Chlorination of florfenicol (FF): reaction kinetics, influencing factors and by-products formation

Article abstract of DOI:10.1039/c6ra23342b

Florfenicol (FF) is a widely used antibiotic, which is commonly found in natural waters. In this study, we investigated the removal fate of FF in two different drinking water treatment plants (DWTPs), which suggest that FF was easily transformed by free available chlorine (FAC) and the potential reactions of FF with FAC was the focus of this study. The oxidation kinetics of FF by FAC (7 × 10^?4 mol) are very rapid with large pseudo-first-order rate constants k_obs = 0.31 min^?1, while FF (5 mg L^?1) can be completely transformed in 30 min. The results showed that high Cl^? (the dominant seawater constituent), Br^?, and lower humic acid (HA, main constituents in freshwater) favor the FF oxidation. 21 degradation products were identified by liquid chromatography-tandems mass spectrometry (LC-MS/MS) and the possible routes for FF chlorination were proposed. These results are of importance toward the goal of assessing the persistence of FF in water chlorination.

Full text of DOI:10.1039/c6ra23342b

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Chlorination of florfenicol (FF): reaction kinetics,
influencing factors and by-products formation†
Cite this: RSC Adv., 2016, 6, 107256
a
ab
Naiyun Gao,‡a Wenhai Chu,‡a Juxiang Chen,‡a
*
Yansen Zhang,‡ Yisheng Shao,‡
Shuo Li,‡a Yue Wang‡a and Shuaixian Xu‡a
Florfenicol (FF) is a widely used antibiotic, which is commonly found in natural waters. In this study, we investigated
the removal fate of FF in two different drinking water treatment plants (DWTPs), which suggest that FF was easily
transformed by free available chlorine (FAC) and the potential reactions of FF with FAC was the focus of this study.
The oxidation kinetics of FF by FAC (7 ꢀ 10ꢁ4 mol) are very rapid with large pseudo-first-order rate constants kobs
¼ 0.31 minꢁ1, while FF (5 mg Lꢁ1) can be completely transformed in 30 min. The results showed that high Clꢁ (the
dominant seawater constituent), Brꢁ, and lower humic acid (HA, main constituents in freshwater) favor the FF
oxidation. 21 degradation products were identified by liquid chromatography-tandems mass spectrometry (LC-
MS/MS) and the possible routes for FF chlorination were proposed. These results are of importance toward the
goal of assessing the persistence of FF in water chlorination.
Received 20th September 2016
Accepted 1st November 2016
DOI: 10.1039/c6ra23342b
www.rsc.org/advances
include direct side effects, such as the effects on growth and
hematopoietic function of children, and promote the develop-
1. Introduction
ment of antimicrobial-resistant bacteria related to the human
microbiome. In addition, the application of orfenicol may
cause adverse effects on the cardiovascular system.14 Therefore,
it is of great importance to investigate the fate and effect of FF
by pertinent environmental transformation processes.
Antibiotics as emerging environmental contaminants have
been linked to the promotion of bacterial resistance and may
cause immune and metabolism diseases, which have received
increasing attention.1,2 Florfenicol (FF) is a broad-spectrum
antibiotic permitted for use as veterinary drugs in animals
used for food production, which belongs to a group of agents
used in veterinary medicine named amphenicols.3,4 Since
chloramphenicol application in foods and animals was pro-
hibited by the European Union in 1994, FF has been suggested
as a potential substitute.5–7 It is used to treat respiratory
diseases of pigs and cattle, and has been approved for use in
China, Japan, Europe, Norway, Canada, and South Korea for the
treatment of various diseases.8–11 In recent years, since it has
been administered to farm animals and released into the
environment, either in leaching from uneaten medicated pel-
leted feed, or through urinary, branchial and faecal excretions,
research has veried a growing amount of FF in the aquatic
environment. FF can persist in the environment for a long
period, and is commonly found in rivers, ponds, treatment
effluents and even in tap waters and bottled waters. According
to Wang et al., FF was found in tap water with the median
In this study, we investigated the fate of FF in two different
drinking water treatment plants (DWTPs), which suggested the
free available chlorine (FAC) plays an important role. Prior
studies indicated that various antibiotics were highly suscep-
tible toward chlorine oxidation and were readily transformed,
however, the persistence, inuence factors, and transformation
for FF chlorination was less well known.15 The purpose of this
study was to determine the reaction kinetics of FF with different
dosages of free chlorine rst. Then, the inuencing factors on
the removal of FF were explored at initial concentrations of FF,
Clꢁ, Brꢁ and the concentration of humic acid. Since aqueous
chlorine is not a strong enough oxidant to mineralize antibi-
otics, numerous transformation products may be formed due to
oxidation or substitution reactions. The transformation prod-
ucts and the possible pathways of FF by chlorination were
identied and inferred. In addition, efforts have been made to
determine the identities of disinfection byproducts (DBPs)
species, containing C-DBPs and N-DBPs, which is essential for
understanding the transformation of FF during chlorination.
