vvEPA
United States
Environmental Protection Agency
EPA Document** 740-Q1-4003
August 2015
Office of Chemical Safety and
Pollution Prevention
TSCA Work Plan Chemical
Technical Supplement - Hazard Assessment of the Brominated
Phthalates Cluster (BPC) Chemicals
Brominated Phthalates Cluster
Flame Retardants
CASRN
26040-51-7
183658-27-7
20566-35-2
77098-07-8
7415-86-3
*
*
NAME
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l,2-bis(2-
ethylhexyl) ester
Benzole acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl ester
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l-[2-(2-
hydroxyethoxy)ethyl] 2-(2-hydroxypropyl) ester
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, mixed
esters with diethylene glycol and propylene glycol
1,2-Benzenedicarboxylic acid, l,2-bis(2,3-dibromopropyl) ester
Confidential A
Confidential B
* Confidential Business Information
August 2015
-------
TABLE OF CONTENTS
TABLE OF CONTENTS 2
1 HUMAN HEALTH HAZARD 3
1.1 TOXICOKINETICS 3
1.2 HAZARD IDENTIFICATION 8
1.3 DATA NEEDS ASSESSMENT 16
2 ECOLOGICAL HAZARD 17
2.1 HAZARD IDENTIFICATION 17
2.2 DATA NEEDS ASSESSMENT 19
REFERENCES 21
LIST OF TABLES
Table 1-1: Structure of Brominated Phthalates Cluster and Associated Chemicals 5
Table 1-2: Availability of human health data for the Brominated Phthalates Cluster 8
Table 1-3: Human Health Data for Brominated Phthalates Cluster 10
Table 2-1: Environmental Effects Data for Brominated Phthalates Cluster 18
Page 2 of 23
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1 HUMAN HEALTH HAZARD
1.1 Toxicokinetics
Limited data are available on the toxicokinetics of the BPC members. Phthalic acid is the
common final metabolite of phthalic acid esters in rats; the main route of excretion being in
urine (Lim et al., 2007). While information for the structural analogue, bis(2-
ethylhexyl)phthalate (DEHP; CASRN 117-81-7) can be used to inform the metabolism and
potential hazard of some of the BPC members, it is not appropriate for all members due to the
differences in metabolites. The metabolites of DEHP and the cluster members are depicted in
Table 1-1.
1,2-Benzenedicarboxylic acid, l,2-bis(2-ethylhexyl) ester (DEHP; CASRN 117-81-7)
The closest structural analog of the cluster members is 1,2-Benzenedicarboxylic acid, l,2-bis(2-
ethylhexyl) ester (DEHP; CASRN 117-81-7). It is readily absorbed and distributed in the body. Its
metabolism involves several pathways and yields a variety of metabolites; more than 30
metabolites have been identified (Lim et al., 2007). The major step in the metabolism of DEHP
is hydrolysis by lipases to mono (2-ethylhexyl)phthalate (MEHP; CASRN 4376-20-9) and 2-
ethylhexanol (2-EH; CASRN 104-76-7). Phthalic acid (PA; CASRN 88-99-3) is the common final
metabolite of phthalic acid esters (Lim et al., 2007). DEHP is excreted via the urine, mainly as
MEHP-metabolites, but some excretion via bile also occurs in rodents. Additionally, there are
animal and human data showing that DEHP is transferred to mothers' milk. The relative extent
to which different metabolites are produced and excreted is very complex and may depend
upon the species, the age of the animal, sex, inter-individual differences, nutrition state, prior
exposure to DEHP, the amount of DEHP administered, and the route of administration (NTP,
2006; OECD, 2005).
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l,2-bis(2-ethylhexyl) ester (TBPH; CASRN
26040-51-7)
Limited data are available on the toxicokinetics of 1,2-Benzenedicarboxylic acid, 3,4,5,6-
tetrabromo-, l,2-bis(2-ethylhexyl) ester (TBPH; CASRN 26040-51-7). Its primary metabolite is
the monoester, mono(2-ethylhexyl) tetrabromophthalate (TBMEHP; CASRN 61776-60-1) which
is then ultimately metabolized to tetrabromophthalic acid (CASRN 13810-83-8). When tested in
vitro, no metabolites of TBPH were detected in human or rat subcellular fractions (Roberts et
al., 2012). However, in the presence of purified porcine carboxylesterase, the formation of
TBMEHP was detected. No phase II metabolites of TBMEHP were detected. The metabolism of
TBPH in humans has not been evaluated (Roberts et al., 2012). No toxicokinetics data were
submitted to EPA under the HPV Challenge Program (ACC, 2004) and additional information
was not publicly available from the European Chemicals Agency (ECHA) site (ECHA, 2013).
Benzole acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl ester (TBB; CASRN 183658-27-7)
Limited data are available on the toxicokinetics of Benzoic acid, 2,3,4,5-tetrabromo-, 2-
ethylhexyl ester (TBB; CASRN 183658-27-7). This member of the cluster differs significantly
Page 3 of 23
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from the other cluster members in that its final metabolite is not tetrabromophthalic acid
(CASRN 13810-83-8) but tetrabromobenzoic acid (TBBA; CASRN 27581-13-1). This was
confirmed in vitro using liver and intestinal subcellular fractions. In all experiments, TBB was
consistently metabolized to 2,3,4,5-tetrabromobenzoic acid (TBBA) via cleavage of the 2-
ethylhexyl chain without requiring added cofactors (Roberts et al., 2012). No phase II
metabolites of TBBA were detected. The metabolism of TBB in humans has not been evaluated
(Roberts et al., 2012).
