Synthesis and Toxicity of Halogenated Bisphenol Monosubstituted-Ethers: Establishing a Library for Potential Environmental Transformation Products of Emerging Contaminant

Article abstract of DOI:10.1002/cbdv.202000481

As an important branch of halogenated bisphenol compounds, the halogenated bisphenol monosubstituted-ether compounds have received a lot of attention in environmental health science because of their toxicity and variability. In this study, a synthetic method for bisphenol monosubstituted-ether byproduct libraries was developed. By using the versatile and efficient method, tetrachlorobisphenol A, tetrabromobisphenol A, and tetrabromobisphenol S monosubstituted alkyl-ether compounds were accessed in 39–82 % yield. Subsequently, the cytotoxicity of 27 compounds were screened using three different cell lines (HepG2, mouse primary astrocytes and Chang liver cells). Compound 2,6-dibromo-4-[3,5-dibromo-4-(2-hydroxyethoxy)benzene-1-sulfonyl]phenol was more toxic than other compounds in various cells, and the sensitivity of this compound to the normal hepatocytes and cancer cells was inconsistent. The compounds 2,6-dichloro-4-(2-{3,5-dichloro-4-[(prop-2-en-1-yl)oxy]phenyl}propan-2-yl)phenol and 2,6-dibromo-4-(2-{3,5-dibromo-4-[(prop-2-en-1-yl)oxy]phenyl}propan-2-yl)phenol were the most toxic to HepG2 cells, and most of the other compounds inhibited cell proliferation. Moreover, typical compounds were also reproductive and developmental toxic to zebrafish embryos at different concentrations. The synthetic byproduct libraries could be used as pure standard compounds and applied in research on environmental behavior and the transformation of halogenated flame retardants.

Full text of DOI:10.1002/cbdv.202000481

DOI: 10.1002/cbdv.202000481
FULL PAPER
Synthesis and Toxicity of Halogenated Bisphenol Monosubstituted-
Ethers: Establishing a Library for Potential Environmental
Transformation Products of Emerging Contaminant
Rui Guo,*a, b Mengxi Cao,*a Ming Hu,a Wenchao Deng,a Wenjuan Zhang,a Yangguang Gao,c
Shihan Ye,d Weixiang Zhou,d and Jianbo Shia, b
a
Hubei Key Laboratory of Environmental and Health Effects of Persistent Toxic Substances, Institute of
Environment and Health, Jianghan University, 8 Sanjiaohu Road, Economic and Technological Development
District, Wuhan 430056, P. R. China
,, e-mail: chyungrui@163.com; caomx@jhun.edu.cn
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Haidian District,
b
Beijing 100085, P. R. China
c
Institute for Interdisciplinary Research, Jianghan University, 8 Sanjiaohu Road, Economic and Technological
Development District, Wuhan 430056, P. R. China
College of Life Sciences, Jianghan University, 8 Sanjiaohu Road, Economic and Technological Development
d
District, Wuhan 430056, P. R. China
As an important branch of halogenated bisphenol compounds, the halogenated bisphenol monosubstituted-
ether compounds have received a lot of attention in environmental health science because of their toxicity and
variability. In this study, a synthetic method for bisphenol monosubstituted-ether byproduct libraries was
developed. By using the versatile and efficient method, tetrachlorobisphenol A, tetrabromobisphenol A, and
tetrabromobisphenol S monosubstituted alkyl-ether compounds were accessed in 39–82% yield. Subsequently,
the cytotoxicity of 27 compounds were screened using three different cell lines (HepG2, mouse primary
astrocytes and Chang liver cells). Compound 2,6-dibromo-4-[3,5-dibromo-4-(2-hydroxyethoxy)benzene-1-
sulfonyl]phenol was more toxic than other compounds in various cells, and the sensitivity of this compound to
the normal hepatocytes and cancer cells was inconsistent. The compounds 2,6-dichloro-4-(2-{3,5-dichloro-4-
[(prop-2-en-1-yl)oxy]phenyl}propan-2-yl)phenol
and
2,6-dibromo-4-(2-{3,5-dibromo-4-[(prop-2-en-1-yl)oxy]-
phenyl}propan-2-yl)phenol were the most toxic to HepG2 cells, and most of the other compounds inhibited cell
proliferation. Moreover, typical compounds were also reproductive and developmental toxic to zebrafish
embryos at different concentrations. The synthetic byproduct libraries could be used as pure standard
compounds and applied in research on environmental behavior and the transformation of halogenated flame
retardants.
Keywords: halogenated bisphenol, versatile synthetic method, standard compounds, new derivatives,
toxicology studies.
nol S (TBBPS) are three main types of bisphenol
compounds that have been utilized widely as halo-
Introduction
Tetrachlorobisphenol A (TCBPA), tetrabromobisphenol genated flame retardants (HFRs). These compounds
A (TBBPA), and TBBPA’s alternative-tetrabromobisphe- can be applied in various items, including building
materials, synthetic textiles, electronic products, plastic
products, and printed circuit boards. For instance,
TBBPA bis(allyl) ether (TBBPA-BAE) and TBBPA bis(2,3-
dibromopropyl) ether (TBBPA-BDBPE) are used as
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/cbdv.202000481
Chem. Biodiversity 2020, 17, e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
additive flame retardants in polymers.[1,2] They can be byproducts are generated.[41,42] Therefore, hydroxy-
released into the environment during the production, group compounds could be used as starting materials
usage, and disposal of HFRs-containing products. Thus, to produce polymers and to react halogenated flame
HFRs have become ubiquitous environmental contam- retardants according to the mechanism used to
inants and are detected frequently in various matrices, extinguish a fire.[43,44] The amount of these compounds
such as air, sewage sludge, sediment, soil, mankind in use as byproducts cannot be ignored.
and animal tissues.[3–15] The levels of TCBPA, TBBPA/S,
The degradation of TBBPA derivatives from bis-
and their derivatives and transformations are increas- hydroxy substitution compounds to monohydroxy
ing year by year in the environment, which leads to substitution compounds have been predicted by the
potential
environmental
and
human-health University of Minnesota Pathway Prediction System
risks.[1,16–23] For instance, they have been detected in (UM-PPS).[18] And the transformed compounds are of
umbilical-cord serum and in breast milk with concen- particular concern, because they may be more toxic to
trations up to 649.45 ng/g and 11 ng/g, the environment and organisms.[44–46] For instance,
respectively.[24,25] Evidence suggests that HFRs exhibit the debromination of tetrabromobisphenol A could
potential neurotoxicity, endocrine disruption effects yield partial TBBPA derivatives under specific
on bio-organisms, and reproductive-development conditions.[47–51] TriBBPA mono(allyl ether) (TriBBPA-
toxicity.[20,26–33]
MAE) and dibromobisphenol mono(allyl ether)(DBBPA-
As an important branch of HFRs, the halogenated MAE) as less-brominated bisphenol derivatives have
bisphenol monosubstituted-ether compounds have been identified through environmental debromination
received a lot of attention in environmental and health transformation.[52] It is imperative to identify the
effects because of their toxicity and ubiquity byproducts and environmental transformation deriva-
(Table 1).[34–40] Meanwhile, these compounds result tives, to clarify the fate of halogenated bisphenol
from HFR production, and various derivatives are monosubstituted-ether compounds, and to reduce the
generated by environmental transformation through risk of environmental hazards.
oxidation or biological processes. An incomplete
In our previous studies, a portion of the products
reaction is the main mechanism by which diverse such as TBBPA allyl ether had been identified consis-
Table 1. Study on the methylation and toxicity of some bisphenol-substituted ether compounds.
