# TSCA Work Plan Chemical

Technical Supplement – Hazard Assessment of the Bro minated

Phthalates Cluster (BPC) Chemicals

Brominated Phthalates Cluster

Flame Retardants

CASRN NAME

26040-51-7 1,2-Benzenedicarboxylic acid, 3,4,5,6-te trabromo-, 1,2-bis(2-

ethylhexyl) ester

183658-27-7 Benzoic acid, 2,3,4,5-tetrabromo-, 2-et hylhexyl ester

20566-35-2 1,2-Benzenedicarboxylic acid, 3,4,5,6-te trabromo-, 1-[2-(2-

hydroxyethoxy)ethyl] 2-(2-hydroxypropyl) ester

77098-07-8 1,2-Benzenedicarboxylic acid, 3,4,5,6-te trabromo-, mixed

esters with diethylene glycol and propylene glycol

7415-86-3 1,2-Benzenedicarboxylic acid, 1,2-bis(2,3 -dibromopropyl) ester

* Confidential A

* Confidential B

* Confidential Business Information

August 2015 United States

Environmental Protection Agency EPA Document# 740-Q1-4003

August 2015

Office of Chemical Safety and

Pollution Prevention

# Page 2 of 23



# TABLE OF CONTENTS

TABLE OF CONTENTS .................................

................................................... ......................... 2

1 HUMAN HEALTH HAZARD ...............................

................................................... ............. 3

T OXICOKINETICS



# .................................................. ................................................... ........................................... 3

H AZARD 

# I DENTIFICATION



# .................................................. ................................................... ............................... 8

D ATA 

# N EEDS 

# A SSESSMENT



# .................................................. ................................................... ........................... 16



# 2 ECOLOGICAL HAZARD .................................

................................................... ............... 17

H AZARD 

# I DENTIFICATION



# .................................................. ................................................... ............................. 17

D ATA 

# N EEDS 

# A SSESSMENT



# .................................................. ................................................... ........................... 19



# REFERENCES ........................................

................................................... ............................. 21

LIST OF TABLES

Table 1-1: Structure of Brominated Phthalates Clust er and Associated Chemicals ....................... 5

Table 1-2: Availability of human health data for th e Brominated Phthalates Cluster ................... 8

Table 1-3: Human Health Data for Brominated Phthala tes Cluster ....................................... ...... 10

Table 2-1: Environmental Effects Data for Brominate d Phthalates Cluster .............................. ... 18

# Page 3 of 23



# 1 HUMAN HEALTH HAZARD

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 DEH P and the cluster members are depicted in

Table 1-1.

1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester (DEHP; CASRN 117-81-7)

The closest structural analog of the cluster member s is 1,2-Benzenedicarboxylic acid, 1,2-bis(2-

ethylhexyl) ester (DEHP; CASRN 117-81-7). It is rea dily absorbed and distributed in the body. Its

metabolism involves several pathways and yields a v ariety 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)phth alate (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 transfer red to mothers’ milk. The relative extent

to which different metabolites are produced and exc reted 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-, 1,2-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-, 1,2-bis(2-ethylhexyl) ester ( TBPH ; CASRN 26040-51-7). Its primary metabolite is

the monoester, mono(2-ethylhexyl) tetrabromophthala te (TBMEHP; CASRN 61776-60-1) which

is then ultimately metabolized to tetrabromophthali c acid (CASRN 13810-83-8). When tested **in**

**vitro** , no metabolites of TBPH were detected in human or rat subcellular fraction s (Roberts **et**

**al** ., 2012). However, in the presence of purified porc ine carboxylesterase, the formation of

TBMEHP was detected. No phase II metabolites of TBM EHP 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 (A CC, 2004) and additional information

was not publicly available from the European Chemic als Agency (ECHA) site (ECHA, 2013).

Benzoic acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl est er (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 di ffers significantly

# Page 4 of 23

from the other cluster members in that its final me tabolite 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-tetrabromobenzo ic 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 o f TBB in humans has not been evaluated

(Roberts et al., 2012).

