment International
33 (2007) 370–375.
Fig. 8. Suggested toxic mechanism of compound 1.
[17] C. Klos, M. Koob, C. Kramer, W. Dekant, P-aminophenol nephrotoxicity: biosyn-
thesis of toxic glutathione conjugates, Toxicology and Applied Pharmacology
115 (1992) 98–106.
[18] I.K. Konstantinou, V.A. Sakkas, T.A. Albanis, Photocatalytic degaradation of
propachlor in aqueous TiO2 suspensions. Determination of the reaction path-
way and identification of intermediate products by various analytical methods,
Water Research 36 (2002) 2733–2742.
[19] M. Kuster, M.J.L. De Alda, M.D. Hernando, M. Petrovic, J. Martin-Alonso, D.
Barcelo, Analysis and occurrence of pharmaceuticals, estrogens, progestogens
and polar pesticides in sewage treatment plant effluents, river water and drink-
ing water in the Llobregat river basin (Barcelona, Spain), Journal of Hydrology
358 (2008) 112–123.
[20] A.Y.C. Lin, T.H. Yu, C.F. Lin, Pharmaceutical contamination in residential, indus-
trial, and agricultural waste streams: risk to aqueous environments in Taiwan,
Chemosphere 74 (2008) 131–141.
case of carbamazepine, fluoxetine 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 into account the potential influence of
photodegradation in evaluating the ecotoxicity of pharmaceuticals.
[21] A.Y.C. Lin, C.A. Lin, H.H. Tung, N.S. Chary, Potential for biodegradation and
sorption of acetaminophen, caffeine, propranolol and acebutolol in lab-
scale aqueous environments, Journal of Hazardous Materials 183 (2010)
242–250.
[22] Q.-T. Liu, T.D. Williams, R.I. Cumming, G. Holm, M.J. Hetheridge, R. Murray-
Smith, Comparative aquatic toxicity of propranolol and its photodegraded
mixtures: algae and rotifer screening, Environmental Toxicology and Chemistry
28 (2009) 2622–2631.
Acknowledgements
This study was supported by the Grants-in-Aid for Scientific
Research of Japanese Society for the Promotion of Science (JSPS
20590122).
[23] V. Matamoros, A. Duhec, J. Albaiges, J.M. Bayona, Photodegradation of car-
bamazepine, ibuprofen, ketoprofen and 17␣-ethinylestradiol in fresh and
seawater, Water, Air, and Soil Pollution 196 (2009) 161–168.
Appendix A. Supplementary data
[24] J.F. Newton, C.H. Kuo, M.W. Gemborys, G.H. Mudge, J.B. Hook, Nephrotoxi-
city of p-aminophenol, a metabolite of acetaminophen, in the Fischer 344 rat,
Toxicology and Applied Pharmacology 65 (1982) 336–344.
[25] J.F. Newton, C.H. Kuo, G.M. Deshone, D. Hoefle, J. Bernstein, J.B. Hook, The role
of p-aminophenol in acetaminophen-induced nephrotoxicity: effect of bis(p-
nitrophenyl) phosphate on acetaminophen and p-aminophenol nephrotoxicity
and metabolism in Fischer 344 rats, Toxicology and Applied Pharmacology 81
(1985) 416–430.
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.
References
[26] M. Petrovic, D. Barcelo, LC–MS for identifying photodegradation products of
pharmaceuticals in the environment, Trends in Analytical Chemistry 26 (2007).
[27] M. Rabiet, A. Togola, F. Brissaud, J.L. Seidel, H. Budzinski, F. Elbaz-Poulichet,
Consequences of treated water recycling as regards pharmaceuticals and drugs
in surface and ground waters of a medium-sized Mediterranean catchment,
Environmental Science and Technology 40 (2006) 5282–5288.
[28] P.H. Roberts, K.V. Thomas, The occurrence of selected pharmaceuticals in
wastewater effluent and surface waters of the lower Tyne catchment, Science
of the Total Environment 356 (2006) 143–153.