Entry
Compounds
Research contents
Reference
[34]
1
Microbial O-methylation
2
3
Microbial O-methylation
[34]
Study on toxic metabolism
[35,36]
4
5
Plasma toxicology study
Toxic effects
[37–39]
[40]
www.cb.wiley.com
(2 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
tently with environmental samples.[18] Because TBBPA/S behavior, toxicity, and transformation of bisphenol
analogs are produced with TBBPA/S as a raw material, monosubstituted-ether compounds. To date, no exam-
while the reaction of commercial BFR products with the ples exist to synthesize the less-brominated bisphenol
corresponding reagents is not complete, they will directly, or to substitute with the hydroxy group as
contain hypothetical monomodified compounds as im- monosubstituted standard compounds. The orienta-
purities. TBBPA mono(allyl ether) (TBBPA-MAE) has been tion synthesis of their monohydroxy substitution
identified as a byproduct of commercial TBBPA disub- compounds is urgently needed to study the occur-
stituted products.[53] TBBPS mono(allyl ether) was also rence, environmental health effect and transformation
identified with the same appearance.[54–56] TBBPA mono of TCBPA, TBBPA/S, and their derivatives in the
(3-hydroxypropyl ether), TBBPA mono(2,3-dihydroxy- environment. At the same time, systematic analysis of
propyl ether),[52] and TBBPA mono(2-hydroxyethyl ether) the cytotoxicity of such monosubstituted derivatives
have been identified as transformation products or provides a reliable environmental impact and health
byproducts of their derivatives.[41]
risk assessment data for further research and evalua-
TBBPA acting as thyroid hormones can disrupt cell tion of the promotion and use of flame retardants,
function and ultimately affect health, researchers have which has great environmental significance.
shown. To date, understanding the potential health
We have developed a simple and efficient method
effects of TBBPA has been limited to the results of to synthesize the monohydroxy substitution byprod-
in vitro testing. In vitro assays have been used to ucts, including TBBPA-MHPE and TBBPA-MDHPE.
identify human cells with different reactive oxygen Mono-, di-, and tribromobisphenol standard com-
species (ROS), such as normal cells, lung cancer cells, pounds were also synthesized using bisphenol A
and cellular immune cells. Until now, detailed toxicity (Scheme 1). Using TCBPA, TBBPA/S, and their deriva-
studies have been conducted on TBBPA or other tives as reaction starting materials, the corresponding
halogenated flame retardants,[57,58] it has been studied products were obtained with very high yields as
that TBBPA can cause acute toxicity, endocrine dis- standard compounds to study the environmental
rupting activity, animal immunotoxicity, neurotoxicity, behavior and transformation of these chemicals. Based
nephrotoxicity and hepatotoxicity. However, mono- on the novel monosubstituted derivatives, we assayed
substituted derivatives are indeed generated by the for cytotoxicity of these compounds in three different
side reactions of the flame retardant production lines of cells (HepG2, mouse primary astrocytes and
process and through further derivatization during Chang liver cells), and zebrafish embryo toxicity for
environmental transformation, and the toxicity of typical compounds at different concentrations, provid-
these compounds have not been systematically ing basic data for environmental risk assessment of
studied until now. Due to the lack of convenient these compounds.
synthetic methods to provide the standard com-
pounds, little is known about the environmental
Scheme 1. Synthesis of halogenated bisphenol monosubstituted-ethers library.
www.cb.wiley.com
(3 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
Synthesis of 1,2-Diol Compounds
Results and Discussion
Synthesis
In the synthesis of TBBPA-MDHPE and TBBPS-MDHPE,
deleterious and strongly oxidizing reagents, such as 4-
methylmorpholine N-oxide (NMO) and osmium tetr-
Synthesis of Brominated Bisphenol Compounds
The common method for obtaining different bromi- oxide (OsO4), were used in previous study.[52] To
nated phenolic compounds is mainly to remove overcome these shortcomings and optimize the reac-
bromine under specific conditions using TBBPA, but tion conditions, we require an efficient method to
did not obtain this product using organic-reagent synthesize diol-compounds from olefin. Catalyst use
methodology.[59] So we attempted to develop a simple has been achieved and has enhanced the conversion
method to obtain bisphenol compounds with different reaction; some substrates completed their reaction in
bromine numbers. As illustrated in Table 2, our initial 5 min with an 85% yield.[60] We used a versatile
studies began with the attempted reaction of BPA method to obtain bisphenol-monoalkyl-diol com-
with N-bromosuccinimide (NBS) using trifluorometha- pounds from bisphenol mono(allyl ether). Initial
nesulfonic acid as an additive reagent in component studies began with the attempted reaction of BPA-02
solvents at room temperature (r.t.) for 12 h, and the with 3-bromoprop-1-ene using sodium hydroxide as
expected product was obtained. According to this an alkali in acetone at r.t. for 3 h, and the title product
method, mono-, di-, and trichlorobisphenol standard BPA mono(allyl ether) (1a) was obtained in a 78%
compounds can be obtained as derivatives using yield (Scheme 2, entry 1). The title product 3-{2-bromo-
bisphenol A and N-chlorosuccinimide (NCS). The 4-[2-(3-bromo-4-hydroxyphenyl)propan-2-yl]phenoxy}-
reaction activity of this method was examined with propane-1,2-diol (2a) was obtained by using 1a as the
different equivalents in the system that contained starting material in moderate to good yields (Scheme 2,
NBS, and obtained the target compounds up to in entry 1). Using optimized conditions, we investigated
85% yield (see the Supporting Information for more the substrate scope for TCBPA, TBBPA/S, and other
details). Another method which using N,N-dimeth- derivatives shown in Scheme 2 (entries 3–5). All
ylformamide (DMF) as the solvent was also developed starting materials reacted smoothly and afforded
to complete the conversions without trifluorometha- corresponding products in moderate to high yields. It
nesulfonic acid.
is worth mentioning that two product types exist
when using BPA-03, because of the unsymmetrical
structure of this compound (Scheme 2, entry 2).
Table 2. Optimizing bromination reaction conditions.