1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, 1-[2-(2-hydroxyethoxy)ethyl] 2-(2-

hydroxypropyl) ester (CASRN 20566-35-2) and 3,4,5,6 tetrabromo-1,2-benzene dicarboxylic

acid, mixed esters with diethylene glycol and propy lene 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 da ta on the toxicokinetics of these substances

are available. Analogous to the other cluster membe rs, the metabolites are expected to be the

corresponding alcohols and the tetrabromophthalic a cid. 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 a vailable from the European Chemicals

Agency (ECHA) site for CASRN 20566-35-2 (ECHA, 2013 ).

1,2-Benzenedicarboxylic acid, 1,2-bis(2,3-dibromopr opyl) 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 attach ed to the benzene ring but are instead on

the side-chains. The metabolites are expected to b e 2,3-dibromopropanol (CASRN 96-13-9) and

the final metabolite, PA. Two mercapturic acid meta bolites of 2,3-dibromopropanol have been

identified in the urine of treated rats (IARC, 2000 ).Page 5 of 23Table 1-1: Structure of Brominated Phthalates Cluster and Associated ChemicalsCASRNNAMESTRUCTUREMetabolites/Hydrolysis Products117-81-7DEHP:,2-Benzenedicarboxylicacid, ,2-bis(2-ethylhexyl)esterSTRUCTURALANALOGof BPCCLUSTERMEMBERSMEHP[Mono(2-ethylhexyl)tetrabromophthalate;CASRN 4376-20-9]12-ethylhexanol(CASRN 104-76-7)Phthalic acid(CASRN 88-99-3)26040-51-7TBPH: 1,2-Benzenedicarboxylicacid, 3,4,5,6-tetrabromo-, 1,2-bis(2-ethylhexyl)esterTBMEHP[Mono(2-ethylhexyl)tetrabromophthalate;CASRN 61776-60-1; noton TSCA inventory]2-ethylhexanol(CASRN 104-76-7)Tetrabromophthalic acid(CASRN 13810-83-8)1CSID:19208, http://www.chemspider.com/Chemical-Structure.19208.html (accessed 15:06, Sep 9, 2013)OHOBrBrBrBrOOHPage 6 of 23CASRNNAMESTRUCTUREMetabolites/Hydrolysis Products183658-27-7TBB: Benzoic acid,2,3,4,5-tetrabromo-,2-ethylhexyl ester2-ethylhexanol(CASRN 104-76-7)Tetrabromobenzoicacid(TBBA: CASRN27581-13-1)20566-35-2TBPA-Diol: 1,2-Benzenedicarboxylicacid, 3,4,5,6-tetrabromo-, 1-[2-(2-hydroxyethoxy)ethyl]2-(2-hydroxypropyl)esterHOCH2CH2OCH2CH2OHDiethylene glycol(CASRN 111-46-6)CH3-CHOHCH2OHPropylene Glycol(CASRN 57-55-6)Tetrabromophthalicacid(CASRN 13810-83-8)77098-07-8TBPA-Diol(MixedEsters): 1,2-Benzenedicarboxylicacid, 3,4,5,6-tetrabromo-, mixedesters with diethyleneglycol and propyleneglycolHOCH2CH2OCH2CH2OHDiethylene glycol(CASRN 111-46-6)CH3-CHOHCH2OHPropylene Glycol(CASRN 57-55-6)Tetrabromophthalicacid(CASRN 13810-83-8)OHOBrBrBrBrOOHOHOBrBrBrBrOOHPage 7 of 23CASRNNAMESTRUCTUREMetabolites/Hydrolysis Products7415-86-3Bromo Alkyl Ester:1,2-Benzenedicarboxylicacid, 1,2-bis(2,3-dibromopropyl) ester2,3-dibromo-1-propanol(CASRN 96-13-9)Phthalic acid(CASRN 88-99-3)CONFIDENTIAL ACONFIDENTIAL BPage 8 of 23Hazard IdentificationThe available hazard data for the BPC cluster members are