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l-[2-(2-hydroxyethoxy)ethyl] 2-(2-
hydroxypropyl) ester (CASRN 20566-35-2) and 3,4,5,6 tetrabromo-l,2-benzene dicarboxylic
acid, mixed esters with diethylene glycol and propylene glycol (CASRN 77098-07-8)
These two cluster members are mixtures which can be considered together as their
composition and metabolites are very similar. No data on the toxicokinetics of these substances
are available. Analogous to the other cluster members, the metabolites are expected to be the
corresponding alcohols and the tetrabromophthalic acid. No toxicokinetics data were
submitted for CASRN 77098-07-8 to EPA under the HPV Challenge Program (Albemarle - GLCC,
2004) and additional information was not publicly available from the European Chemicals
Agency (ECHA) site for CASRN 20566-35-2 (ECHA, 2013).
1,2-Benzenedicarboxylic acid, l,2-bis(2,3-dibromopropyl) ester (CASRN 7415-86-3)
No data are available on the toxicokinetics of this cluster member. It differs from the other
cluster members in that the bromines are not attached to the benzene ring but are instead on
the side-chains. The metabolites are expected to be 2,3-dibromopropanol (CASRN 96-13-9) and
the final metabolite, PA. Two mercapturic acid metabolites of 2,3-dibromopropanol have been
identified in the urine of treated rats (IARC, 2000).
Page 4 of 23
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Table 1-1: Structure of Brominated Phthalates Cluster and Associated Chemicals
CASRN
117-81-7
26040-51-7
NAME
DEHP: ,2-
Benzenedicarboxylic
acid, ,2-bis(2-
ethylhexyl)ester
STRUCTURAL
ANALOG of BPC
CLUSTER
MEMBERS
TBPH: 1,2-
Benzenedicarboxylic
acid, 3,4,5,6-
tetrabromo-, 1,2-
bis(2-ethylhexyl)
potpf
cold
STRUCTURE
QvJ-
J^ °
EKJ°
I
el
Bf O
3l 1 II ^ -Bo
'--^ -^ ~~Q-^ ~~~^
Br' Y T % !1
°r /\Pll
Metabolites/Hydrolysis Products
CH3
/
X-3
f \^
1
•^s
MEHP
[Mono(2-ethylhexyl)
tetrabromophthalate;
CASRN 4376-20-9]1
„ „
v_/
"HOrJ\s
B.^)=c ~\_,
!K / V.
TBMEHP
[Mono(2-ethylhexyl)
tetrabromophthalate;
CASRN 61776-60-1; not
on TSCA inventory]
*
/+^ * • x
OH
2-ethylhexanol
(CASRN 104-76-7)
OH
\
HO /=\
Phthalicacid
(CASRN 88-99-3)
^
1
^-^^^\
OH
2-ethylhexanol
(CASRN 104-76-7)
Br 0
Dr JL 11
Dl •s. ^^C1^ ^X^\
^r^^Y OH
JL ^JL OH
Br y^ ^n^
Br O
Tetrabromophthalic acid
(CASRN 13810-83-8)
1 CSID: 19208, http://www.chemspider.com/Chemical-Structure.19208.html (accessed 15:06, Sep 9, 2013)
Page 5 of 23
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CASRN
183658-27-7
20566-35-2
77098-07-8
NAME
TBB: Benzoic acid,
2,3,4,5-tetrabromo-,
2-ethylhexyl ester
TBPA-Diol: 1,2-
Benzenedicarboxylic
acid, 3,4,5,6-
tetrabromo-, 1-[2-(2-
hydroxyethoxy)ethyl]
2-(2-hydroxypropyl)
ester
TBPA-Diol (Mixed
Esters): 1,2-
Benzenedicarboxylic
acid, 3,4,5,6-
tetrabromo-, mixed
esters with diethylene
glycol and propylene
glycol
STRUCTURE Metabolites/Hydrolysis Products
0 Br
/\ ^- .--v^ Ji ,v Br
H,C' - ^y o" j^~Y
\CH< "^y-^-er
"
Br
Sr O r'' ""^"'^OH
Y^Y""°
B.-^-A^^O-^J-QH
Sir O
,0 -"•-.
6r O r' ^-*" OH
1 U
br .X >L _,x
7 T 1
Br^Y'^Y'0"^" OH
Br O
"^
I
y^*^ ~^\
OH
2-ethylhexanol
(CASRN 104-76-7)
HOCH2CH2OCH2C
H2OH
Diethylene glycol
(CASRN 111-46-6)
CHa-CHOH-
CH2OH
Propylene Glycol
(CASRN 57-55-6)
HOCH2CH2OCH2C
H2OH
Diethylene glycol
(CASRN 111-46-6)
CHa-CHOH-
CH2OH
Propylene Glycol
(CASRN 57-55-6)
Br 0
Br, II
"Y^Y^^OH
A J
Brx ^
Br
Tetrabromobenzoic
acid
(TBBA: CASRN
27581-13-1)
Br 0
Dr JL 11
LD\ 's. ^*O^ j**1^^*.
^^^] OH
J\^L /OH
\^\C
Br O
Tetrabromophthalic
acid
(CASRN 13810-83-8)
Br 0
Dr JL 11
Dl \ ^^C1^ j^^^
^I^^Y OH
JL /JL OH
.^^^*****. *^^^^^ .x*1
Br O
Tetrabromophthalic
acid
(CASRN 13810-83-8)
Page 6 of 23
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CASRN
7415-86-3
CONFIDENTIAL A
CONFIDENTIAL B
NAME
Bromo Alkyl Ester:
1,2-
Benzenedicarboxylic
acid, 1,2-bis(2,3-
dibromopropyl) ester
STRUCTURE
Br
O
||
r^V ^cr"
^ lA
0
Metabolites/Hydrolysis Products
^.Bt
X
Br
I
BrCH 2 ~~ CH — CH 2 ~" OH
2,3-dibromo-l-
propanol
(CASRN 96-13-9)
OH
HO ^V— >
O % '
Phthalicacid
(CASRN 88-99-3)
Page 7 of 23
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1.2
Hazard Identification
The available hazard data for the BPC cluster members are summarized in Table 1-3 and Table 2-1. Table 1-3 also shows some
hazard data for the structural analog, DEHP, for reference. The data are discussed below.