Entry
Equivalent of NBS
Product
Yield[a]
Yield[b]
1
2
3
1.0
2.5
3.0
BPA-01
BPA-02
BPA-03
78%
85%
60%
75%
76%
65%
[a]
[b]
BPA (1.0 equiv.), NBS (0.8–4.0 equiv.), CF3SO3H (3.3 equiv.). BPA (1.0 equiv.), NBS (0.8–4.0 equiv.).
www.cb.wiley.com
(4 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
Scheme 2. Synthesis of bisphenol-monoalkene, bisphenol-monoalkyl-diol and bisphenol-monoalkyl alcohol compounds.
www.cb.wiley.com
(5 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
Synthesis of Mono-Ol Compounds
could find practical application in polymer research
and in the development of the synthesis of other
As an extension of the above bisphenol-monoalkyl bisphenol compounds.
dialcohol, a different chain length bisphenol-mono-
alkyl alcohol reaction was implemented as displayed
in Scheme 2. A simpler and shorter reaction condition
with atom economy was implemented instead of the
Toxic Effects of Halogenated Bisphenol Monosubstituted-
Ethers Compounds
former experimental program that used 9-borabicyclo The results showed that different compounds had
[3.3.1]nonane (9-BBN), anhydrous furanidine, NaOH different cytotoxicity in Figure 1. Generally, most
and H2O2 as the reagents. Mono-ethanol and propanol compounds had low cytotoxicity in HepG2, mouse
ether compounds were obtained from TCBPA, TBBPA/ primary astrocytes and Chang liver cells after 24 h
S, and the derivatives with isolated yields from 39% to exposure compared with that of TBBPA. From the
81% (Scheme 2, entries 3–5). Corresponding products data, IC50 values of Compound 3e were 332.7 μM
were obtained for compound BPA-03 in 84% yield in a (HepG2 cells), 455.8 μM (mouse primary astrocytes)
reaction (for example, the yield of compounds 3b–1 and 1593 μM (Chang liver cells), respectively. Com-
and 3b–2 in a reaction system) (Scheme 2, entry 2). pound 3e was insensitive to two hepatocyte models
The highly efficient synthesis of the bisphenol-mono- (HepG2 and Chang liver cells). Compounds 1c and 1d
alkyl-diol compounds was achieved by using a catalyst were highly toxic in HepG2 cells with IC50 values of
without deleterious and strongly oxidizing reagents, 991 μM and 588.8 μM, respectively, and the 24-h IC50
and more atom economy was implemented instead of of compound 1d to mouse primary astrocytes was
the complicated experimental procedures that were 1478 μM. Most of the other compounds induced cell
used to yield bisphenol-monoalkyl-alcohol compounds proliferation and the fitting curve was like the trend of
(Scheme 1). With its operational simplicity, this method compound 3c (Figure 1,c). The 24-h IC50 of BPA to ZFL
Figure 1. Concentration-response relationship for the inhibitory/stimulating effect of individual bisphenol monosubstituted ether
*
compounds on HepG2 (a), mouse primary astrocytes (b) and Chang Liver (c) cell lines after 24 h of exposure. ‘ ’ refers to the
experimental data, the solid line (–) is the fitted concentration response curve (standard deviation, n=6).
www.cb.wiley.com
(6 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
cell lines was 367.1 μM.[61] A549 cell lines showed (Figure 2,a). Compound 2c was highly toxic to zebra-
decreased cell viability when treated by TBBPA with a fish embryos at 2×10À 4 mol/L and 1×10À 4 mol/L
concentration of 29.42 μM for 48 h.[62] The in vitro concentrations (Figure 2,b). The embryotoxicity to
toxicity of TBBPA has been shown to differ between zebrafish were mainly manifested in the presence of
cell lines with IC50 ranging from 50 to 200 μM.[63] Our pericardial edema, spinal curvature, tail deformity and
results, in combination with these studies, indicated delayed hatch in zebrafish (Figure 2,c–f), and more
low acute cell toxicity of bisphenol monosubstituted- details were also shown in the Supporting Information.
ether byproducts compared with TBBPA, in particular, All studies were conducted in accordance with the
they could be used as a supplement and enhancement guidelines for the care and use of experimental
of the cytotoxicity studies for TCBPA and TBBPS animals at Jianghan University.
monosubstituted derivatives. Further studies of the
By comparison with the reported synthetic meth-
long term toxicity with low concentration exposure of ods, the newly synthesized mono-substituted deriva-
these compounds are needed.
tives are used as standard compounds for bisphenol
compound byproducts or environmental transforma-
tion compounds, providing new insight into environ-
mental-contaminants identification. The synthetic
method could also provide and establish reliable
Study of Zebrafish Embryo Toxicity for Typical Bisphenol
Monosubstituted Ether Compounds
The results showed that compounds 1c and 2c had technical guarantee for the determination and quanti-
zebrafish embryo toxicity in Figure 2. Generally, the fication of TCBPA and TBBPA/S derivatives. Further-
two compounds had reproductive and developmental more, research on the cytotoxicity and zebrafish
toxic to zebrafish embryos at different concentrations. embryo toxicity of a series of compounds provides a
The toxicity of compound 1c to zebrafish embryos was scientific basis to evaluate comprehensively the envi-
the greatest at 1×10À 4 mol/L, 2×10À 5 mol/L concen- ronmental and health risks of related HFRs.
tration, but lower at 2×10À 4 mol/L concentration
Figure 2. Zebrafish embryotoxicity study of typical bisphenol monosubstituted ether compounds. The death rate of compound 1c
(a) and compound 2c (b) exposure. ‘1’, ‘2’, ‘3’, ‘4’ and ‘5’ refers to 10, 125, 250, 500, and 1000 μM, respectively. The malformation of
embryos included (c) pericardial edema, (d) spinal curvature, (e) tail deformity and (f) delayed hatch.
www.cb.wiley.com
(7 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
Conclusions
400 (400 MHz and 101 MHz). All NMR chemical shifts
were reported with the solvent resonance as internal
In this study, we developed the simple methods to standard. All cell culture and toxicity test procedures
obtain brominated bisphenol compounds, then, syn- in the experiments were performed according to
thesized TBBPA, TCBPA and TBBPA/S derivatives sub- standardized protocols according to the literature.
stituted with different functional groups to build the Laboratory animal handling and animal welfare meet
halogenated bisphenol monosubstituted-ethers com- the requirements of the Jianghan University Ethics
pound libraries, finally evaluated the cytotoxicity of Committee, and the experimental animal use license
these derivative compounds and the zebrafish embryo number is SYXK2012-0042.