[29] R. Rosal, A. Rodriguez, J.A. Perdigon-Melon, A. Petre, E. Garcia-Calvo, M.J. Gomez,
A. Aguera, A.R. Fernandez-Alba, Occurrence of emerging pollutants in urban
wastewater and their removal through biological treatment followed by ozona-
tion, Water Research 44 (2010) 578–588.
[1] R. Andreozzi, V. Caprio, R. Marotta, D. Vogna, Paracetamol oxidation from aque-
ous solutions and H2O2/UV system, Water Research 37 (2003) 993–1004.
[2] R. Andreozzi, M. Raffaele, P. Nicklas, Pharmaceuticals in STP effluents and
their solar photodegradation in aquatic environment, Chemosphere 50 (2003)
1319–1330.
[3] M. Crane, C. Watts, T. Boucard, Chronic aquatic environmental risks from expo-
sure to human pharmaceuticals, Science of the Total Environment 367 (2006)
23–41.
[4] M. DellaGreca, A. Fiorentino, M. Isidori, M. Lavorgna, L. Previtera, M. Rubino,
F. Temussi, Toxicity of prednisolone, dexamathasone and their photochemical
derivatives on aquatic organisms, Chemosphere 54 (2004) 629–637.
[5] M. DellaGreca, M.R. Iesce, L. Previtera, M. Rubino, F. Temussi, A new photoprod-
uct of the drug furosemide in aqueous media, Environmental Chemistry Letters
2 (2004) 155–158.
[6] A. Ginebreda, I. Munoz, M.L. De Alda, R. Brix, J. Lopez-Doval, D. Barcelo, Envi-
ronmental risk assessment of pharmaceuticals in rivers: relationships between
hazard indexes and aquatic macroinvertebrate diversity indexes in the Llobre-
gat River (NE Spain), Environment International 36 (2010) 153–162.
[30] J.S. Teeter, R.D. Meyerhoff, Environmental fate and chemistry of raloxifene
hydrochloride, Environmental Toxicology and Chemistry 21 (2002) 729–736.
[31] A.G. Trovo, R.F.P. Nogueira, A. Aguera, C. Sirtori, A.R. Fernandez-Alba, Pho-
todegradation of sulfamethoxazole in various aqueous media:persistence,
toxicity and photoproducts assessment, Chemosphere 77 (2009) 1292–1298.

K. Kawabata et al. / Journal of Photochemistry and Photobiology A: Chemistry 249 (2012) 29–35
35
[32] K. Uwai, M. Tani, Y. Ohtake, S. Abe, A. Maruko, T. Chiba, Y. Hamaya, Y. Ohkubo,
M. Takeshita, Photodegradation products of propranolol:the structures and
pharmacological studies, Life Sciences 78 (2005) 357–365.
[33] H. Yamamoto, Y. Nakamura, S. Moriguchi, Y. Nakamura, Y. Honda, I. Tamura,
Y. Hirata, A. Hayashi, J. Sekizawa, Persistence and partitioning of eight
selected pharmaceuticals in the aquatic environment:laboratory photoly-
sis, biodegradation, and sorption experiments, Water Research 43 (2009)
351–362.
[34] L. Yang, L.E. Yu, M.B. Ray, Degradation of paracetamol in aqueous solutions by
TiO2 photocatalysis, Water Research 42 (2008) 3480–3488.
[35] F. Yuan, C. Hu, X. Hu, D. Wei, Y. Chen, J. Qu, Photodegradation and toxicity
changes of antibiotics in UV and UV/H2O2 process, Journal of Hazardous Mate-
rials 185 (2011) 1256–1263.
[36] X. Zhang, F. Wu, X.W. Wu, P. Chen, N. Deng, Photodegradation of acetaminophen
in TiO2 suspended solution, Journal of Hazardous Materials 157 (2008)
300–307.