Table 1-2: Availability of human health data for the Brominated Phthalates Cluster
Brominated Phthalates Cluster Members
Endpoint
Acute Oral
Toxicity
LD50 (mg/kg)
Acute Dermal
Toxicity LDso
(mg/kg)
CASRN
26040-51-72
TBPH: 1,2-
Benzenedicarboxyl
ic acid, 3,4,5,6-
tetrabromo-, 1,2-
bis(2-ethylhexyl)
ester
X
X
CASRN
183658-27-73
TBB: Benzole
acid, 2,3,4,5-
tetrabromo-,
2-ethylhexyl
ester
CASRN
20566-35-24
TBPA-Diol: 1,2-
Benzenedicarb
oxylic acid,
3,4,5,6-
tetrabromo-,
l-[2-(2-
hydroxyethoxy)
ethyl] 2-(2-
hydroxypropyl)
ester
ECHA
ECHA
CASRN
77098-07-85
TBPA-Diol: 1,2-
Benzenedicarbox
ylic acid, 3,4,5,6-
tetrabromo-,
mixed esters
with diethylene
glycol and
propylene glycol
X
X
CASRN
7415-86-3
1,2-
Benzenedicarbox
ylic acid, 1,2-
bis(2,3-
dibromopropyl)
ester
Confidential
A
Confidential
B
2 Screening-level data available from the HPV Challenge submission: http://www.epa. gov/hpv/pubs/summaries/phthacid/c 15484tc.htm
3 Data available for Firemaster BZ 54 (TBB/TBPH mixture)
4 Screening-level data are available from ECHA [(European Chemicals Agency): http://apps.echa.europa.eu/registered/data/dossiers/DISS-9ea569dl-072b-18ab-
e044-00144f67d031/DISS-9ea569dl-072b-18ab-e044-00144f67d031 DISS-9ea569dl-072b-18ab-e044-00144f67d031.html1 For risk assessment, the adequacy
of these data is indeterminable without access to the full studies.
5 Screening-level data available from the HPV Challenge submission: http://www.epa.gov/chemrtk/pubs/summaries/12benznd/cl5091tc.htm
Page 8 of 23
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Brominated Phthalates Cluster Members
Endpoint
Acute
Inhalation
Toxicity
LCso (mg/L)
Repeated-Dose
Toxicity
Oral
NOAEL/
LOAEL
(mg/kg-day)
Reproductive
Toxicity
NOAEL/
LOAEL
(mg/kg-day)
Developmental
Toxicity
NOAEL/
LOAEL
(mg/kg-day)
Genetic
Toxicity -
Gene Mutation
In vitro
Genetic
Toxicity -
Chromosomal
Aberrations
In vitro
Genetic
Toxicity -
Chromosomal
Aberrations
In vivo
Skin Irritation
CASRN
26040-51-72
X
X
X
X
X
CASRN
183658-27-73
—
CASRN
20566-35-24
ECHA
—
CASRN
77098-07-85
X
X
—
CASRN
7415-86-3
—
Confidential
A
—
Confidential
B
—
Page 9 of 23
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Brominated Phthalates Cluster Members
Endpoint
Eye Irritation
Sensitization
CASRN
26040-51-72
X
X
CASRN
183658-27-73
—
—
CASRN
20566-35-24
—
—
CASRN
77098-07-85
—
—
CASRN
7415-86-3
—
—
Confidential
A
—
—
Confidential
B
—
—
X denotes available data; - denotes no adequate data
Table 1-3: Human Health Data for Brominated Phthalates Cluster
Endpoint
Acute Oral
Toxicity
LDso (mg/kg)
CASRN
117-81-76
DEHP: 1,2-
Benzendicarboxylic
acid, 2-bis(2-
ethylhexyl ester)
>20,000
Brominated Phthalates Cluster Members
CASRN
26040-51-77
TBPH: 1,2-
Benzenedicarboxylic acid,
3,4,5,6-tetrabromo-, 1,2-
bis(2-ethylhexyl) ester
>5000
(>95%)
CASRN
183658-27-7
TBB: Benzoicacid,
2,3,4,5-tetrabromo-
, 2-ethylhexyl ester
(Firemaster® BZ-54)10
>5000
CASRN
20566-35-28
TBPA-Diol: 1,2-
Benzenedicarboxyl
ic acid, 3,4,5,6-
tetrabromo-, l-[2-
(2-
hydroxyethoxy)eth
yl] 2-(2-
hydroxypropyl)
ester
>2000
(Saytex RB 79
20566-35-2)
CASRN
77098-07-89
TBPA-Diol: 1,2-
Benzenedicarboxylic
acid, 3,4,5,6-
tetrabromo-, mixed
esters with diethylene
glycol and propylene
glycol
>10,000
(PM-PHT-4 Diol)
CASRN
7415-86-3
1,2-
Benzenedicarbox
ylic acid, 1,2-
bis(2,3-
dibromopropyl)
ester
6 ECHA: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7eba3b-31b2-3fdl-e044-00144f67d249/DISS-9c7eba3b-31b2-3fdl-e044-
00144f67d249 DISS-9c7eba3b-31b2-3fdl-e044-00144f67d249.html
7 HPV Challenge submission: http://www.epa.gov/hpv/pubs/summaries/phthacid/cl5484tc.htm
8 ECHA: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9ea569dl-072b-18ab-e044-00144f67d031/DISS-9ea569dl-072b-18ab-e044-
00144f67d031 DISS-9ea569dl-072b-18ab-e044-00144f67d031.html For risk assessment, the adequacy of these data is indeterminable without access to the
full studies.