toxicity of typical compounds. And we anticipate that
a simple method to obtain TCBPA, TBBPA/S derivatives
General Procedure for Preparation of Bisphenol
will find wide application in organic synthesis, environ-
Mono(Allyl Ether)
mental and toxicology studies. The novel study route
suggested the generation of new derivatives and To a solution of bisphenol compound (1.00 equiv.) and
probable research on the exposure, absorption and allyl bromide (1.10 equiv.) in acetone, a sodium
transformation pathways, and degradation products of hydroxide aqueous solution (1.80 equiv.) was added
commercial TCBPA and TBBPA/S derivatives. The dropwise at room temperature. The reaction mixture
cytotoxicity study showed that the cytotoxicity of the was stirred for 3 h. Then, the mixture was diluted with
compounds with different structures was quite differ- dichloromethane, washed with water, filtered and
ent, and the sensitivity of normal hepatocytes and dried over MgSO4. The residue was purified by column
cancer cells were inconsistent after exposure to the chromatography on silica gel after removing the
same compound. Compounds 1c and 2c had a certain solvent, eluting with hexanes/AcOEt (v/v) to afford the
degree of toxicity to zebrafish embryos at different title product 1. 2-Bromo-4-(2-{3-bromo-4-[(prop-2-en-
concentrations and had a variety of teratogenic effects 1-yl)oxy]phenyl}propan-2-yl)phenol (1a) as the repre-
on their embryonic development. Cytotoxicity and sentative. 1a was prepared following Method A from
zebrafish embryos toxicity assays enhanced the under- 4,4’-(propane-2,2-diyl)bis(2-bromophenol) (3.84 g,
standing of the potential risks of these derivatives 10.0 mmol) as a pale white oil (3.30 g, 78%).[52] Rf =
exposure to ecological and human health. Subsequent 0.40 (hexanes/AcOEt 5:1 (v/v)). 1H-NMR (400 MHz,
research on environmental transformation, degrada- CD3OD): 7.34 (d, J=4.8, 1H), 7.28 (d, J=4.8, 1H), 7.04
tion or toxicity will continue to be implemented in our (d, J=6.4, 1H), 6.96 (d, J=6.4, 1H), 6.80 (s, 1H), 6.78 (s,
laboratory. The study also contributed to understand 1H), 5.97–6.03 (m, J=4.9, 1H), 5.45–5.42 (dd, J=6.4,
the fate, risk assessment, and the resulting health 1.8, 1H), 5.19–5.23 (dd, J=12.4, 4.8, 1H), 4.52–4.50 (d,
impacts of the transformation products of their J=6.4, 2H), 1.53 (s, 6H). 13C-NMR (101 MHz, CD3OD):
derivatives in a detailed investigation in the environ- 153.9, 152.8, 145.4, 143.9, 133.9, 132.2, 131.8, 127.8,
ment.
127.6, 117.3, 116.6, 114.1, 112.3, 110.2, 70.3, 42.2, 31.1.
HR-ESI-MS (m/z): calc. for C18H17Br2O2 [M–H]À ,
424.95748; found 424.95810.
Experimental Section
General
General Procedure for Preparation of Bisphenol Mono-
alkyl-Diol Compounds
Unless otherwise noted, all the starting materials and
solvents were purchased from commercial suppliers To a solution of 1.5 mL of H2O and 2 N H2SO4 (400 μL,
and directly used. MeOH was purchased from Alfa 0.4 mmol, 0.200 equiv.), NaIO4 (642 mg, 3 mmol,
Aesar. CDCl3, (D6)acetone, dimethyl sulfoxide (DMSO) 1.50 equiv.) was added. After all solids were dissolved,
°
and CD3OD were purchased from Sigma-Aldrich. the solution was cooled to 0 C. A 0.1 M solution of
Reactions were monitored by thin layer chromatog- RuCl3 (100 μL, 0.01 mmol, 0.005 equiv.) was added,
raphy (TLC). Silica gel (200–300 mesh) was purchased and the mixture was stirred until the color turned
from Qingdao Haiyang Chemical Co., China. Cell bright yellow, then, followed by adding AcOEt (6 mL)
Counting Kit-8 (CCK-8) were purchased from Biosharp and acetonitrile (6 mL). Continue stirring for another
(Beijing, China). Cell culture medium and fetal calf 5 min. The olefin (2 mmol, 1.00 equiv.) was added to
1
serum were obtained from Gibco (Glasgow, UK). H- the mixture, and the slurry was stirred until all starting
and 13C-NMR were recorded on a Bruker AVANCE AV material was exhausted. A saturated NaHCO3 solution
www.cb.wiley.com
(8 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
General Procedure for Preparation of Bisphenol
Mono(3-Hydroxypropyl Ether)
(15 mL) and a saturated Na2S2O3 solution (20 mL) were
added to quench the reaction. The aqueous layer was
extracted with AcOEt (3×30 mL). After the combined
organic layer was dried over MgSO4, the solvent was To a solution of bisphenol compound (1.00 equiv.) and
evaporated in vacuum. The crude product was purified 3-bromo-1-propanol (1.05 equiv.) in acetone, a sodium
by flash chromatography, furnishing the title product hydroxide aqueous solution (1.80 equiv.) was added
2.
3-{2-Bromo-4-[2-(3-bromo-4-hydroxyphenyl)- dropwise at r.t. The system was stirred for 2–5 h. The
propan-2-yl]phenoxy}propane-1,2-diol (2a) as the reaction mixture was diluted with dichloromethane
representative. 2a was prepared following Method B and washed with water. The organic layer was dried
from
2-bromo-4-(2-{3-bromo-4-[(prop-2-en-1-yl)oxy] over MgSO4. After removal of the solvent, the residue
phenyl}propan-2-yl)phenol (1a; 2.12 g, 5.0 mmol) as a was purified by column chromatography on silica gel,
pale yellow solid (1.87 g, 82%). Rf =0.40 (hexanes/ eluting with hexanes/AcOEt (v/v) to afford the title
1
AcOEt 3:1 (v/v)). H-NMR (400 MHz, CD3OD): 7.33 (d, product 4. 2-Bromo-4-{2-[3-bromo-4-(3-hydroxypro-
J=8.4, 1H), 7.26 (d, J=8.4, 1H), 7.10–7.06 (dd, J=6.4, poxy)phenyl]propan-2-yl}phenol (4a) as the repre-
1.8, 1H), 6.89–6.94 (dd, J=12.6, 6.4, 1H), 6.90 (d, J= sentative. 4a was prepared following Method D from
12.4, 1H), 6.80 (d, J=12.4, 1H), 4.06–4.02 (m, J=4.8, 4,4’-(propane-2,2-diyl)bis(2-bromophenol) (3.84 g,
1H), 4.04–3.98 (m, J=4.8, 2H), 3.79–3.76 (dd, J=6.4, 10.0 mmol) as a pale yellow solid (3.18 g, 72%). Rf =
1.8, 1H), 3.72–3.68 (dd, J=6.4, 1.8, 1H), 1.54 (s, 6H). 0.40 (hexanes/AcOEt 3:1 (v/v)). 1H-NMR (400 MHz,
13C-NMR (101 MHz, CD3OD): 154.2, 152.8, 145.6, 144.0, CD3OD): 7.35–7.34 (d, J=4.8, 1H), 7.28–7.27 (d, J=4.8,
132.2, 131.9, 128.0, 127.7, 116.6, 113.9, 112.3, 110.2, 1H), 7.14–7.12 (dd, J=12.4, 4.8, 1H), 7.01–7.68 (dd, J
71.3, 70.9, 63.9, 42.2, 31.0. HR-ESI-MS (m/z): calc. for =12.4, 4.8, 1H), 6.94–6.92 (d, J=8.4, 1H), 6.81–6.79 (d,
C18H19Br2O4 [M–H]À , 458.96296; found 458.96390. J=8.4, 1H), 4.14–4.11 (t, J=4.8, 2H), 3.81–3.78 (t, J=
Melting range: 122.8~132.0 C, melting point: 127.1 C. 4.8, 2H), 2.04–1.98 (m, J=4.8, 2H), 1.59 (s, 6H). 13C-
°
°
NMR (101 MHz, CD3OD): 154.7, 153.2, 145.6, 144.3,
132.5, 132.2, 128.04, 128.01, 116.8, 113.9, 112.5, 110.4,
General Procedure for Preparation of Bisphenol
66.9, 59.6, 42.5, 33.2, 31.2. HR-ESI-MS (m/z): calc. for
Mono(2-Hydroxyethyl Ether)
C18H19Br2O3 [MÀ H]À , 442.96805; found 442.96890.