concentration of 8.9 ng Lꢁ1 12 In addition, up to 2.84 mg Lꢁ1 for
.
orfenicol was detected in pond water of Southern Jiangsu in
China.13 The possible health consequences of FF exposure also
aState Key Laboratory of Pollution Control Reuse, Tongji University, Shanghai 200092,
China. E-mail: shaoyisheng2014@126.com
bChina Academy of Urban Planning and Design, Beijing 100037, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra23342b
2. Materials and methods
2.1. Materials
White crystalline powder of orfenicol (C12H14Cl2FNO4S, CAS
‡ Present address: 1239 Siping Road, Shanghai, P. R. China.
no. 73231-34-2, MW 358.21) was supplied by of Sigma Company
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and used as received. A stock solution of free chlorine (HClO) performance liquid chromatography tandem mass spectrom-
was prepared from 5% liquid sodium hypochlorite (Sinopharm etry (HPLC-MSMS). First, a full scan mass spectrum was ob-
Chemical Reagent Co., Ltd., China) and standardized by the tained from a low possible m/z value to a large m/z, and then
DPD (N,N-diethyl-p-phenylenediamine, Sigma, >99%) colori- a selected ion monitor (SIM) scan with appropriate mass range
metric method.16 All reagents, which were purchased through was acquired. The injection volume is 10 mL. Chromatographic
commercial companies and used without further purication, column: MGIII C18 column (150 mm ꢀ 2.1 mm, 3 mm) had
were prepared in solutions using Milli-Q water (from a Millipore mobile phase ow rate: 0.25 mL minꢁ1, column temperature:
Milli-Q Ultrapure Gradient A10 purication system).
40 ꢂC, injection volume: 10 mL, mobile phase A pure water
(including 0.1% formic acid), mobile phase D acetonitrile, and
isocratic elution program of 0–20.0 min 90% mobile phase A
and 10% mobile phase D. Electrospray ionization (ESI) was
performed in the positive mode with sheath gas pressure and
aux gas pressure with the optimum values set at 20 and 5 psi
2.2. Experimental procedures
Chlorination experiments were conducted under pseudo rst-
order conditions where HOCl was in excess ($10 folds of CAP
mole) with a reaction time of 30 min. In a typical experiment,
a 200 mL volume of FF solution (5 mg Lꢁ1) was prepared in
a batch reactor. FAC solution was subsequently added to initiate
reactions at oxidant: substrate molar ratios ranging from 50 : 1
to 5 : 1. The chlorination was quenched at xed time intervals
with Na2S2O3, which molar is 120% of chlorine. A matrix of
experiments was conducted with aqueous solutions of FF to
examine the inuence on the removal efficiency. Matrix vari-
ꢂ
respectively. The capillary temperature was set at 320 C. The
ion spray voltage was set at 3500 V. DBPs were analyzed by
a Thermo TSQ Quantum XLS Triple Quadruple GC-MSMS
(Thermo Fisher, USA), with medium polarity column (TG-
5MS, 30 m ꢀ 0.25 mm ꢀ 0.50 mm), based on the method ever
used.17,18
ables included initial chlorine concentration (0.625–10 mg Lꢁ1
,
3. Results and discussion
3.1. Removal of FF at two different DWTPs
as Cl2), Clꢁ (15, 25 and 50 mmol Lꢁ1), Brꢁ/HOCl (0.1–1) and
humic acid (0–1 mg Lꢁ1). NaCl (100 mM) and KBr (100 mM)
were added to some reactors to examine the effects of Clꢁ and
Brꢁ respectively. All experiments were conducted in duplicates
or triplicates.