summarized in Table 1-3 and Table 2-1. Table1-3 also shows somehazard 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 ClusterBrominated Phthalates Cluster MembersEndpointCASRN26040-51-72CASRN183658-27-73CASRN20566-35-24CASRN77098-07-85CASRN7415-86-3ConfidentialAConfidentialBTBPH: 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, 1,2-bis(2-ethylhexyl)esterTBB: Benzoicacid, 2,3,4,5-tetrabromo-,2-ethylhexylesterTBPA-Diol: 1,2-Benzenedicarboxylic acid,3,4,5,6-tetrabromo-,1-[2-(2-hydroxyethoxy)ethyl] 2-(2-hydroxypropyl)esterTBPA-Diol: 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-,mixed esterswith diethyleneglycol andpropylene glycol1,2-Benzenedicarboxylic acid, 1,2-bis(2,3-dibromopropyl)esterAcute OralToxicityLD50(mg/kg)X—ECHAX———Acute DermalToxicity LD50(mg/kg)X—ECHAX———2Screening-level data available from the HPV Challenge submission:http://www.epa.gov/hpv/pubs/summaries/phthacid/c15484tc.htm3Data available for Firemaster BZ 54 (TBB/TBPH mixture)4Screening-level data are available from ECHA [(European Chemicals Agency):http://apps.echa.europa.eu/registered/data/dossiers/DISS-9ea569d1-072b-18abe044-00144f67d031/DISS-9ea569d1-072b-18ab-e044-00144f67d031_DISS-9ea569d1-072b-18ab-e044-00144f67d031.html] For risk assessment, the adequacyof these data is indeterminable without access to the full studies.5Screening-level data available from the HPV Challenge submission:http://www.epa.gov/chemrtk/pubs/summaries/12benznd/c15091tc.htmPage 9 of 23Brominated Phthalates Cluster MembersEndpointCASRN26040-51-72CASRN183658-27-73CASRN20566-35-24CASRN77098-07-85CASRN7415-86-3ConfidentialAConfidentialBAcuteInhalationToxicityLC50(mg/L)———X———Repeated-DoseToxicityOralNOAEL/LOAEL(mg/kg-day)X ——————ReproductiveToxicityNOAEL/LOAEL(mg/kg-day)———————DevelopmentalToxicityNOAEL/LOAEL(mg/kg-day)———————GeneticToxicity –Gene MutationIn vitroX —ECHAX———GeneticToxicity –ChromosomalAberrationsIn vitroX——————GeneticToxicity –ChromosomalAberrationsIn vivoX——————Skin IrritationX——————Page 10 of 23Brominated Phthalates Cluster MembersEndpointCASRN26040-51-72CASRN183658-27-73CASRN20566-35-24CASRN77098-07-85CASRN7415-86-3ConfidentialAConfidentialBEye IrritationX——————SensitizationX——————X denotes available data; - denotes no adequate dataTable 1-3: Human Health Data for Brominated Phthalates ClusterBrominated Phthalates Cluster MembersEndpointCASRN117-81-76CASRN26040-51-77CASRN183658-27-7CASRN20566-35-28CASRN77098-07-89CASRN7415-86-3DEHP: 1,2-Benzendicarboxylicacid, 2-bis(2-ethylhexyl ester)TBPH: 1,2-Benzenedicarboxylic acid,3,4,5,6-tetrabromo-, 1,2-bis(2-ethylhexyl) esterTBB: Benzoic acid,2,3,4,5-tetrabromo-, 2-ethylhexyl esterTBPA-Diol: 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, 1-[2-(2-hydroxyethoxy)ethyl] 2-(2-hydroxypropyl)esterTBPA-Diol: 1,2-Benzenedicarboxylicacid, 3,4,5,6-tetrabromo-, mixedesters with diethyleneglycol