AEPA
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United States Office of Chemical Safety and
Environmental Protection Agency Pollution Prevention
Draft Risk Evaluation for
Cyclic Aliphatic Bromides Cluster
(HBCD)
Systematic Review Supplemental File for the TSCA Risk Evaluation:
Data Extraction Tables for Human Health Hazard Studies
Br Br
Br
CASRN
NAME
25637-99-4
Hexabromocyclododecane
3194-55-6
1,2,5,6,9,10-Hexabromocyclododecane
3194-57-8
1,2,5,6-Tetrabromocyclooctane
June 2019
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Hexabromocyclododecane (HBCD)
TABLE OF CONTENTS
1 STUDY DATA EXTRACTION 3
1.1 Key and Supporting Study Data 3
1.2 Animal / In Vivo Data Identified from OPPT Literature Search 15
1.3 Mechanistic / In Vitro Data Identified from OPPT Literature Search 28
1.4 Epidemiological Study Data 35
2
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Hexabromocyclododecane (HBCD)
1 Study Data Extraction
Note: Unacceptable studies not included in data extraction tables
1.1 Key and Supporting Study Data
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Endocrine
Reproductive
Rat,
Crl:CD(SD),
M/F (n=16-
48/group)
Oral, diet
FO males: 0, 10,
101 or
1008 mg/kg-day;
F0 females: 0, 14,
141 or
1363 mg/kg-day;
F1 males: 0, 11,
115 or
1142 mg/kg-day;
F1 females: 0, 14,
138 or
1363 mg/kg-day
F0: 10 weeks
prior to mating
Fl: post-weaning
through necropsy
F1/F2 offspring:
continuous
maternal exposure
throughout
gestation/
lactation
NOAEL = 101
mg/kg-day (M)
LOAEL = 14
mg/kg-day (F)8
Increase in TSH
in F0 females at
low dose;
Decreased T4 in
F0 males and
females at high
dose; increased
incidence of
decreased
thyroid follicle
size in males in
F0 males at mid
dose
(Etna et al..
2008)
High
Endocrine
Reproductive
Rat, Wistar,
M/F (n=6-
10/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started one
spermatogenic
cycle (males: 70
days) or two
estrous cycles
(females: 14 days)
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning through
postnatal week 11
NOAEL = 100
mg/kg-day (M/F)8
No statistically
significant
effects on T3 or
T4 levels,
absolute thyroid
weight or thyroid
histopathology in
males or females
(Van der
Ven et al.
2009)
High
3
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Endocrine
Subchronic
Rat,
Crl:CD(SD)IG
S BR, M/F
(n=10-
20/group)
Oral,
gavage
0, 100, 300 or 1000
mg/kg-day
Exposure started
on approximately
postnatal week 7
for 90 days
followed by a 28-
day recovery
period
LOAEL = 100
mg/kg-day (M)
NOAEL = 100
mg/kg-day (F)8
Decreased T4
levels in males at
low dose and
females at mid
dose
{WIL
Research,
2001,
787787}
High
Endocrine
Short-term
Rat, Wistar,
M/F (n=7-
10/group)
Oral,
gavage
0,0.3, 1,3, 10, 30,
100 or 200 mg/kg-
day
28 days, starting
on postnatal
week 11
BMDLio
[decreased T4] =
55.5 mg/kg-day
(F)8
BMDLio
[increased absolute
thyroid weight] =
1.6 mg/kg-day (F)8
Significant dose-
response trends
for decreased T4
levels and
increased
absolute and
relative thyroid
weight in
females; dose-
dependent
increases in
thyroid
activation (i.e.,
follicle size,
epithelial cell
height,
vacuolation and
nuclear size)
were reported
qualitatively for
males and
females
(Van der
Ven et al.