Chlorine is usually added at the beginning (e.g., prechlorina-
tion) or at the end (e.g., disinfection) of the water treatment
process, depending on the treatment objectives. This study
investigated the fate of FF in two different drinking water
treatment plants. One DWTP uses sediment, ltration, ozone–
BAC and disinfection as treatment process, while the other
DWTP uses prechlorination for add. The chlorine doses used in
prechlorination for raw water were 1–2 mg Lꢁ1. According to
Table 1, prechlorination was effective for the removal of FF,
which was completely degraded in this process with a range
concentration of 11.7, 30.6, 1.62 ng Lꢁ1 respectively. However,
the FF was limited degradation with sediment, ltration and
ozone–BAC with a removal rate of 2.94%, 21.21% and 34.62%
respectively. The results were in accordance with previous
studies showing chlorine was more effective for the elimination
of antibiotics.17,19,20
2.3. Chemical analysis
The samples (1000 mL) of water from different DWTPs were
extracted and preconcentrated to 5 mL using Supelclean ENVI-
18 SPE tubes. Prior to solid phase extraction, samples were
passed through 0.45 mm cellulose nitrate membrane lters
(Schleicher and Schuell, Germany). Analyses for the FF
substrates were performed by an LC-MS/MS system, equipped
with a chromatographic column MGIII C18 column (150 mm ꢀ
2.1 mm, 3 mm), thermostat (40 ꢂC) at a ow rate (0.4 mL minꢁ1).
The composition of the mobile phase A and D was 0.1% formic
acid and acetonitrile, while gradient elution programs were 0–
2.0 min 90%–50% mobile phase A, 2.0–2.5 min 50–0% mobile
phase A, 2.5–4.5 min 0% mobile phase A, 4.5–5 min 0–90%
mobile phase A. MS analyses were conducted using negative
3.2. Removal of FF by free chlorine oxidation
mode electro spray ionization (ESIꢁ), monitoring the transitions Kinetic analysis of FF with FAC is modeled using the assump-
357 / 153.3 m/z for FF. The mass collision energy voltage was tion of second-order kinetics, that is, rst order with respect to
typically set to 20 eV. The capillary temperature was set at each reactant, and the reaction can be described by the
350 ꢂC. The products of FF were measured using high- following equation:
Table 1 Removal rate of FF during drinking water treatment
Process
FF (ng Lꢁ1
)
Removal rate
Process
FF (ng Lꢁ1
)
Removal rate
100%
Raw water
Sediment
Filtration
Ozone–BAC
Finished water
6.12
5.94
4.68
3.06
1.08
Raw water
Prechlorination
Sediment
Filtration
Ozone–BAC
Finished water
11.7, 30.6, 1.62
2.94%
ND
ND
ND
ND
ND
21.21%
34.62%
64.71%
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kobs and initial FF concentration was then analyzed with linear
tting of the kinetics results shown in Table 2. Poor linear
correlation coefficients r2 with 0.90 suggested that kobs had poor
dependence on the initial FF concentration, because of the
shortage of FAC in high FF concentration. A similar trend was
observed for other pharmaceuticals, including antipyrine.24
d½FFꢃ
dt
¼ ꢁkapp½FFꢃ ½Cl2ꢃ ¼ ꢁkobs½FFꢃ
(1)
t
t
t
where kapp represents the apparent second-order rate constants
for the overall reaction. [Cl2]t is in excess with respect to [FF]t,
the total concentration of chlorine remains almost constant
during the reaction and pseudo-rst-order kinetics takes place,
being kobs the corresponding pseudo rst-order rate constant.