and propyleneglycol1,2-Benzenedicarboxylic acid, 1,2-bis(2,3-dibromopropyl)esterAcute OralToxicityLD50(mg/kg)>20,000 >5000(>95%)—>2000(Saytex RB 7920566-35-2)>10,000(PM-PHT-4 Diol)—(Firemaster® BZ-54)10>50006ECHA:http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7eba3b-31b2-3fd1-e044-00144f67d249/DISS-9c7eba3b-31b2-3fd1-e044-00144f67d249_DISS-9c7eba3b-31b2-3fd1-e044-00144f67d249.html7HPV Challenge submission:http://www.epa.gov/hpv/pubs/summaries/phthacid/c15484tc.htm8ECHA:http://apps.echa.europa.eu/registered/data/dossiers/DISS-9ea569d1-072b-18ab-e044-00144f67d031/DISS-9ea569d1-072b-18ab-e044-00144f67d031_DISS-9ea569d1-072b-18ab-e044-00144f67d031.htmlFor risk assessment, the adequacy of these data isindeterminable without access to thefull studies.9Screening-level data available from the HPV Challenge submission:http://www.epa.gov/chemrtk/pubs/summaries/12benznd/c15091tc.htm10(NICNAS, 2004)Page 11 of 23Brominated Phthalates Cluster MembersEndpointCASRN117-81-76CASRN26040-51-77CASRN183658-27-7CASRN20566-35-28CASRN77098-07-89CASRN7415-86-3Acute DermalToxicity LD50(mg/kg)19,800 >3090(>95%)—>20,000(FM-PHT-4 Diol20566-35-2)>20,000(PM-PHT-4 Diol)—(Firemaster® BZ-54)14>2000AcuteInhalationToxicityLC50(mg/L)10,620 [LC0](mg/m3)— —>0.008(FM-PHT-4 Diol20566-35-2)— —Repeated-DoseToxicityOralNOAEL/LOAEL(mg/kg-day)(rat; diet chronic)NOAEL=29-36LOAEL=146-181(rat; 28-d diet)NOAEL =223(2000 ppm)LOAEL = 2331(20,000 ppm)(>95%)—— — —(Firemaster® BZ-54)14Rat (28-d gavage)NOEL = Not establishedLOEL = 160Repeated-DoseToxicityInhalationNOAEC/LOAEC(mg/L-day)NOAEC=50 mg/m3LOAEC=1000 mg/m3——— ——ReproductiveToxicityOralNOAEL/LOAEL(mg/kg-day)(Rat; 3-gen)NOAEL=46-48LOAEL=359-391(parental)NOAEL(offspring)=1.4LOAEL(offspring)=4.8-4.9(Rat; 2-gen)NOAEL=165 (highest dose tested)NOAEL(parental) = 50LOAEL(parental) =165NOAEL(off-spring)=50LOAEL(off-spring)=165(Firemaster® BZ-54)14— — —Page 12 of 23Brominated Phthalates Cluster MembersEndpointCASRN117-81-76CASRN26040-51-77CASRN183658-27-7CASRN20566-35-28CASRN77098-07-89CASRN7415-86-3DevelopmentalToxicityNOAEL/LOAEL(mg/kg-day)MaternalToxicityDevelopmentalToxicity(Rat)NOAEL = 200LOAEL =1000NOAEL=200LOAEL=1000(Rat)NOAEL = 50LOAEL =100NOAEL=50LOAEL=100(Firemaster® BZ-54)14———GeneticToxicity –Gene MutationIn vitro— Negative(>95%)—Negative(Saytex RB 7920566-35-2)Negative(Saytex RB 79)—GeneticToxicity –ChromosomalAberrationsIn vitroNegative(SCE)Positive(>95%)————GeneticToxicity –ChromosomalAberrationsIn vivoNegative Negative(>95%)————Skin IrritationSlightly irritatingSlightly irritating(>95%)————Eye Irritation— Slightly irritating(>95%)————SensitizationNot sensitizing(skin orrespiratory)Not sensitizing(>95%)————CarcinogenicityPositive(rat)—————Measured data in bold; NE = Not established; — indicates no data or no reliable data for this endpoint;(%) = % purity or identity of thetest substance