9 Screening-level data available from the HPV Challenge submission: http://www.epa.gov/chemrtk/pubs/summaries/12benznd/cl5091tc.htm
10 (NICNAS, 2004)
Page 10 of 23
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Endpoint
Acute Dermal
Toxicity LDso
(mg/kg)
Acute
Inhalation
Toxicity
LCso (mg/L)
Repeated-Dose
Toxicity
Oral
NOAEL/
LOAEL
(mg/kg-day)
Repeated-Dose
Toxicity
Inhalation
NOAEC/
LOAEC
(mg/L-day)
Reproductive
Toxicity
Oral
NOAEL/
LOAEL
(mg/kg-day)
CASRN
117-81-76
19,800
10,620 [LCo]
(mg/m3)
(rat; diet chronic)
NOAEL=29-36
LOAEL
=146-181
NOAEC=
50 mg/m3
LOAEC=
1000 mg/m3
(Rat; 3-gen)
NOAEL=46-48
LOAEL=359-391
(parental)
NOAEL(off-
spring)=1.4
LOAEL(off-
spring)=4.8-4.9
Brominated Phthalates Cluster Members
CASRN
26040-51-77
>3090
(>95%)
CASRN
183658-27-7
—
(Firemaster® BZ-S4)14
>2000
—
(rat; 28-d diet)
NOAEL =223
(2000 ppm)
LOAEL = 2331
(20,000 ppm)
(>95%)
—
—
(Firemaster® BZ-S4)14
Rat (28-d gavage)
NOEL = Not established
LOEL=160
—
—
(Rat; 2-gen)
NOAEL=165 (highest dose tested)
NOAEL(parental) = 50
LOAEL(parental) =
165
NOAEL(off-spring)=50
LOAEL(off-spring)=165
(Firemaster® BZ-S4)14
CASRN
20566-35-28
>20,000
(FM-PHT-4 Diol
20566-35-2)
>0.008
(FM-PHT-4 Diol
20566-35-2)
—
—
—
CASRN
77098-07-89
>20,000
(PM-PHT-4 Diol)
—
—
—
—
CASRN
7415-86-3
—
—
—
—
—
Page 11 of 23
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Endpoint
Developmental
Toxicity
NOAEL/
LOAEL
(mg/kg-day)
Maternal
Toxicity
Developmental
Toxicity
Genetic
Toxicity -
Gene Mutation
In vitro
Genetic
Toxicity -
Chromosomal
Aberrations
In vitro
Genetic
Toxicity -
Chromosomal
Aberrations
In vivo
Skin Irritation
Eye Irritation
Sensitization
Carcinogenicity
CASRN
117-81-76
(Rat)
NOAEL = 200
LOAEL =1000
NOAEL=200
LOAEL=1000
—
Negative
(SCE)
Negative
Slightly irritating
—
Not sensitizing
(skin or
respiratory)
Positive
(rat)
Brominated Phthalates Cluster Members
CASRN
26040-51-77
CASRN
183658-27-7
(Rat)
NOAEL = 50
LOAEL =100
NOAEL=50
LOAEL=100
(Firemaster® BZ-54)14
Negative
(>95%)
Positive
(>95%)
Negative
(>95%)
Slightly irritating
Slightly irritating
Not sensitizing
(>95%)
—
—
—
—
—
—
—
—
CASRN
20566-35-28
—
Negative
(Saytex RB 79
20566-35-2)
—
—
—
—
—
—
CASRN
77098-07-89
—
Negative
(Saytex RB 79)
—
—
—
—
—
—
CASRN
7415-86-3
—
—
—
—
—
—
—
—
Measured data in bold; NE = Not established; — indicates no data or no reliable data for this endpoint; (%) = % purity or identity of the
test substance
Page 12 of 23
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1,2-Benzenedicarboxylic acid, l,2-bis(2-ethylhexyl) ester (DEHP; CASRN117-81-7)
Several assessments are available on the toxicity and risks of phthalates. EPA has published a
screening-level hazard characterization for phthalate esters (EPA, 2010a) and has revised the
action plan for phthalates (EPA, 2012d); both of which use data for bis(2-ethylhexyl)phthalate
(DEHP; CASRN 117-81-7) to ascribe hazard. DEHP is metabolized by esterases to mono (2-
ethylhexyl)phthalate (MEHP; CASRN 4376-20-9), its lexicologically active monoester (Springer
et al., 2012). DEHP is a known peroxisome proliferator and male reproductive toxicant in
rodents. It induces hepatotoxicity in rodents, most likely as a result of MEHP-induce activation
of peroxisome proliferator activated receptor alpha (PPARa) (Ward et al., 1998 cited in Springer
et al., 2012). The developing male reproductive system in rats is highly sensitive to the effects
of these phthalates, which decrease fetal male testosterone levels (Parks et al., 2000 cited in
Springer et al., 2012). In 2006, the National Toxicology Program (NTP) deliberated on the
reproductive toxicity of DEHP and concluded the following: there is serious concern that
certain intensive medical treatments of male infants may result in DEHP exposure levels that
adversely affect development of the male reproductive tract, there is concern for adverse
effects on development of the reproductive tract in male offspring of pregnant and
breastfeeding women undergoing certain medical procedures involving high DEHP exposures,
there is concern for the effects of DEHP exposure on the development of the male reproductive
tract for infants less than one year old and less so for male children older than one year old and
there is concern for adverse effects of DEHP exposure on development of the male
reproductive tract in male offspring of pregnant women not medically exposed to DEHP and
some concern for reproductive toxicity in adults exposed to DEHP at 1-30 u.g/kg bw/day (NTP,
2006). It is this toxicity to the male reproductive system from DEHP exposure, a phthalate ester,
that is of specific concern for this cluster of brominated phthalate esters.