2006)
High
4
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Endocrine
Develop-
Rat,
Oral, diet
0, 15, 146 or 1505
Maternal
NOAEL = 15
Increased
(Saeeusa ef
High
mental
Crj:CD(SD)IG
S, M/F
(n=20/group)
mg/kg-day
exposure from
GD 10 to PND 20
followed by
8-week non-
exposure period
through postnatal
week 11
mg/kg-day (M),
146 mg/kg-day (F)8
relative thyroid
weight and
decreased T3 in
male offspring at
postnatal week
11 at mid dose;
increased
incidence of
thyroid follicular
cell hypertrophy
in maternal
females at high
dose
al. 2009)
Endocrine
Short-term
Mouse,
BALB/c, F
(n=6-8)
Oral, diet
0 or 199 mg/kg-
day
28-day exposure
starting on PND
26
LOAEL = 199
mg/kg-day (F)8
Increased
follicle: colloid
ratio
{Maranghi,
2013,
1927558}
High
Immune
Short-term
and
mechanistic
Mouse,
BALB/c, F
(n=6-7/group)
Oral, diet
Approximately
1700 mg/kg-day,
based on average
food consumption
and body weight (0
or 1% HBCD)
28 days
NOAEL = 1700
mg/kg-day (F)8
No changes in
functional
immune
endpoints in
respiratory
syncytial virus -
infected mice
(infectivity based
on viral titers,
lung histology,
cytokine levels,
numbers of BAL
and spleen cell
populations)
{Watanabe,
2010,
1927692}
Medium
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Hepatic
Reproductive
Rat,
Crl:CD(SD),
M/F (n=26-
48/group)
Oral, diet
FO males: 0, 10,
101 or
1008 mg/kg-day;
F0 females: 0, 14,
141 or
1363 mg/kg-day;
F1 males: 0, 11,
115 or
1142 mg/kg-day;
F1 females: 0, 14,
138 or
1363 mg/kg-day
F1 offspring: 0, 17,
168 or
1570 mg/kg-day;
F2 offspring: 0, 15,
139 or
1360 mg/kg-day
F0: 10 weeks
prior to mating
Fl: post-weaning
through necropsy
F1/F2 offspring:
continuous
maternal exposure
throughout
gestation/
lactation
NOAEL = 10
mg/kg-day (M), 14
mg/kg-day (F)8
Increased
relative liver
weight in F0, Fl
and F2 males
and Fl females
at mid dose
CEina et al.„
2008)
High
Hepatic
Reproductive
Rat, Wistar,
M/F (n=8-
10/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started one
spermatogenic
cycle (males: 70
days) or two
estrous cycles
(females: 14 days)
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning through
postnatal week 11
BMDLio — 8.6
mg/kg-day (F)8
Significant dose-
response trend
for decreased
ALP activity in
females
(Van der
Ven et al.
2009)
High
6
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Hepatic
Subchronic
Rat,
Crl:CD(SD)IG
S BR, M/F
(n=19-
20/group)
Oral,
gavage
0, 100, 300 or 1000
mg/kg-day
Exposure started
on approximately
postnatal week 7
for 90 days
followed by a 28-
day recovery
period
LOAEL = 100
mg/kg-day (M/F)9
Increased
relative liver
weight and
hepatocellular
vacuolization in
males and
females at low
dose; decreased
ALP in females
at low dose
{WIL
Research,
2001,
787787}
High
Hepatic
Short-term
Rat, Wistar,
M/F (n=6-
10/group)
Oral,
gavage
0,0.3, 1,3, 10, 30,
100 or 200 mg/kg-
day
28 days, starting
on postnatal
week 11
BMDLio [ALP
activity] = 18.9
mg/kg-day (F)8
BMDL20 [absolute
liver weight] =
22.9 mg/kg-day
(F)8
Significant dose-
response trend
for increased
absolute liver
weight and
decreased ALP
activity in
females
(Van der
Ven et al.