°
°
To a solution of bisphenol compound (1.00 equiv.) and Melting range: 102.7~107.6 C, melting point: 103.6 C.
2-bromoethanol (1.05 equiv.) in acetone, a sodium
hydroxide aqueous solution (1.80 equiv.) was added
Cell Viability Assay
dropwise at r.t. The system was stirred for 2–5 h, then,
diluted with dichloromethane and washed with water. To evaluate toxicity of HFR compounds in vitro, the
The organic layer was dried over MgSO4. After removal cell viability assay was used to screen the toxicity of 27
of the solvent, the residue was purified by column compounds (including all synthetic compounds,
chromatography on silica gel, eluting with hexanes/ TBBPA, TCBPA and TBBPS) in HepG2 cells, mouse
AcOEt (v/v) to afford the title product 3. 2-Bromo-4- primary astrocytes and Chang liver cells. The chem-
{2-[3-bromo-4-(2-hydroxyethoxy)phenyl]propan-2-
icals’ solutions were made as stock solutions and
yl}phenol (3a) as the representative. 3a was prepared prepared freshly before exposure experiment. We
following Method C from 4,4’-(propane-2,2-diyl)bis(2- dissolved TBBPA, TCBPA and the other compounds in
bromophenol) (3.84 g, 10.0 mmol) as a pale yellow serum-free medium and the final concentration of
solid (2.61 g, 61%). Rf =0.40 (hexanes/AcOEt 3:1 (v/v)). DMSO was less than 0.1%. HepG2 cells, mouse primary
1H-NMR (400 MHz, CD3OD): 7.36–7.35 (d, J=4.8, 1H), astrocytes and Chang liver cells were seeded into 96-
7.27–7.26 (d, J=4.8, 1H), 7.15–7.12 (dd, J=12.4, 4.8, well plates at a cell density of 10,000 cells/well. After
1H), 7.01–6.98 (dd, J =12.4, 4.8, 1H), 6.96–6.94 (d, J= culturing overnight, the medium were changed to
12.4, 1H), 6.81–6.79 (d, J=12.4, 1H), 4.10–4.08 (t, J= 100 μL serum-free medium containing different con-
4.8, 2H), 3.91–3.89 (t, J=4.8, 2H), 1.59 (s, 6H). 13C-NMR centrations of bisphenol derivatives (diluted to 10,
(101 MHz, CD3OD): 154.8, 153.2, 145.9, 144.3, 132.6, 125, 250, 500, and 1000 μM, respectively). Reagent
132.2, 128.04, 128.02, 116.8, 114.5, 112.7, 110.4, 71.9, blank and control group (0.1% DMSO, V/V) of 6
61.6, 42.5, 31.2. HR-ESI-MS (m/z): calc. for C17H17Br2O3 parallel were conducted. After exposure for 24 h, the
[M–H]À , 428.95240; found 428.95303. Melting range: exposed solution was aspirated, and 100 μL of the
°
°
122.5~125.5 C, melting point: 123.8 C.
medium diluted CCK-8 reagent (10%) were added in
the dark, and the incubation was continued to 2 h in a
www.cb.wiley.com
(9 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
Author Contribution Statement
carbon dioxide incubator, and the absorbance at
450 nm was measured by a microplate reader (Spec-
traMax i3x, Molecular Device, USA). The mean and R. Guo, M. Hu, and W. Deng performed the organic
standard deviation of each set of data were calculated synthesis experiments. R. Guo, M. Cao, S. Ye, and W.
and further converted to a percentage relative to the Zhou performed the biological experiments, contrib-
control group. Cell viability=(ODDrug–ODBlank)/ uted samples and analysis tools. Y. Gao and W. Zhang
(ODControl–ODBlank)×100%. Cell inhibition=1–cell via- analyzed the data. R. Guo analyzed the data and wrote
bility. Regression analysis was performed using non- the article. R. Guo and J. Shi conceived and designed
linear least-squares fit, and the IC50 (half inhibitory the experiments.
concentration) value was obtained using GraphPad
Prism 5.0 software.
References
Zebrafish Embryo Cultivation and Drug Exposure
[1] A. Covaci, S. Harrad, M. A. E. Abdallah, N. Ali, R. J. Law, D.
Herzke, C. A. de Wit, ‘Novel brominated flame retardants: A
review of their analysis, environmental fate and behaviour’,
Environ. Int. 2011, 37, 532–556.
[2] A. Bergman, A. Ryden, R. J. Law, J. de Boer, A. Covaci, M.
Alaee, L. Birnbaum, M. Petreas, M. Rose, S. Sakai, N.
Van den Eede, I. van der Veen, ‘A novel abbreviation
standard for organobromine, organochlorine and organo-
phosphorus flame retardants and some characteristics of
the chemicals’, Environ. Int. 2012, 49, 57–82.
[3] Z. Wang, C. Xu, W. Wang, L. Duan, Z. Li, B. Zhao, B. Ji, ‘High-
color-purity and high-efficiency non-doped deep-blue
electroluminescent devices based on novel anthracene
derivatives’, New J. Chem. 2012, 36, 662–667.
[4] A. Schecter, M. Pavuk, O. Päpke, J. J. Ryan, L. Birnbaum, R.