1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l,2-bis(2-ethylhexyl) ester (TBPH; CASRN
26040-51-7)
b/s(2-Ethylhexyl)-3,4,5,6-tetrabromophthalate (TBPH) exhibits low acute toxicity to rats and
rabbits via the oral and dermal routes, respectively. It is slightly irritating to the skin and eyes in
rabbits and was not a skin sensitizer in guinea pigs. In a dietary repeat-dose study in rats, there
was a slight body weight decrease in females and clinical biochemistry perturbations
(decreased alanine aminotransferase activity, decreased calcium and decreased phosphorus
levels) at the highest concentration tested (2331 mg/kg-day). The NOAEL was designated as 223
mg/kg-day. TBPH was not mutagenic in bacteria in vitro but did induce chromosomal
aberrations in mammalian cells in vitro. TBPH did not induce micronuclei in mice in vivo. No
data are available for the reproductive/developmental toxicity endpoint.
In a non-guideline study, Springer et al., (2012) compared the toxicity of the primary metabolite
of TBPH [mono(2-ethylhexyl) tetrabromophthalate (TBMEHP; CASRN 61776-60-1)] with that of
DEHP [mono (2-ethylhexyl)phthalate (MEHP; CASRN 4376-20-9)]. Dust collected from homes,
offices, and cars was measured for TBPH by gas chromatography followed by mass
spectrometry. Pregnant rats were gavaged with TBMEHP (200 or 500 mg/kg) or corn oil on
gestational days 18 and 19, and dams and fetuses were evaluated histologically for toxicity.
TBMEHP was also evaluated for deiodinase inhibition using rat liver microsomes and for
Page 13 of 23
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peroxisome proliferator-activated receptor (PPAR) a and y activation using murine FAO cells
and NIH 3T3 LI cells. They found that in contrast to DEHP, TBMEHP did not exhibit anti-
androgenic activity. However, it did exhibit liver toxicity attributable to a PPAR a mode of action
which is similar to that observed for DEHP/MEHP.
Benzole acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl ester (TBB; CASRN183658-27-7)
Limited toxicity data are available for Benzoic acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl ester
(TBB; CASRN 183658-27-7). The available data (Chemtura, 2012a, 2013a; NICNAS, 2004) are for
the commercial product, Firemaster® BZ-54. This commercial product is a mixture of TBB and 2-
ethylhexyl tetrabromophthalate (TBPH; CASRN 26040-51-7) (Chemtura, 2010). Firemaster® BZ-
54 exhibits low acute toxicity via the oral and dermal routes of exposure. In a 28-day repeated
dose study in rats, kidney effects (cortical tubular epithelial regeneration) and increased levels
of mean serum chloride were observed at all dose levels. The females appeared more sensitive
to the test substance (significant differences in organ weights, changes in clinical chemistry
parameters, decreased in mean body weight gain); the no observed adverse effect level was
not determined. The lowest observed effect level was 160 mg/kg-day. The effects observed in
parental animals in the two-generation reproductive toxicity study with Firemaster® BZ-54 were
lower body weights and body weight gains during the premating periods in the parental and
first generation females at the highest dose tested. First generation males also had lower body
weights in the premating period but body weight gain was unaffected by treatment. At the
highest dose tested, both generations of offspring had lower body weights at birth and
throughout lactation which resulted in the lower premating body weights of the first female
generation. Another effect of treatment was lower spleen weights at lactation day 21 in the
first generation male pups and both pup sexes of the second generation. There were no
adverse effects on reproductive performance or fertility in rats in this study up to the highest
dose tested (165 mg/kg-day). Based on these observations, the NOAELfor parental and
neonatal toxicity was designated 50 mg/kg-day; the NOAEL for reproductive toxicity was 165
mg/kg-day (highest dose tested).
In the prenatal developmental toxicity study with Firemaster®BZ-54 in rats, maternal toxicity
included clinical findings (increased incidence of animals with sparse hair in the abdominal
region), lower gestation body weights and body weight gain, and lower gestation food
consumption at doses greater than or equal to 100 mg/kg-day. Fetal body weights were lower
than controls at these doses. At 300 mg/kg-day, examination of the fetuses indicated fused
cervical vertebral neural arches which were considered treatment-related (litter incidence of
8%). In addition, there was also an increased litter incidence for fetal ossification variations
involving additional ossification centers to the cervical vertebral neural arches, incomplete
ossified skull bones (jugal, parietal, and squamosal), and unossified sternebrae. Based on these
observations, the NOAEL for maternal and developmental toxicity were designated 50 mg/kg-
day.
Page 14 of 23
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1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l-[2-(2-hydroxyethoxy)ethyl] 2-(2-
hydroxypropyl) ester (CASRN 20566-35-2) and 3,4,5,6 tetrabromo-l,2-benzene dicarboxylic
acid, mixed esters with diethylene glycol and propylene glycol (CASRN 77098-07-8)
CASRNs 20566 and 77098-07-8 exhibit low acute toxicity to rats and rabbits via the oral and
dermal routes, respectively. They are not mutagenic to bacteria in vitro. No additional data are
available on these cluster members.