2006)
High
Hepatic
Short-term
Rat, Sprague-
Dawley, M/F
(n=12/group)
Oral,
gavage
0, 125, 350 or 1000
mg/kg-day
28-day exposure
starting at
approximately
postnatal week 6
followed by a 14-
day recovery
period
LOAEL = 125
mg/kg-day (M/F)8
Increased
relative liver
weight in
females at low
dose; decreased
ALT in males at
low dose
{WIL
Research,
1997,
787758}
High
Hepatic
Develop-
mental
Rat,
Cij:CD(SD)IG
S, M/F
(n=20/group)
Oral, diet
0, 15, 146 or 1505
mg/kg-day
Maternal
exposure from
GD 10 to PND 20
followed by
8-week non-
exposure period
through postnatal
week 11
NOAEL = 146
mg/kg-day (M/F)8
Increased
relative liver
weight and
increased
incidence of
hepatocellular
vacuolar
degeneration in
male and female
offspring on
PND 20 at high
dose
(Saeeusa et
al. 2009)
High
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Species/
Effect
Study Type
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Hepatic
Short-term
Mouse,
Oral, diet
0 or 199 mg/kg-
28-day exposure
LOAEL = 199
Increased
{Maranghi,
High
BALB/c, F
day
starting on PND
mg/kg-day (F)8
relative liver
2013,
(n=10-15)
26
weight and
increased
incidences of
periportal
lymphatic
infiltration,
tissue congestion
and vacuolation
in hepatocytes
1927558}
Neurological
Reproductive
Rat,
Oral, diet
F1 males: 0, 11,
F0: 10 weeks
NOAF.L =115
Decreased
(Etna et al..
High
Crl:CD(SD),
115 or
prior to mating
mg/kg-day (M),
surface righting
2008)
M,F (n=13-24
1142 mg/kg-day;
Fl: post-weaning
138 mg/kg-day (F)8
response time in
litters
F1 females: 0, 14,
through necropsy
Fl males at the
evaluated for
138 or
F1/F2 offspring:
high dose;
surface
1363 mg/kg-day;
continuous
decreased mid-
righting reflex
F1 offspring: 0, 17,
maternal exposure
air righting
response time
168 or
throughout
reflex
and mid-air
1570 mg/kg-day;
gestation/
completion rate
righting reflex
F2 offspring 0, 15,
lactation
in F2 females at
rate; n=20-
139 or
high dose;
46/group
1360 mg/kg-day
decreased
evaluated for
absolute brain
T-maze swim
weight in Fl and
test trial time
F2 males and
and brain
females at high
weight)
dose
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Neurological
Develop-
mental
Rat, Long-
Evans, M/F
(n=8-10 litters
evaluated for
righting reflex,
grip strength
and tail pinch
response;
n=4/group
evaluated for
go/no-go task
and random
ratio task)
Oral,
gavage
0, 3, 10 or
30 mg/kg-day
Fl: continuous
maternal exposure
fromGD 1
throughout
gestation until
parturition
LOAEL = 3
mg/kg-day (M/F)8
Decreased
percentage of
pups (males and
females
combined) per
litter that did not
response to tail
pinch on PNDs
1-21 at low dose
{Miller-
Rhodes,
2014,
2528337}
Medium
Neurological
Acute
Mouse,
NMR1, M
(n=10/group)
Oral,
gavage
0, 0.9 or
13.5 mg/kg
Single dose on
PND 10
LOAEL = 0.9
mg/kg (M)8
Decrease in
horizontal
locomotion and
rearing at 0-20
minutes at low
dose; increase in
Morris water
maze time on
day 4 at low dose
(Ericksson
et al, 2006)
Medium
9
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Neurological
Reproductive
Rat, Wistar,
M/F (n=4-
6/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started at
10 (males) or 20
(females) weeks
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning until
sacrifice (at
approximately
postnatal
week 20)
BMDLs [BAEP] =
0.9 mg/kg-day
(M)8
BMDL20
[catalepsy] = 3.0
mg/kg-day (M), 0.6
mg/kg-day (F)8
Significant dose-
response trends
in brainstem
auditory evoked
potentials
(BAEPs)
(increased click
threshold) inFl
males and
catalepsy (box,
foreleg,
decreased
movement
latency) inFl
males and
females
(Lilienthal et
al. 2009)
High
Neurological
Reproductive
Rat, Wistar,
M/F (n=8-
10/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started one
spermatogenic
cycle (males: 70
days) or two
estrous cycles
(females: 14 days)
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning through
postnatal week 11
BMDL10 = 108.3
mg/kg-day (M)8
Significant dose-
response trend in
brain weight in
Fl males, with
most groups
showing an
increase, relative
to controls
(Van der
Ven et al.