First-order kinetics with respect to FF were veried by con-
ducting experiments under excess FAC conditions (5, 10, 20 and
50 folds) where FF loss on a log scale was well correlated with
time (r2 > 0.98) for all replicates. This may suggest that the
presence of reaction products in solution hasn't signicantly
affected the effective collisions between FF and FAC, which is
similar with other organic pollutions.21,22 The pseudo-rst-order
rate constants (kobs) observed for reactions of FF with free
chlorine were obtained from the slopes of regression lines tted
to plots of ln([FF]) vs. time in the presence of excess FAC, which
was clearly dependent on chlorine dose, as shown in Fig. 1. For
FAC concentrations of 7 ꢀ 10ꢁ5, 1.4 ꢀ 10ꢁ4, 2.8 ꢀ 10ꢁ4 and 7 ꢀ
10ꢁ4 mol, the kobs were 0.043, 0.062, 0.120 and 0.312 minꢁ1. FF
elimination was also fast, being almost completely removed
aer half an hour, when the FAC dose was 7.0 ꢀ 10ꢁ4 mol. The
half time (t1/2) of FF was calculated in this study, which can be
used to predict a given residual FAC concentration in the water
distribution system. While FAC concentrations increase from 7
ꢀ 10ꢁ5 mol to 70 ꢀ 10ꢁ5 mol, the t1/2 decreases from 15.75 to
2.28 min. It can be observed that the concentration increases of
the chlorine will accelerate the reaction, as it occurs with other
micropollutants.23
3.3. Inuence of chloride and bromide
The inuence of chloride (Clꢁ) and bromide (Brꢁ) have been
studied in this experiments performed with an initial chlorine
dose of 2.8 ꢀ 10ꢁ4 mol. As seen in Fig. 2, the chlorination is
sensitive to chloride, while kobs increased from 0.14 to 0.20
minꢁ1 when 15 mM chloride was added. In addition, the reac-
tion rate constants increased to 0.33 and 0.45 minꢁ1, which was
observed under 25 and 50 mM chloride respectively. This
behavior, which is similar to that reported with other anthro-
pogenic chemicals, suggests the presence of Clꢁ in solution
could obviously improve the degradation rates.25,26 The plau-
sible explanation can be derived from the observation that
under these conditions, Cl2 can be formed from HOCl and
Clꢁ.27 The reversible formation of Cl2 is shied to the le in the
presence of chloride, as seen in eqn (2). Since Cl2 is more
electrophilic than HOCl, its presence could accelerate FF
degradation.
Table 2 kobs values for initial concentrations of FF at temperature of 15
ꢄ 2 ꢂC, pH of 5.7, reaction time of 30 min, initial 0.37–10 mg Lꢁ1, and
chlorine dosage of 2.8 ꢀ 10ꢁ4
M
Investigation of FF removal by FAC was then carried out at
various initial FF concentrations of 0.37–10 mg Lꢁ1. As can be
seen from Table 1, increasing initial FF concentration resulted
in the decrease of the removal efficiency. The reaction rate kobs
were 0.24, 0.22, 0.14 and 0.08 minꢁ1 for the initial toxin
concentrations of 1.37, 2.5, 5.01 and 10 mg Lꢁ1. It is obvious
that higher concentrations need longer reaction time. As the
initial pharmaceuticals concentration increased (0.37–
10 mg Lꢁ1), the amount of time increased from 10 to 60 min for
FF removal with >90% elimination. The correlation between
[FF]0 (mg Lꢁ1
)
kobs (minꢁ1
)
r2
[FF]0 (mg Lꢁ1
)
kobs (minꢁ1
)
r2
0.37
0.46
0.66
1.37
2.50
0.34
0.38
0.27
0.24
0.22
0.97 3.64
0.99 4.48
0.96 5.01
0.99 7.50
0.99 10.00
0.21
0.18
0.14
0.11
0.08
0.98
0.99
0.99
0.97
0.95
Fig. 2 Effect of different chloride concentration on FF degradation by
Fig. 1 The evolution of kobs and t1/2 with chlorine dose (temperature chlorination (temperature 15 ꢄ 2 ꢂC, pH 5.7 and chlorination dose
15 ꢄ 2 ꢂC, pH 5.7 and chlorination dose 2.8 ꢀ 10ꢁ4 mol).
2.8 ꢀ 10ꢁ4 M).
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with chlorine.33,34 The concentrations of HA vary depending on
the vegetation near the water source, the concentration of algae
in water and the time of the year. In this study, the inuence of
the HA dose was investigated from 0 to 1 mg Lꢁ1, as seen in
Fig. 4. The pseudo-rst-order degradation rate of FF decreased
with an increasing concentration of HA, while the reaction rate
decrease since the oxidation rate of FF was decreased from 0.15
to 0.10 minꢁ1 with an HA increase from 0 to 1 mg Lꢁ1. In
addition, the increase of HA concentration in samples to 100 mg
Lꢁ1 led to the decrease of FF removal during chlorination from
99% to 97%. Similar results for antibiotics were also reported in
other chlorination processes.35
In general, unsaturated hybridized carbon is more suscep-
tible to chlorine attack.36 The reaction mechanisms between
chlorine and HA have been reported to react via oxidation (i.e.,
cleaving carbon–carbon double bonds) and/or substitution (i.e.,
replacement of functional groups by a chlorine molecule),
producing organic halides, ketone and aldehyde.37 As a result,
these micro-environmental changes would hinder the elimina-
tion of FF in the chlorination process. Higher chlorine doses
must be used in waters with high humic acid content in order to
reach the chlorine required to degrade FF completely.
k1
ꢁ
þ
ƒƒƒƒƒ!