1,2-Benzenedicarboxylic acid, l,2-bis(2,3-dibromopropyl) ester (CASRN 7415-86-3)
No data are available for this cluster member.
Confidential A and Confidential B.
Confidential A is subject to a consent order whose testing is triggered by production volume. No
data are available for this cluster member or Confidential B.
Commercial Products (Firemaster® 550 and Firemaster® BZ-54)
The commercial product cited in the literature (Firemaster® 550) is comprised of a mixture of
two of the members of the brominated phthalates cluster (TBPH and TBB) as well as two
phosphates: triphenyl phosphate (TPP; CASRN 115-86-6) and isopropylated triphenyl phosphate
(ITPP; CASRN 68937-41-7) (Chemtura, 2012b). Available screening-level data on these
phosphates (ECHA, 2013; EPA, 2010b; OECD, 2002) suggest that these constituents pose a
hazard to human health and the environment. Firemaster® BZ-54 does not have phosphates in
its formulation (Chemtura, 2010, 2013a).
Triphenyl phosphate (TPP; CASRN 115-86-6)
Triphenyl phosphate (TPP) exhibits low acute toxicity via the oral (rats, mice, rabbits and guinea
pigs) and dermal (rabbits) routes. TPP is not irritating to the skin and is slightly irritating to the
eyes. There is evidence (case reports) of skin sensitization in humans. Oral repeat dose studies
in rats showed a slight depression in body weight gain and an increase in liver weights at 350
mg/kg-day; the NOAEL was 70 mg/kg-day. TPP did not induce immediate or delayed
neuropathy in hens and cats. TPP was not mutagenic in bacteria or mammalian cells in vitro. No
adverse effects on fertility or development were found in rats fed up to 700 mg/kg-day TPP
during gametogenesis prior to mating and throughout mating and gestation. TPP did not show
carcinogenic potential in a mouse lung adenoma assay (OECD, 2002).
Isopropylated triphenyl phosphate (ITPP; CASRN 68937-41-7)
The acute oral and dermal toxicity of isopropylated triphenyl phosphate (ITPP) in rats is low.
ITPP is not irritating to rabbit skin but is irritating to rabbit eyes. ITPP was neurotoxic to hens.
No additional data were available or considered reliable for the EPA hazard characterization
(EPA, 2010b). In the submission to the European Chemicals Agency (ECHA, 2013), data for
several commercial products suggest that ITPP exhibits chronic toxicity. In addition, data from
an oral gavage reproductive/developmental toxicity screening test showed that rats treated
with Reofos 65 exhibited poor reproductive performance at 400 mg/kg-day (only dose tested)
(ECHA, 2013). In a combined repeated-dose/reproductive/developmental toxicity screening test
with the same compound, rats exhibited increased ovary/oviduct, adrenal gland (males and
Page 15 of 23
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females) and liver (males only) weights and decreased epididymal weights with corresponding
macroscopic and/or microscopic changes in these tissues at 25 mg/kg-day. The NOAEL for
systemic toxicity was not established. Male and female reproductive performance was also
adversely affected at dose levels of 100 and 400 mg/kg-day, manifested by significant
reductions in fertility and copulation/conception indices. Early postnatal development was also
affected at dose levels of 100 and 400 mg/kg/day. The number of pups born and live litter size
were decreased in these groups, while the numbers of pups found dead or euthanized in
extremis were increased; all pups from five of six litters in the 400 mg/kg-day group were either
found dead or euthanized in extremis prior to PND 4. The NOAEL for
reproductive/developmental toxicity was 25 mg/kg-day.
The potential for exposure to the brominated phthalates cluster (BPC) members during
chemical manufacture is not clearly understood. Similarly, there is evidence for potential
exposure to some of the cluster members during occupational use of products containing some
of the cluster members. There is also evidence to suggest potential consumer exposure to the
BPC members during the use of some of the products containing some of the BPC members.
An overview of the data for the structural analog, bis(2-ethylhexyl)phthalate (DEHP; CASRN
117-81-7), was presented. It could be argued that conservatively, these data could be used to
characterize the hazard for the brominated phthalates cluster (BPC) members. However,
available data suggest that the mode of action of DEHP that elicits chronic (specifically
reproductive and developmental) toxicity is not the same as that of the BPC members. In
addition, the available data support this hypothesis. There is uncertainty characterizing the
hazard for the BPC members because the chronic (including reproductive/developmental)
toxicity observed in animal studies with the BPC members is via a mode of action not
considered relevant to humans or at concentrations that either do not raise immediate
concerns, or which are difficult to attribute to a particular chemical because the data were
obtained using a commercial mixture.
Based on the available data for TBPH, there is a low hazard for acute toxicity. In the screening-
level dietary study in rats with TBPH (described above), the potential for liver toxicity was
observed by perturbations in clinical chemistry values. However, some liver effects have been
attributed to a mode of action, peroxisome proliferation (peroxisome proliferator activated
receptor; PPARa), not considered relevant to humans (Springer et al., 2012). The repeated-dose
study with the commercial product Firemaster® BZ-54 showed the potential for kidney effects
at the lowest dose tested, indicating that the kidney may be a potential target organ (NICNAS,
2004). In the two-generation reproductive toxicity study and a prenatal developmental toxicity
study with the commercial product Firemaster® BZ-54 (TBPH/TBB mixture), showed the
potential to affect fetal development at high doses. The uncertainty of using the data for the
commercial product to characterize the hazard for TBPH or TBB lies in the attribution of the
toxicity observed to either mixture component. No toxicity studies with TBB alone are available;
Page 16 of 23
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however, given that the metabolites of TBPH and TBB are different, it is expected that any
toxicity observed would not be by the same mode of action or attributable to the same
chemical. Springer et al., (Springer et al., 2012) observed the potential for endocrine disruption
with the metabolites of TBPH and TBB suggesting that the potential for
reproductive/developmental toxicity needs to be explored further. It would also be useful to
identify the targets organs of toxicity for TBB, if any. Screening level data do not suggest a
concern for carcinogenicity and the potential for a mode of action not relevant to humans
(PPARa) further lowers the potential concern and the need for data for this chronic toxicity
endpoint.