# Page 13 of 23

1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester (DEHP; CASRN 117-81-7)

Several assessments are available on the toxicity a nd risks of phthalates. EPA has published a

screening-level hazard characterization for phthala te esters (EPA, 2010a) and has revised the

action plan for phthalates (EPA, 2012d); both of wh ich 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 t oxicologically active monoester (Springer

et al., 2012). DEHP is a known peroxisome prolifera tor 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 (PPARα) (Ward **et al** ., 1998 cited in Springer

**et al** ., 2012). The developing male reproductive system i n rats is highly sensitive to the effects

of these phthalates, which decrease fetal male test osterone 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 fol lowing: there is serious concern that

certain intensive medical treatments of male infant s may result in DEHP exposure levels that

adversely affect development of the male reproducti ve tract, there is concern for adverse

effects on development of the reproductive tract in male offspring of pregnant and

breastfeeding women undergoing certain medical proc edures involving high DEHP exposures,

there is concern for the effects of DEHP exposure o n the development of the male reproductive

tract for infants less than one year old and less s o for male children older than one year old and

there is concern for adverse effects of DEHP exposu re on development of the male

reproductive tract in male offspring of pregnant wo men not medically exposed to DEHP and

some concern for reproductive toxicity in adults ex posed to DEHP at 1-30 μg/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 bro minated phthalate esters.

1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, 1,2-bis(2-ethylhexyl) ester (TBPH; CASRN

26040-51-7)

**bis** (2-Ethylhexyl)-3,4,5,6-tetrabromophthalate ( TBPH) exhibits low acute toxicity to rats and

rabbits via the oral and dermal routes, respectivel y. It is slightly irritating to the skin and eyes i n

rabbits and was not a skin sensitizer in guinea pig s. In a dietary repeat-dose study in rats, there

was a slight body weight decrease in females and c linical biochemistry perturbations

(decreased alanine aminotransferase activity, decre ased calcium and decreased phosphorus

levels) at the highest concentration tested (2331 m g/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/development al toxicity endpoint.

In a non-guideline study, Springer **et al** ., (2012) compared the toxicity of the primary meta bolite

of TBPH [mono(2-ethylhexyl) tetrabromophthalate (TBMEHP; C ASRN 61776-60-1)] with that of

DEHP [mono (2-ethylhexyl)phthalate (MEHP; CASRN 437 6-20-9)]. Dust collected from homes,

offices, and cars was measured for TBPH by gas chromatography followed by mass

spectrometry. Pregnant rats were gavaged with TBMEH P (200 or 500 mg/kg) or corn oil on

gestational days 18 and 19, and dams and fetuses we re evaluated histologically for toxicity.

TBMEHP was also evaluated for deiodinase inhibition using rat liver microsomes and for

# Page 14 of 23

peroxisome proliferator-activated receptor (PPAR) α and γ activation using murine FAO cells

and NIH 3T3 L1 cells. They found that in contrast t o DEHP, TBMEHP did not exhibit antiandrogenic activity. However, it did exhibit liver toxicity attributable to a PPAR α mode of action

which is similar to that observed for DEHP/MEHP.

Benzoic acid, 2,3,4,5-tetrabromo-, 2-ethylhexyl est er (TBB; CASRN 183658-27-7)

Limited toxicity data are available for Benzoic aci d, 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 com mercial product is a mixture of TBB and 2-

ethylhexyl tetrabromophthalate ( TBPH ; CASRN 26040-51-7) (Chemtura, 2010). Firemaster® B Z54 exhibits low acute toxicity via the oral and der mal routes of exposure. In a 28-day repeated

dose study in rats, kidney effects (cortical tubula r epithelial regeneration) and increased levels

of mean serum chloride were observed at all dose le vels. The females appeared more sensitive

to the test substance (significant differences in o rgan weights, changes in clinical chemistry

parameters, decreased in mean body weight gain); th e no observed adverse effect level was