ƒƒƒƒƒ
Cl þ H O
HOCl þ Cl þ H
kCl ¼ k1=k2
(2)
2
2
2
k2
It is well known that naturally occurring bromide in raw
waters is readily incorporated into the degradation during water
chlorination.28 To investigate the role of bromide during chlo-
rination of FF, the [Brꢁ]/[HOCl] ratio was investigated ranging
from 0 to 1. As seen in Fig. 3, FF oxidation was signicantly
enhanced in the presence of bromide. The observed pseudo-
rst-order rate (kobs) increased linearly (r2 ¼ 0.96) with an
increasing bromide concentration. Similar results were also
observed in other drugs chlorination in the presence of
bromide.29
This positive effect of bromine is due to the higher values of
bromination rate constants compared to chlorination, while
bromide is oxidized by chlorination, as seen in eqn (3).
HOCl + Brꢁ / HOBr + Clꢁ, k1 ¼ 1550 Mꢁ1 sꢁ1
(3)
HOBr (E0red ¼ +1.630 V) has a higher redox potential than
HOCl (E0red ¼ +1.331 V), and its reactions with some groups of
unsaturated compounds have rate constants several orders of
magnitude higher than those of HOCl.30,31 Moreover, the activ-
ities of electrophilic substitution are more favorable for the Br
atom due to its higher electron density and smaller bond
strength relative to the Cl atom.32 Under our experimental
conditions, the reaction rate increased with the Brꢁ/HOCl ratio
increase, which implies the oxidation power of HOBr was likely
to exceed that of HOCl. It should be mentioned that the
bromination reaction of antibiotics was faster and more effi-
cient than chlorination, and this difference may also affect the
environmental risk of antibiotics.
3.5. Products identication in FF chlorination
Although the degradation of the target compound seems to be
completed in the time frame of the reaction, a series of degra-
dation products are produced. There is growing concern about
the development of transformation mechanisms of organic
pollutants and their inactive byproducts.38,39 In this study,
various transformation products may be generated during the
chlorination. Hypochlorous acid is more likely to induce small
modications in the parent compound's structures than when
oxidized. Based on the information detected by LC-MS/MS,
3.4. Chlorination in presence of humic acid (HA)
Humic acid (HA) containing a signicant amount of the organic reaction pathways for FF with chlorine are proposed as shown
carbon is ubiquitous in surface waters, and it is an important in Fig. 5. In total we identied 21 byproducts for FF, and their
precursor of DBPs in drinking water resulting from the reaction chromatograms are provided in ESI Fig. S1–S21.† In addition,
Fig. 3 Effect of bromide concentration on FF degradation by chlori-
nation (temperature 15 ꢄ 2 ꢂC, pH 5.7 and chlorination dose 2.8 ꢀ 10ꢁ4 Fig. 4 Effect of HA concentration on FF degradation by chloriꢁn4ation
M).
(temperature 15 ꢄ 2 ꢂC, pH 5.7 and chlorination dose 2.8 ꢀ 10 M).
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Fig. 5 Proposed destruction pathways of FF during chlorination.