No data are available for CASRN 7415-86-3. The acute toxicity of CASRNs 20566-35-2 and
77098-07-8 is considered low. No data for repeated-dose or reproductive/developmental
toxicity are available for CASRNs 20566-35-2 and 77098-07-8. The need for human health data
for these chemicals is dependent on the potential exposure during manufacture and the
potential for at least CASRNs 20566-35-2 and 77098-07-8 to be released from the polymer
backbone.
2 ECOLOGICAL HAZARD
The environmental hazard of brominated phthalates reviewed and summarized in this section is
based on studies located and reviewed from EPA's TSCATS databases (public), public literature
searches, and other confidential sources; information from confidential sources not already
public were excluded from this assessment. Full study reports were not located for all identified
studies. Available hazard data are summarized in Table 2-1 and described below.
Page 17 of 23
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Table 2-1: Environmental Effects Data for Brominated Phthalates Cluster
Test Substance
Firemaster® BZ-54
TBPH:1,2-
Benzenedicarboxylic acid,
3,4,5,6-tetrabromo-, 1,2-
bis(2-ethylhexyl) ester
PM-PHT-4 Diol: 2-(2-
hydroxyethoxy) ethyl 2-
hydroxy propyl 3,4,5,6
tetrabromobenzene
dicarboxylate
Composi
tion
TBB/TBPH
>95%
TBPH
Not Stated
Test
Organism
Fish
Daphnid
Daphnid
Algae
Fish
Daphnid
Daphnid
Algae
Fish
Species
Oncorhynchus
mykiss
Daphnia
magna
Daphnia
carinata
Selenastrum
capricornutum
Oncorhynchus
mykiss
Daphnia
magna
Daphnia
magna
Desmodesmus
subspicatus
Lepomis
macrochirus
Test
Guideline
OECD TG 203
OECD TG 202
OECD TG 201
OECD TG 203
OECD TG 202
OECD TG 202
OECD TG 201
EPA-660/3-
75-009, April,
1975.
Duration
96-h
48-h
15-d
96-h
96-h
48-h
48-h
72-h
96-h
Endpoint
LC50
EC50
ChV
EC50
ChV
EC50
EC50
EC50
EC50
ChV
LC50
Value (mg/L)
NES
0.42
0.022
NES
NES
NES
0.3
NES
NES
NES
12
Reference
Chemtura (2013a)
Chemtura (2013a)
Access: UTS Pty Ltd (2003)
as cited in NICNAS, 2004
Chemtura (2013a)
ECHA (accessed 9/2013)
IUCLID, 2004 as submitted
to the HPV Challenge
Program
ECHA (accessed 9/2013)
ECHA (accessed 9/2013)
ECHA (under CASRN 20566-
35-2 accessed 11/2013)
Page 18 of 23
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In general, insufficient experimental data are available to characterize hazard that would result
from chronic exposure to wildlife populations. Currently, information from experimental
studies that address standard aquatic toxicity endpoints are limited to two chronic invertebrate
studies conducted on two different species and two different flame retardant formulations (BZ-
54 and pure TBPH) that present conflicting conclusions. Additional studies are available that
attempt to address population level effects using approaches that would not be sufficient to
support a full risk assessment, but can be used to support qualitative hazard concerns for the
brominated phthalates. One such study, a long term mesocosm study (de Jourdan et al., 2014;
de Jourdan et al., 2012), demonstrates that the benthic community composition exhibited
significantly lower diversity and greater abundance of Chironomids in cosms treated with 500
ng BZ-54/g sediment compared to the controls and suggests aquatic and/or sediment dwelling
invertebrate populations may be impacted by chronic exposure.
Acute aquatic base-set toxicity data were available for TBPH/TBB that also suggest aquatic
invertebrates as the most sensitive species; however, given the low water solubility and high
Log Kow of TBPH/TBB and the use of solvents and/or test concentrations above the limit of
solubility, there is concern that these effects do not represent environmental conditions. A
single acute fish toxicity study was available for cluster members with a Log Kow of less than 5
that suggests moderate toxicity; however, given results from TBPH/TBB, aquatic invertebrates
are likely more sensitive than fish. Acute experimental data are not available for Confidential A
and Confidential B, but Confidential A is subject to a consent order whose testing is triggered by
production volume.
Commercial products cited in the literature as containing brominated phthalates (i.e.,
Firemaster® 550 and Firemaster® BZ-54) are considered to be known mixtures of the
brominated phthalates/esters TBPH and TBB (Firemaster® BZ-54) (Chemtura, 2013a) or
mixtures of the brominated phthalates/esters TBPH and TBB in addition to triphenyl phosphate
(TPP; CASRN 115-86-6) and isopropylated triphenyl phosphate (ITPP; CASRN 68937-41-7)
(Firemaster® 550) (Chemtura, 2012b). These latter aryl phosphates are considered to have a
mode of action unlike the brominated phthalates cluster and may exert toxic effects on
exposed organisms different than those noted for the brominated phthalates. However,
insufficient experimental data are available to characterize ecotoxicity of the Firemaster® 550
formulation and, thus, a comparison of the more homogenous brominated phthalate
formulations to the more heterogeneous aryl phosphate and brominated phthalate
formulations cannot be made. Risk determination of aryl phosphates is outside the scope of the
brominated phthalates data needs assessment. Screening-level data on these phosphates are
available in (ECHA, 2013; EPA, 2010b; OECD, 2002).