2009)
High
10
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Neurological
Subchronic,
Mechanistic
(study
primarily
reports
mechanistic
endpoints)
Mouse,
C57BL/6J, M
(n=6/treatment
group; n=4
controls)
Oral,
gavage
0 or 25 mg/kg-day
1 time/day for 30
days
NOAEL = 25
mg/kg-day (M)8
No changes in
concentrations of
dopamine or its
metabolites in
striatum tissue
{Genskow,
2015,
2919804}
Medium
Reproductive
Reproductive
Rat,
Crl:CD(SD), F
(n=8-
46/group)
Oral, diet
FO: 0, 14, 141 or
1363 mg/kg-day;
Fl: 0, 14, 138 or
1363 mg/kg-day;
Fl offspring: 0, 17,
168 or
1570 mg/kg-day;
F2 offspring 0, 15,
139 or
1360 mg/kg-day
F0: 10 weeks
prior to mating
Fl: post-weaning
through necropsy
F1/F2 offspring:
continuous
maternal exposure
throughout
gestation/
lactation
NOAEL = 14
mg/kg-day (F)8
Decreased
primordial
follicles inFl
females at mid
dose
(Etna et al.„
2008)
High
Reproductive
Reproductive
Rat, Wistar, F
(n=4-
10/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started one
spermatogenic
cycle (males: 70
days) or two
estrous cycles
(females: 14 days)
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning through
postnatal week 11
BMDLio ~ 82.2
mg/kg-day (F)8
Significant dose-
response trend
for delayed time
to vaginal
opening inFl
females
(van der
Ven et al.
2009)
High
11
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Reproductive
Develop-
mental
Rat,
Crj:CD(SD)IG
S, F (n=10-
14/group)
Oral, diet
0, 15, 146 or 1505
mg/kg-day
Maternal
exposure from
GD 10 to PND 20
followed by an
8-week non-
exposure period
through postnatal
week 11
NOAEL = 1505
mg/kg-day (F)8
No effects on
pregnancy
outcomes (e.g.,
number of
implantation
sites, gestation
duration, litter,
size) in F0
animals or time
to vaginal
opening, AGD or
relative ovary or
uterus weights in
F1 offspring
(Saeeusa ef
al. 2009)
High
Reproductive
Short-term
Mouse,
BALB/c, F
(n=10-
15/group)
Oral, diet
0 or 199 mg/kg-
day
28-day exposure
starting on PND
26
LOAEL = 199
mg/kg-day (F)8
Increased
testosterone and
testosterone/estra
diol levels
{Maranghi,
2013,
1927558}
High
Reproductive
Subchronic
Rat,
Crl:CD(SD)IG
S BR, F
(n=10/group)
Oral,
gavage
0, 100, 300 or 1000
mg/kg-day
Exposure started
on approximately
postnatal week 7
for 90 days
followed by a 28-
day recovery
period
NOAEL = 1000
mg/kg-day (F)8
No effects on
absolute or
relative ovary
with oviduct
weight or uterus
with cervix
weight
{WIL
Research,
2001,
787787}
High
Reproductive
Short-term
Rat, Sprague-
Dawley, F
(n=6/group)
Oral,
gavage
0, 125, 350 or 1000
mg/kg-day
28-day exposure
starting at
approximately
postnatal week 6
followed by a 14-
day recovery
period
NOAEL = 1000
mg/kg-day (F)8
No effects on
relative ovary
with oviduct
weight
{WIL
Research,
1997,
787758}
High
12
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Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Develop-
mental
Reproductive
Rat,
Crl:CD(SD),
M/F (n= 13-
24
litters/group)
Oral, diet
F1 offspring: 0, 17,
168 or
1570 mg/kg-day;