the main pathways of FF chlorination undergo the following molecule, resulting in the formation of products 16, 17, 18 and
processes: 19, with the m/z 279, 96, 106 and 188 respectively. This degra-
(1) Chlorine substitution. The chlorine electrophilic attack dation type was reported in the previous studies for the aqueous
on aromatic ring and the amino group of FF leading to the chlorination of cimetidine and triazines.46,47 Chlorination then
formation of mono-, di-, tri-, and tetra-FF (products 1–6) by converts intermediate 18 to intermediate 20, which may cleave
successive chlorination, corresponding to m/z 391.5, 426, 460.5 by a mechanism similar to that forming product 16. Product 20
and 495. The full scan chromatogram of m/z at 391.5 (product 1 with aldehydic groups is unsaturated, which can be oxidized to
and product 2) and 460.5 (product 4 and product 5) has two an acid group (product 21, m/z 122) during aqueous chlorination
different peaks (compounds), which is the isomer. A penta-FF without incorporating chlorine into the molecule. The formation
was not detected in this study, due to a penta-chloro interme- of product 20 should be taken into account as aldehydes in
diate being involved in the ring-opening step.40 In addition, the particular have been involved in some odor troubles.48
modication of the benzene ring was an important step, while
In addition, the formation mechanism of C-DBPs and N-
aromatic compounds were the primary contributors to trihalo- DBPs during chlorination for FF (5 mg Lꢁ1) has also been
methanes (THM) formation.41 The N-chlorinated is consistent measured at 24 h of contact time with oxidant to substrate
with results obtained by other researchers for the reaction of molar ratios 20 : 1. By GC/MSMS analysis, chloroform (TCM),
other antibiotics such as trimethoprim and sulfamethoxazole carbon tetrachloride (CTC), bromodichloromethane (BDCM),
with free chlorine.42,43 On the other hand, replacing the meth- tetrachloroethylene (PCE), bromochloroacetonitrile (BCAN),
ylsulfonyl group by Cl, led to product m/z 314.5 (product 7). The trichloroacetone (TCAce), N-nitrosodi-n-propylamine (NDPA)
replace of methylsulfonyl was also found in the photo- were detected with concentrations of 12.30, 0.01, 8.25, 0.01,
degradation experiments by the photo induced chlorination 0.01, 0.03 and 0.01 mg Lꢁ1. This nding was consistent with
reaction.44 Subsequently, chlorination convert product 7 to previous studies that among the most commonly formed DBPs
products 8, 9 and 10, which may be by the same mechanism of are the trihalomethanes (THMs), while chloroform (CHCl3) is
chlorine substitution on the aromatic ring. As ESI is a so oen predominant.49
ionization technique, there was no notable fragmentation of
ions in the mass spectrum to conrm the exact position of the
chlorine on the aromatic ring.45 Moreover, there is a degrada-
4. Conclusions
tion product corresponding to orfenicol amine resulting in In this study, FAC was suggested to play an important role in the
amide bond hydrolysis corresponding to m/z 248 (product 11), removal of FF in DWTPs. Several chlorination experiments were
which then transform to products 12, 13, 14 and 15 (m/z 282.5, conducted in order to evaluate the effects on FF degradation. FF
317, 351.5 and 387) through electrophilic attack of HOCl. The can be removed effectively by chlorination, which is dependent
hydrolysis product (product 11) of FF has also been observed in on the initial chlorine dose. The presence of Clꢁ and Brꢁ are
other previous studies.44
favorable for FF oxidation, while HA hinders elimination. In
(2) Fragmentation cleavage. A number of studies suggest addition, 21 different byproducts were found during chlorina-
that chlorine could have reacted with the higher organic objects, tion. This is an important issue which needs more exploration
breaking down the larger molecules to smaller molecules.18 The as some of these degradation products may be more toxic than
oxidation of FF leads to the cleavage of the original drug the parent compounds.
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12 H. Wang, N. Wang, B. Wang, Q. Zhao, H. Fang, C. Fu,
C. Tang, F. Jiang, Y. Zhou, Y. Chen and Q. Jiang,
Antibiotics in Drinking Water in Shanghai and Their
Contribution to Antibiotic Exposure of School Children,
Environ. Sci. Technol., 2016, 50, 2692–2699.
13 R. Wei, F. Ge, M. Chen and R. Wang, Occurrence of
ciprooxacin, enrooxacin, and orfenicol in animal
wastewater and water resources, J. Environ. Qual., 2012, 41,
1481–1486.
Acknowledgements
This work was nancially supported by the National Natural
Science Foundation of China (No. 51178321), the National
Major Project of Science & Technology Ministry of China (No.
2012ZX07403-001; 2012ZX07403-002; No. 2008ZX07421-002),
and the Specialized Research Fund for the Doctoral Program
of Higher Education (No. 20120072110050). We are also
thankful to the reviewers for their valuable advice to improve
this manuscript.
14 B. Bektemuroglu and M. Sireli, The effect of chloramphenicol
and orfenicol on electrocardiogram in guinea pigs, Ankara
Univ. Vet. Fak. Derg., 2011, 58, 155–160.
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