The goal of this data needs assessment is to identify information that is currently needed to
characterize environmental risk. In order to determine whether there are risks to the aquatic,
-------
benthic, and terrestrial environment, both hazard and exposure data are needed to address the
following key questions:
1. How do levels of brominated phthalates measured in effluent and surface water
compare to levels that produce adverse effects in aquatic invertebrates, fish, or plants?
2. How do levels of brominated phthalates measured in sediment compare to levels that
produce adverse effects in sediment invertebrates?
3. How do levels of brominated phthalates measured in soil compare to levels that
produce adverse effects in soil invertebrates and plants?
4. Given the levels of brominated phthalates detected in avian species during
biomonitoring, what is the likely exposure route and at what level are adverse
population level effects expected?
5. Are there persistent or bioaccumulative degradates that may result in a hazard concern?
Based on current knowledge of the class, the additives, i.e. TBPH, TBB and 1,2-
Benzenedicarboxylic acid, l,2-bis(2,3-dibromopropyl) ester (CASRN 7415-86-3) are likely to
exhibit differences in environmental mobility and bioavailability than the remaining cluster
members (reactives) [/.eTBPA-Diol: 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, l-[2-(2-
hydroxyethoxy)ethyl] 2-(2-hydroxypropyl) ester (CASRN 20566-35-2) and TBPA-Diol: 1,2-
Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, mixed esters with diethylene glycol and
propylene glycol (CASRN 77098-07-8)]. Data needs are being assessed for the brominated
phthalate ester clusters separately for TBPH/TBB and the remaining cluster members based on
this perceived difference in transport and bioavailability that will affect testing
recommendations.
Insufficient experimental data are available to assess chronic aquatic, sediment, and terrestrial
hazard across the brominated phthalates cluster. This includes the fish, aquatic invertebrates,
aquatic plants, sediment dwelling organisms, terrestrial invertebrates, terrestrial plants, and
avian taxa. Experimental data to assess all acute aquatic hazard endpoints are limited to
chemicals with a Log Kow of > 5. These data suggest increased sensitivity to aquatic
invertebrates with high hazard concerns even though physicochemical properties suggest
limited bioavailability following acute exposure. Most studies reviewed used a solvent or
emulsifier to solubilize the test substance over time in solution. Use of a solvent may confound
the results when effects are observed, but in all cases a solvent control was included for
comparison.
Given the low water solubility and high log Kow of TBPH and TBB, these cluster members are
expected to be found in the sediment, sludge and soil. Monitoring data are available that
support predicted partitioning to sediment, soil, and sludge and suggest likely chronic exposure.
Organisms likely exposed for which no experimental data are available include sediment
invertebrates and terrestrial organisms (e.g., plants, invertebrates and birds). Based on the
likely long-term exposure, chronic hazard data should be provided. Due to difficulties
interpreting studies of mixtures, experimental data should be conducted on pure substances
(e.g., >90% purity).
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Likely exposure pathways based on predictive and experimental physicochemical and fate
parameters and reported release information for TBPH and TBB suggests minimal persistence
in the water column and limited/no processing or manufacturing releases to water due to
regulatory action. No monitoring data are available to suggest the presences of brominated
phthalates in surface water, but monitoring of biota in water bodies has identified TBB/TBPH in
aquatic organisms suggesting chronic exposure ecotoxicity data for water column organisms
are limited to two chronic aquatic invertebrate studies on TBPH and Firemaster® BZ-54
(TBB/TBPH) that report conflicting results. Since data suggest high chronic hazard to aquatic
invertebrates, data from additional independent chronic aquatic invertebrate studies on TBPH
and TBB are needed to verify chronic aquatic invertebrate toxicity.
The two remaining brominated phthalates cluster members (i.e., CASRNs 20566-35-2 and
77098-07-8) have no monitoring data, little hazard data, and represent the more soluble and
bioavailable members of the cluster. These reactive cluster members are physically
incorporated into end-use products and, thus, less likely to be released to the environment
from their end-use products. Release from manufacturing and processing prior to reactive
incorporation into the end-use product represents a potential pathway of exposure to the
environment. Thus, further characterization of exposure pathways is needed to determine
ecotoxicity data needs for these cluster members.
No data are available for CASRN 7415-86-3.
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Albemarle - GLCC (Albemarle Corporation and Great Lakes Chemical Corporation). 2004. High
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7709-07-8). Baton Rouge, LA and West Lafayette, IN.
http://www.epa.gov/chemrtk/pubs/summaries/12benznd/cl5091tp.pdf.
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Pollution Prevention and Toxics, Washington, DC), July 14, 2010.
Chemtura (Chemtura Corporation). 2012a. TSCA Work Plan Chemicals for Assessment During
2013 and 2014 for 2-Ethylhexyl-2,3,4,5-Tetrabromobenzoate, Bis(2-Ethylhexyl)-3,4,5,6-
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Material Safety Data Sheet, Middlebury, CT.
de Jourdan, B. P., M. L. Hanson, D. C. Muir, and K. R. Solomon. 2014. Fathead Minnow
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EPA (US Environmental Protection Agency). 2010b. Screening-Level Hazard Characterization for
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