not determined. The lowest observed effect level wa s 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 gai n 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 pr emating body weights of the first female

generation. Another effect of treatment was lower s pleen weights at lactation day 21 in the

first generation male pups and both pup sexes of th e second generation. There were no

adverse effects on reproductive performance or fert ility in rats in this study up to the highest

dose tested (165 mg/kg-day). Based on these observa tions, the NOAEL for 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 F iremaster®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 weig ht gain, and lower gestation food

consumption at doses greater than or equal to 100 m g/kg-day. Fetal body weights were lower

than controls at these doses. At 300 mg/kg-day, exa mination of the fetuses indicated fused

cervical vertebral neural arches which were conside red treatment-related (litter incidence of

8%). In addition, there was also an increased litte r incidence for fetal ossification variations

involving additional ossification centers to the ce rvical vertebral neural arches, incomplete

ossified skull bones (jugal, parietal, and squamosa l), and unossified sternebrae. Based on these

observations, the NOAEL for maternal and developmen tal toxicity were designated 50 mg/kgday.

# Page 15 of 23

1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, 1-[2-(2-hydroxyethoxy)ethyl] 2-(2-

hydroxypropyl) ester (CASRN 20566-35-2) and 3,4,5,6 tetrabromo-1,2-benzene dicarboxylic

acid, mixed esters with diethylene glycol and propy lene 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, 1,2-bis(2,3-dibromopr opyl) 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 Confi dential B.

Commercial Products (Firemaster® 550 and Firemaster ® BZ-54)

The commercial product cited in the literature (Fir emaster® 550) is comprised of a mixture of

two of the members of the brominated phthalates clu ster ( TBPH and TBB ) as well as two

phosphates: triphenyl phosphate ( TPP ; CASRN 115-86-6) and isopropylated triphenyl phosp hate

( ITPP ; CASRN 68937-41-7) (Chemtura, 2012b). Available sc reening-level data on these

phosphates (ECHA, 2013; EPA, 2010b; OECD, 2002) sug gest that these constituents pose a

hazard to human health and the environment. Firema ster® 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, m ice, rabbits and guinea

pigs) and dermal (rabbits) routes. TPP is not irrit ating to the skin and is slightly irritating to the

eyes. There is evidence (case reports) of skin sens itization in humans. Oral repeat dose studies

in rats showed a slight depression in body weight g ain 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 fo und 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 assa y (OECD, 2002).

Isopropylated triphenyl phosphate (ITPP; CASRN 6893 7-41-7)

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 rel iable for the EPA hazard characterization

(EPA, 2010b). In the submission to the European Che micals Agency (ECHA, 2013), data for

several commercial products suggest that ITPP exhib its chronic toxicity. In addition, data from

an oral gavage reproductive/developmental toxicity screening test showed that rats treated

with Reofos 65 exhibited poor reproductive performa nce at 400 mg/kg-day (only dose tested)

(ECHA, 2013). In a combined repeated-dose/reproduct ive/developmental toxicity screening test

with the same compound, rats exhibited increased ov ary/oviduct, adrenal gland (males and

# Page 16 of 23

females) and liver (males only) weights and decreas ed epididymal weights with corresponding

macroscopic and/or microscopic changes in these tis sues at 25 mg/kg-day. The NOAEL for

systemic toxicity was not established. Male and fem ale 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 i ndices. Early postnatal development was also

affected at dose levels of 100 and 400 mg/kg/day. T he number of pups born and live litter size

were decreased in these groups, while the numbers o f 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-da y.