Rosen, ‘Polybrominated diphenyl ethers (PBDEs) in US
mothers’ milk’, Environ. Health Perspect. 2003, 111, 1723–
1729.
[5] R. A. Hites, J. A. Foran, S. J. Schwager, B. A. Knuth, M. C.
Hamilton, D. O. Carpenter, ‘Global Assessment of Polybro-
minated Diphenyl Ethers in Farmed and Wild Salmon’,
Environ. Sci. Technol. 2004, 38, 4945–4949.
[6] R. A. Hites, ‘Electron Impact and Electron Capture Negative
Ionization Mass Spectra of Polybrominated Diphenyl Ethers
and Methoxylated Polybrominated Diphenyl Ethers’, Envi-
ron. Sci. Technol. 2008, 42, 2243–2252.
[7] L. Zhu, R. A. Hites, ‘Brominated Flame Retardants in Tree
Bark from North America’, Environ. Sci. Technol. 2006, 40,
3711–3716.
[8] A. Salamova, R. A. Hites, ‘Discontinued and Alternative
Brominated Flame Retardants in the Atmosphere and
Precipitation from the Great Lakes Basin’, Environ. Sci.
Technol. 2011, 45, 8698–8706.
To evaluate zebrafish embryotoxicity of compounds 1c
and 2c, zebrafish embryos were exposed to different
concentrations of each compound. Zebrafish of AB
strain obtained from the China Zebrafish Resource
Center (Wuhan, China) was used in the exposure
experiment. The embryos were collected and cultured
in a six-well plate with 30 eggs per well and 2 ml of
exposure solution. The exposure experiments con-
sisted of five concentration gradients (1×10À 3 mol/L,
2×10À 4 mol/L, 1×10À 4 mol/L, 2×10À 5 mol/L, 1×10À 5
mol/L, respectively) and one control group with three
replicates of each group. The drugs were dissolved in
DMSO and diluted to each concentration with fresh
fish culture water. The final concentration of DMSO of
exposure group and control group was 0.1%. The
embryo exposure was performed in a constant tem-
°
perature incubator at 28 C. The dead embryos and
exposed solution were removed and changed twice a
day. The mortality rate was recorded at 12 hpf (hour
post fertilization), 24 hpf, 36 hpf, 48 hpf, 60 hpf, 72 hpf.
The malformation was recorded at 72 hpf. The em-
bryos with malformation were imaged by a micro-
scope (SteREO Discovery.V20, Zeiss) and a color CCD
(506 color, Zeiss).
Acknowledgements
[9] A. Salamova, R. A. Hites, ‘Brominated and Chlorinated
Flame Retardants in Tree Bark from Around the Globe’,
Environ. Sci. Technol. 2013, 47, 349–354.
This work is supported by the National Natural Science
Foundation of China (No. 21707049), the First Middle-
aged and Young Talent Training Project of Jianghan
University and the State Key Laboratory of Environ-
mental Chemistry and Ecotoxicology, RCEES, CAS (No.
KF2016-08). We thank Dr. Guangliang Liu (Florida
International University) for helpful discussions.
[10] T. Hamers, J. H. Kamstra, E. Sonneveld, A. J. Murk, M. H. A.
Kester, P. L. Andersson, J. Legler, A. Brouwer, ‘In vitro
profiling of the endocrine-disrupting potency of bromi-
nated flame retardants’, Toxicol. Sci. 2006, 92, 157–173.
[11] S. Horikoshi, T. Miura, M. Kajitani, N. Horikoshi, N. Serpone,
‘Photodegradation of tetrahalobisphenol-A (X=Cl, Br)
flame retardants and delineation of factors affecting the
process’, Appl. Catal. B 2008, 84, 797–802.
[12] N. Yin, S. Liang, S. Liang, R. Yang, B. Hu, Z. Qin, A. Liu, F.
Faiola, ‘TBBPA and its alternatives disturb the early stages
www.cb.wiley.com
(10 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
of neural development by interfering with the NOTCH and
mo-4,4’-isopropylidenediphenol (TBBPA): implications for
risk assessment’, Arch. Toxicol. 2014, 88, 553–573.
[26] S. Liang, S. Liang, H. Zhou, N. Yin, F. Faiola, ‘Typical
halogenated flame retardants affect human neural stem
cell gene expression during proliferation and differentia-
tion via glycogen synthase kinase 3 beta and T3 signaling’,
Ecotoxicol. Environ. Saf. 2019, 183, 109498.
[27] S. Liang, S. Liang, F. Faiola, ‘Toxicogenomic analyses of the
effects of BDE-47/209, TBBPA/S and TCBPA on early neural
development with a human embryonic stem cell in vitro
differentiation system’, Toxicol. Appl. Pharmacol. 2019, 379,
114685.
[28] H. Lilienthal, C. M. Verwer, L. T. van der Ven, A. H. Piersma,
J. G. Vos, ‘Exposure to tetrabromobisphenol A (TBBPA) in
Wistar rats: neurobehavioral effects in offspring from a
one-generation reproduction study’, Toxicology 2008, 246,
45–54.
[29] Y. Yu, Z. Yu, H. Chen, Y. Han, M. Xiang, X. Chen, R. Ma, Z.
Wang, ‘Tetrabromobisphenol A: Disposition, kinetics and
toxicity in animals and humans’, Environ. Pollut. 2019, 253,
909–917.
[30] L. T. Van der Ven, T. Van de Kuil, A. Verhoef, C. M. Verwer,
H. Lilienthal, P. E. Leonards, U. M. Schauer, R. F. Canton, S.
Litens, F. H. De Jong, T. J. Visser, W. Dekant, N. Stern, H.
Hakansson, W. Slob, M. Van den Berg, J. G. Vos, A. H.
Piersma, ‘Endocrine effects of tetrabromobisphenol-A
(TBBPA) in Wistar rats as tested in a one-generation
reproduction study and a subacute toxicity study’, Toxicol-
ogy 2008, 245, 76–89.
[31] S. Wu, Z. Zhu, J. Chen, M. Wu, L. Qiu, ‘Transcriptomic
analyses of human bronchial epithelial cells BEAS-2B
exposed to brominated flame retardant (tetrabromobi-
sphenol A)’, Environ. Toxicol. 2019, 34, 742–752.
[32] J. M. McCormick, M. S. Paiva, M. M. Haeggblom, K. R.
Cooper, L. A. White, ‘Embryonic exposure to tetrabromobi-
sphenol A and its metabolites, bisphenol A and tetrabro-
mobisphenol A dimethyl ether disrupts normal zebrafish
(Danio rerio) development and matrix metalloproteinase
expression’, Aquat. Toxicol. 2010, 100, 255–262.
[33] G. A. Knudsen, L. M. Jacobs, R. K. Kuester, I. G. Sipes,
‘Absorption, distribution, metabolism and excretion of
intravenously and orally administered tetrabromobisphe-
nol A 2,3-dibromopropyl ether in male Fischer-344 rats’,
Toxicology 2007, 237, 158–167.