F2 offspring 0, 15,
139 or
1360 mg/kg-day
F0: 10 weeks
prior to mating
Fl: post-weaning
through necropsy
F1/F2 offspring:
continuous
maternal exposure
throughout
gestation/
lactation
NOAEL = 139
mg/kg-day (M), 15
mg/kg-day (F)8
Decreased pup
weight inFl and
F2 males at high
dose; decreased
F2 pup viability
index in litters at
high dose on
PNDs 4 and 21;
delayed eye
opening at mid
dose in F2
females
(Etna et al.„
2008)
High
Develop-
mental
Develop-
mental
Rat,
Crj:CD(SD)IG
S, M/F (n=20-
28/group)
Oral, diet
0, 15, 146 or 1505
mg/kg-day
Maternal
exposure from
GD 10 to PND 20
followed by
8-week non-
exposure period
through postnatal
week 11
NOAEL = 1505
mg/kg-day (M),
146 mg/kg-day
(F)8
Decreased pup
weight inFl
females at
puberty onset
(~PND 35) at
high dose
(Saeeusa et
at 2009)
High
Develop-
mental
Reproductive
Rat, Wistar,
M/F (n=9-
>28/group)
Oral, diet
0,0.1,0.3, 1,3, 10,
30 or 100 mg/kg-
day
F0: exposure
started one
spermatogenic
cycle (males: 70
days) or two
estrous cycles
(females: 14 days)
prior to mating
Fl: continuous
maternal exposure
throughout
gestation/
lactation; dietary
exposure post
weaning through
postnatal week 11
BMDLio [pup
body weight at
necropsy (weaning
age)] =62.7
mg/kg-day (M),
57.9 mg/kg-day
(F)8
BMDLio [tibia
trabecular bone
mineral density] =
0.056 mg/kg-day
(F)8
Significant dose-
response trends
for decreased
body weight in
Fl male and
female pups
(PND 4-21) and
decreased tibia
trabecular bone
mineral density
inFl female
pups at postnatal
week 11
(Van der
Ven et aL
2009)
High
13
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
"able 1. Summary of Key and Supporting Study Data for HBCD
Target
Organ/
System
Study Type
Species/
Strain/Sex
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect
Measured
Reference
Data Quality
Evaluation
Develop-
mental
Develop-
mental
immuno-
toxicity
Rat, Sprague-
Dawley, M
(n=10/group)
Oral, diet
0, 15, 146 or 1505
mg/kg-day
Fl: maternal
exposure from
GD 10 to
postnatal week 3
followed by an 8-
week non-
exposure period
through postnatal
week 11
NOAEL = 1505
mg/kg-day (M)8
No effects onFl
pup weight
{Hachisuka,
2010,
1403765}
Medium
Develop-
mental
Short-term
Mouse,
BALB/c, F
(n=10-
15/group)
Oral, diet
0 or 199 mg/kg-
day
28-day exposure
starting on PND
26
NOAEL = 199
mg/kg-day (F)8
No effects on
body weight gain
{Maranghi,
2013,
1927558}
High
14
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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
1.2 Animal I In Vivo Data Identified from OPPT Literature Search
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Body Weight
Short-term
(1-30 days)
Mouse
Balb/c -
[mouse]
Female
(8/group)
Oral
4.6e-05, 0.107,
116 mg/kg-
bw/day
Not Reported
Not Reported
NOAEL=
0.107 mg/kg -
bw/day
Increased body weight
gain and relative liver
weight; decreased
relative spleen, thymus
and adipose weight;
increased liver
triglycerides and serum
AST, ALT;
microvesicular
accumulation of lipids
(histo. exam.); decreased
serum triglycerides.