# Data Needs Assessment

The potential for exposure to the brominated phthal ates cluster (BPC) members during

chemical manufacture is not clearly understood. Sim ilarly, there is evidence for potential

exposure to some of the cluster members during occu pational use of products containing some

of the cluster members. There is also evidence to s uggest 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 phthalat es cluster (BPC) members. However,

available data suggest that the mode of action of D EHP 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 hypothesi s. There is uncertainty characterizing the

hazard for the BPC members because the chronic (inc luding reproductive/developmental)

toxicity observed in animal studies with the BPC me mbers 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 screeninglevel dietary study in rats with TBPH (described above), the potential for liver toxicit y was

observed by perturbations in clinical chemistry val ues. However, some liver effects have been

attributed to a mode of action, peroxisome prolifer ation (peroxisome proliferator activated

receptor; PPARα), 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 kidn ey 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 t oxicity studies with TBB alone are available;

# Page 17 of 23

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 exp lored 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

(PPARα) further lowers the potential concern and th e need for data for this chronic toxicity

endpoint.

No data are available for CASRN 7415-86-3. The acut e 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 77 098-07-8. The need for human health data

for these chemicals is dependent on the potential e xposure 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

Hazard Identification

The environmental hazard of brominated phthalates r eviewed and summarized in this section is

based on studies located and reviewed from EPA’s TS CATS databases (public), public literature

searches, and other confidential sources; informati on from confidential sources not already

public were excluded from this assessment. Full stu dy reports were not located for all identified

studies. Available hazard data are summarized in Ta ble 2-1 and described below.Page 18 of 23Table 2-1: Environmental Effects Data for Brominated Phthalates ClusterTest SubstanceCompositionTestOrganismSpeciesTestGuidelineDurationEndpointValue (mg/L)ReferenceFiremaster® BZ-54TBB/TBPHFish**Oncorhynchus mykiss** OECD TG 203 96-h LC50 NES Chemtura (2013a)Daphnid**Daphnia magna** OECD TG 202 48-h EC50 0.42 Chemtura (2013a)Daphnid**Daphnia carinata** 15-d ChV 0.022 Access: UTS Pty Ltd (2003)as cited in NICNAS, 2004Algae**Selenastrum capricornutum** OECD TG 201 96-h EC50ChVNESNESChemtura (2013a)TBPH:1,2-Benzenedicarboxylic acid,3,4,5,6-tetrabromo-, 1,2-bis(2-ethylhexyl) ester>95%TBPHFish**Oncorhynchus mykiss** OECD TG 203 96-h EC50 NES ECHA (accessed 9/2013)Daphnid**Daphnia magna** OECD TG 202 48-h EC50 0.3 IUCLID, 2004 as submittedto the HPV ChallengeProgramDaphnid**Daphnia magna** OECD TG 202 48-h EC50 NES ECHA (accessed 9/2013)Algae**Desmodesmus subspicatus** OECD TG 201 72-hEC50ChVNESNESECHA (accessed 9/2013)PM-PHT-4 Diol:2-(2-hydroxyethoxy) ethyl 2-hydroxy propyl 3,4,5,6tetrabromobenzenedicarboxylateNot StatedFish**Lepomis macrochirus** EPA-660/3-75-009, April,1975.96-h LC50 12 ECHA (under CASRN 20566-35-2 accessed 11/2013)

# In general, insufficient experimental data are avai lable to characterize hazard that would result

from chronic exposure to wildlife populations. Curr ently, information from experimental

studies that address standard aquatic toxicity endp oints are limited to two chronic invertebrate

studies conducted on two different species and two different flame retardant formulations (BZ54 and pure TBPH ) that present conflicting conclusions. Additional studies are available that

attempt to address population level effects using a pproaches 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 ter m mesocosm study (de Jourdan et al., 2014;

de Jourdan et al., 2012), demonstrates that the ben thic 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 s uggests 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; howeve r, given the low water solubility and high

Log K

ow 

# 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 res ults from TBPH/TBB , aquatic invertebrates

are likely more sensitive than fish. Acute experimental data are not available for Confidentia l A

and Confidential B, but Confidential A is subject t o a consent order whose testing is triggered by

production volume.