WNT pathways’, Environ. Sci. Technol. 2018, 52, 5459–5468.
[13] J. Verreault, W. A. Gebbink, L. T. Gauthier, G. W. Gabrielsen,
R. J. Letcher, ‘Brominated Flame Retardants in Glaucous
Gulls from the Norwegian Arctic: More Than Just an Issue
of Polybrominated Diphenyl Ethers’, Environ. Sci. Technol.
2007, 41, 4925–4931.
[14] R. J. Letcher, S. Chu, ‘High-Sensitivity Method for Determi-
nation of Tetrabromobisphenol-S and Tetrabromobisphe-
nol-A Derivative Flame Retardants in Great Lakes Herring
Gull Eggs by Liquid Chromatography–Atmospheric Pres-
sure Photoionization–Tandem Mass Spectrometry’, Envi-
ron. Sci. Technol. 2010, 44, 8615–8621.
[15] G. Su, R. J. Letcher, D. J. McGoldrick, S. M. Backus, ‘Halo-
genated Flame Retardants in Predator and Prey Fish From
the Laurentian Great Lakes: Age-Dependent Accumulation
and Trophic Transfer’, Environ. Sci. Technol. 2017, 51, 8432–
8441.
[16] H. Hakk, R. J. Letcher, ‘Metabolism in the toxicokinetics and
fate of brominated flame retardants–A review’, Environ.
Int. 2003, 29, 801–828.
[17] A. Covaci, S. Voorspoels, M. A. E. Abdallah, T. Geens, S.
Harrad, R. J. Law, ‘Analytical and environmental aspects of
the flame retardant tetrabromobisphenol-A and its deriva-
tives’, J. Chromatogr. A 2009, 1216, 346–363.
[18] G. Qu, A. Liu, L. Hu, S. Liu, J. Shi, G. Jiang, ‘Recent advances
in the analysis of TBBPA/TBBPS, TBBPA/TBBPS derivatives
and their transformation products’, TrAC Trends Anal.
Chem. 2016, 83, 14–24.
[19] Y. Zhang, W. Xu, Q. Lou, Y. Li, Y. Zhao, W. Wei, Z. Qin, H.
Wang, J. Li, ‘Tetrabromobisphenol A disrupts vertebrate
development via thyroid hormone signaling pathway in a
developmental stage dependent manner’, Environ. Sci.
Technol. 2014, 48, 8227–8234.
[20] G. Qu, J. Shi, T. Wang, J. Fu, Z. Li, P. Wang, T. Ruan, G. Jiang,
‘Identification of tetrabromobisphenol A diallyl ether as an
emerging neurotoxicant in environmental samples by
bioassay-directed fractionation and HPLC-APCI-MS/MS’,
Environ. Sci. Technol. 2011, 45, 5009–5016.
[21] F. Ji, C. Wang, H. Wang, G. Liu, B. Chen, L. Hu, G. Jiang, M.
Song, Y. Liang, ‘Tetrabromobisphenol A (TBBPA) exhibits
specific antimicrobial activity against Gram-positive bac-
teria without detectable resistance’, Chem. Commun. 2017,
53, 3512–3515.
[22] Y. Tian, A. Liu, G. Qu, C. Liu, J. Chen, E. Handberg, J. Shi, H.
Chen, G. Jiang, ‘Silver ion post-column derivatization
electrospray ionization mass spectrometry for determina-
[34] K. W. George, M. M. HÄggblom, ‘Microbial O-Methylation of
the Flame Retardant Tetrabromobisphenol-A’, Environ. Sci.
Technol. 2008, 42, 5555–5561.
tion of tetrabromobisphenol
A derivatives in water
[35] B. Uhnáková, R. Ludwig, J. Pěknicová, ‘Biodegradation of
tetrabromobisphenol A by oxidases in basidiomycetous
fungi and estrogenic activity of the biotransformation
products’, Bioresour. Technol. 2011, 102, 9409–9415.
[36] D. Zalko, C. Prouillac, A. Riu, E. Perdu, L. Dolo, I. Jouanin, C.
Canlet, L. Debrauwer, J. Cravedi, ‘Biotransformation of the
flame retardant tetrabromo-bisphenol A by human and rat
sub-cellular liver fractions’, Chemosphere 2006, 64, 318–
327.
[37] H. Hakk, G. Larsen, Å. Bergman, ‘Metabolism, excretion and
distribution of the flame retardant tetrabromobisphenol-A
in conventional and bile-duct cannulated rats’, Xenobiotica
2000, 30, 881–890.
samples’, RSC Adv. 2015, 5, 17474–17481.
[23] M. Teng, J. Jin, Q. Fu, Y. Cai, J. Chen, F. Wei, ‘Selective
separation of polychlorinated naphthalene (PCNs), hexab-
romocy-clododecanes (HBCDs) and tetrabromobisphenol A
(TBBPA) in soil matrices’, Sci. Bull. 2013, 58, 500–506.
[24] R. Cariou, J. P. Antignac, D. Zalko, A. Berrebi, J. P. Cravedi,
D. Maume, P. Marchand, F. Monteau, A. Riu, F. Andre, B.
Le Bizec, ‘Exposure assessment of French women and their
newborns to tetrabromobisphenol-A: occurrence measure-
ments in maternal adipose tissue, serum, breast milk and
cord serum’, Chemosphere 2008, 73, 1036–1041.
[25] T. Colnot, S. Kacew, W. Dekant, ‘Mammalian toxicology and
human exposures to the flame retardant 2,2’,6,6’-tetrabro-
www.cb.wiley.com
(11 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland

Chem. Biodiversity 2020, 17, e2000481
[38] G. A. Knudsen, J. M. Sanders, A. M. Sadik, ‘Disposition and
[52] A. Liu, J. Shi, G. Qu, L. Hu, Q. Ma, M. Song, C. Jing, G. Jiang,
‘Identification of emerging brominated chemicals as the
transformation products of tetrabromobisphenol A (TBBPA)
derivatives in soil’, Environ. Sci. Technol. 2017, 51, 5434–
5444.
kinetics of Tetrabromobisphenol A in female Wistar Han
rats’, Toxicol. Rep. 2004, 1, 214–223.
[39] U. M. D. Schauer, W. Völkel, W. Dekant, ‘Toxicokinetics of
tetrabromobisphenol a in humans and rats after oral
administration’, Toxicol. Sci. 2006, 91, 49–58.
[53] G. Qu, A. Liu, T. Wang, C. Zhang, J. Fu, M. Yu, J. Sun, N. Zhu,
Z. Li, G. Wei, Y. Du, J. Shi, S. Liu, G. Jiang, ‘Identification of
tetrabromobisphenol A allyl ether and tetrabromobisphe-
nol A 2,3-dibromopropyl ether in the ambient environment
near a manufacturing site and in mollusks at a coastal
region’, Environ. Sci. Technol. 2013, 47, 4760–4767.