Commercial products cited in the literature as cont aining brominated phthalates ( **i.e.**

, Firemaster® 550 and Firemaster® BZ-54) are consider ed 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 p hosphate (ITPP; CASRN 68937-41-7)

(Firemaster® 550) (Chemtura, 2012b). These latter a ryl phosphates are considered to have a

mode of action unlike the brominated phthalates clu ster and may exert toxic effects on

exposed organisms different than those noted for th e brominated phthalates. However,

insufficient experimental data are available to cha racterize ecotoxicity of the Firemaster® 550

formulation and, thus, a comparison of the more hom ogenous brominated phthalate

formulations to the more heterogeneous aryl phospha te and brominated phthalate

formulations cannot be made. Risk determination of aryl phosphates is outside the scope of the

brominated phthalates data needs assessment. Screen ing-level data on these phosphates are

available in (ECHA, 2013; EPA, 2010b; OECD, 2002).



# Data Needs Assessment

The goal of this data needs assessment is to identi fy information that is currently needed to

characterize environmental risk. In order to determ ine whether there are risks to the aquatic,

# Page 20 of 23

benthic, and terrestrial environment, both hazard a nd 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 a quatic 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 p lants?

4. Given the levels of brominated phthalates detected in avian species during

biomonitoring, what is the likely exposure route an d 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 additi ves, i.e. TBPH, TBB and 1,2-

Benzenedicarboxylic acid, 1,2-bis(2,3-dibromopropyl ) ester (CASRN 7415-86-3) are likely to

exhibit differences in environmental mobility and b ioavailability than the remaining cluster

members (reactives) [ **i.e** TBPA-Diol : 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo- , 1-[2-(2-

hydroxyethoxy)ethyl] 2-(2-hydroxypropyl) ester (CAS RN 20566-35-2) and TBPA-Diol : 1,2-

Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, mixe d esters with diethylene glycol and

propylene glycol (CASRN 77098-07-8)]. Data needs ar e 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 bioavail ability that will affect testing

recommendations.

Insufficient experimental data are available to ass ess chronic aquatic, sediment, and terrestrial

hazard across the brominated phthalates cluster. Th is includes the fish, aquatic invertebrates,

aquatic plants, sediment dwelling organisms, terres trial invertebrates, terrestrial plants, and

avian taxa. Experimental data to assess all acute a quatic hazard endpoints are limited to

chemicals with a Log K

ow 

# of > 5. These data suggest increased sensitivity t o aquatic

invertebrates with high hazard concerns even though physicochemical properties suggest

limited bioavailability following acute exposure. M ost studies reviewed used a solvent or

emulsifier to solubilize the test substance over ti me in solution. Use of a solvent may confound

the results when effects are observed, but in all c ases a solvent control was included for

comparison.

Given the low water solubility and high log K

ow 

# of TBPH and TBB , these cluster members are

expected to be found in the sediment, sludge and so il. Monitoring data are available that

support predicted partitioning to sediment, soil, a nd sludge and suggest likely chronic exposure.

Organisms likely exposed for which no experimental data are available include sediment

invertebrates and terrestrial organisms (e.g., plan ts, invertebrates and birds). Based on the

likely long-term exposure, chronic hazard data shou ld be provided. Due to difficulties

interpreting studies of mixtures, experimental data should be conducted on pure substances

( **e.g.** , ≥ 90 % purity).

# Page 21 of 23

Likely exposure pathways based on predictive and ex perimental physicochemical and fate

parameters and reported release information for TBPH and TBB suggests minimal persistence

in the water column and limited/no processing or ma nufacturing 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 biot a in water bodies has identified TBB / TBPH in

aquatic organisms suggesting chronic exposure ecoto xicity data for water column organisms

are limited to two chronic aquatic invertebrate stu dies on TBPH and Firemaster® BZ-54

( TBB/TBPH ) that report conflicting results. Since data sugge st high chronic hazard to aquatic

invertebrates, data from additional independent chr onic aquatic invertebrate studies on TBPH

and TBB are needed to verify chronic aquatic invertebrate toxicity.

The two remaining brominated phthalates cluster mem bers ( **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 manufactu ring and processing prior to reactive

incorporation into the end-use product represents a potential pathway of exposure to the

environment. Thus, further characterization of expo sure 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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