[54] A. Liu, G. Qu, M. Yu, Y. Liu, J. Shi, G. Jiang, ‘Tetrabromobi-
sphenol-A/S and nine novel analogs in biological samples
from the Chinese Bohai Sea: Implications for trophic
transfer’, Environ. Sci. Technol. 2016, 50, 4203–4211.
[55] A. Liu, Y. Tian, N. Yin, M. Yu, G. Qu, J. Shi, Y. Du, G. Jiang,
‘Characterization of three tetrabromobisphenol-S deriva-
tives in mollusks from Chinese Bohai Sea: A strategy for
novel brominated contaminants identification’, Sci. Rep.
2015, 5, 11741–11752.
[56] A. Liu, J. Shi, Z. Shen, ‘Identification of Unknown Bromi-
nated Bisphenol S Congeners in Contaminated Soils as the
Transformation Products of Tetrabromobisphenol S Deriva-
tives’, Environ. Sci. Technol. 2018, 52, 10480–10489.
[57] L. Liang, X. Jin, Z. Li, S. Liu, Y. Li, R. Su, H. Su, ‘TBBPA
regulates calcium-mediated lysosomal exocytosis and
thereby promotes invasion and migration in hepatocellular
carcinoma’, Ecotoxicol. Environ. Saf. 2020, 192, 110255.
[58] J. Gu, X. Chen, Y. Wang, J. Gu, X. Chen, Y. Wang, L. Wang, K.
Szlavecz, Y. Ma, R. Ji, ‘Bioaccumulation, Physiological
Distribution, and Biotransformation of Tetrabromobisphe-
nol A (TBBPA) in the Geophagous Earthworm Metaphire
guillelmi–Hint for Detoxification Strategy’, J. Hazard. Mater.
2020, 388, 122027.
[40] D. N. Margalit, L. Romberg, R. B. Mets, A. M. Hebert, T. J.
Mitchison, M. W. Kirschner, D. RayChaudhuri, ‘Targeting cell
division: Small-molecule inhibitors of FtsZ GTPase perturb
cytokinetic ring assembly and induce bacterial lethality’,
Proc. Natl. Acad. Sci. USA 2004, 101, 11821–11826.
[41] P. H. Howard, D. C. G. Muir, ‘Identifying New Persistent and
Bioaccumulative Organics Among Chemicals in Commerce.
III: Byproducts, Impurities, and Transformation Products’,
Environ. Sci. Technol. 2013, 47, 5259–5266.
[42] A. B. Gomez, J. Boer, P. E. G. Leonards, ‘A Novel Brominated
Triazine-based Flame Retardant (TTBP-TAZ) in Plastic
Consumer Products and Indoor Dust’, Environ. Sci. Technol.
2014, 48, 4468–4474.
[43] P. Ferrini, S. Koelewijn, J. V. Aelst, ‘Zeolites as sustainable
catalysts for the selective synthesis of renewable bisphe-
nols from lignin-derived monomers’, ChemSusChem 2017,
10, 2249–2257.
[44] T. Debenest, F. Gagne, A. N. Petit, C. Andre, M. Kohli, C.
Blaise, ‘Ecotoxicity of a brominated flame retardant (tetra-
bromobisphenol A) and its derivatives to aquatic organ-
isms’, Comp. Biochem. Physiol. Part C 2010, 152, 407–412.
[45] J. G. Pressman, S. D. Richardson, T. F. Speth, ‘Simmons,
Concentration, Chlorination, and Chemical Analysis of
Drinking Water for Disinfection Byproduct Mixtures Health
Effects Research: U. S. EPA’s Four Lab Study’, Environ. Sci.
Technol. 2010, 44, 7184–7192.
[46] M. Gonsior, C. Mitchelmore, A. Heyes, ‘Bromination of
Marine Dissolved Organic Matter following Full Scale
Electrochemical Ballast Water Disinfection’, Environ. Sci.
Technol. 2015, 49, 9048–9055.
[47] F. Sun, B. A. Kolvenbach, P. Nastold, ‘Degradation and
metabolism of tetrabromobisphenol A (TBBPA) in sub-
merged soil and soil-plant systems’, Environ. Sci. Technol.
2014, 48, 14291–14299.
[59] H. Choi, D. Chi, ‘A facile debromination reaction: Can
bromide now be used as a protective group in aromatic
systems?’, J. Am. Chem. 2001, 123, 9202–9203.
[60] B. Plietker, M. Niggemann, ‘An improved protocol for the
RuO4-catalyzed dihydroxylation of Olefins’, Org. Lett. 2003,
18, 3353–3356.
[48] X. Wang, X. Hu, H. Zhang, ‘Photolysis kinetics, mechanisms,
and pathways of tetrabromobisphenol A in water under
simulated solar light irradiation’, Environ. Sci. Technol.
2015, 49, 6683–6690.
[49] F. Li, J. Wang, B. Jiang, ‘Fate of tetrabromobisphenol A
(TBBPA) and formation of ester- and ether-linked bound
residues in an oxic sandy soil’, Environ. Sci. Technol. 2015,
49, 12758–12765.
[61] J. Yang, K. M. Chan, ‘Evaluation of the toxic effects of
brominated compounds (BDE-47, 99, 209, TBBPA) and
bisphenol A (BPA) using a zebrafish liver cell lines, ZFL’,
Aquat. Toxicol. 2015, 159, 138–147.
[62] S. Wu, M. Wu, M. Qi, L. Zhong, L. Qiu, ‘Effects of novel
brominated flame retardant TBBPA on human airway
epithelial cell (A549) in vitro and proteome profiling’,
Environ. Toxicol. 2018, 33, 1245–1253.
[50] K. Lin, J. Ding, X. Huang, ‘Debromination of tetrabromobi-
sphenol A by nanoscale zerovalent iron: kinetics, influenc-
ing factors, and pathways’, Ind. Eng. Chem. Res. 2012, 51,
8378–8385.
[63] S. Strack, T. Detzel, M. Wahl, B. Kuch, H. F. Krug, ‘Cytotox-
icity of TBBPA and effects on proliferation, cell cycle and
MAPK pathways in mammalian cells’, Chemosphere 2007,
67, S405–S411.
[51] X. Li, H. Liu, X. Jia, ‘Novel approach for removing
brominated flame retardant from aquatic environments
using Cu/Fe-based metal-organic frameworks: A case of
hexabromocyclododecane (HBCD)’, Sci. Total Environ.
2018, 621, 1533–1541.
Received June 15, 2020
Accepted September 12, 2020
www.cb.wiley.com
(12 of 12) e2000481
© 2020 Wiley-VHCA AG, Zurich, Switzerland