Bernhard et
al (2016)
High
Body Weight
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Cardiovascular
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
15
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Cardiovascular
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Clinical
Chemistry/
Biochemical
Short-term
(1-30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Clinical
Chemistry/
Biochemical
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, increased
liver weight, increased
prothrombin time,
albumin, and chloride
ACC
(2002)
High
16
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Clinical
Chemistry/
Biochemical
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, centrilobular
hepatocellular
hypertrophy, increased
liver weight, increased
total protein, decreased
alkaline phosphatase
ACC
(2002)
High
Gastrointestinal
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Gastrointestinal
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
17
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Hematological
and Immune
Short-term
(1-30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Hematological
and Immune
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, increased
liver weight, increased
prothrombin time,
albumin, and chloride
ACC
(2002)
High
Hematological
and Immune
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
18
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Hepatic
Short-term
(1-30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Hepatic
Short-term (1-
30 days)
Mouse
Balb/c -
[mouse]
Female
(8/group)
Oral
4.6e-05, 0.107,
116 mg/kg-
bw/day
Not Reported
Not Reported
NOAEL=
0.107 mg/kg -
bw/day
Increased body weight
gain and relative liver
weight; decreased
relative spleen, thymus
and adipose weight;
increased liver
triglycerides and serum
AST, ALT;
microvesicular
Accumulation of lipids
(histo. exam.); decreased
serum triglycerides.
Bernhard et
High
Hepatic
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, increased
liver weight, increased
prothrombin time,
albumin, and chloride
ACC
(2002)
High
19
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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Hepatic
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, centrilobular
hepatocellular
hypertrophy, increased
liver weight, increased
total protein, decreased
alkaline phosphatase
ACC
(2002)
High
Mortality
Acute (<24
hr)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
5312 mg/kg-
bw/day
Not Reported
LC50 = 5312
mg/m3
Reviewer
Agreed with
Author
No effects were noted in
body weight or signs of
toxicity.
Song et al
(2016)
High
Mortality
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 1000
mg/kg - bw/day
Follicular cell
hypertrophy in thyroid,
decreased T4 levels,
increased prostate gland
weight, decreased
survival
ACC
High
Mortality
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
High
20
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Neurological/Be
havior
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Neurological/Be
havior
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Not Reported
Short-term (1-
30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
21
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Not Reported
Short-term (1-
30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Not Reported
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, increased
liver weight, increased
prothrombin time,
albumin, and chloride
ACC
(2002)
High
Not Reported
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, increased
liver weight, increased
prothrombin time,
albumin, and chloride
ACC
(2002)
High
Not Reported
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, centrilobular
hepatocellular
hypertrophy, increased
liver weight, increased
total protein, decreased
alkaline phosphatase
ACC
(2002)
High
22
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Not Reported
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
LOAEL = 100
mg/kg - bw/day
Hepatocellular
vacuolation, centrilobular
hepatocellular
hypertrophy, increased
liver weight, increased
total protein, decreased
alkaline phosphatase
ACC
(2002)
High
Nutrition and
Metabolic/Adult
Exposure Body
Weight
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Ocular and
Sensory
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
High
Ocular and
Sensory
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
High
23
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Renal
Short-term
(1-30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Renal
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Renal
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
24
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Thyroid
Short-term
(1-30 days)
Rat Other
Female
(6/group)
Oral
0, 3, 30 mg/kg-
bw/day
7 days
Not Reported
NOAEL = 30
mg/kg - bw/day
Liver weight
Miller et al
(2016)
Medium
Reproductive
Short-term
(1-30 days)
Rat
Sprague-
Dawley -
[rat] Both
(5/group)
Inhalation
0, 132,545.8,
2166 mg/kg-
bw/day
6 hours/day 7
days/week
for 14 weeks
NOAEL = 2166
mg/m3
Reviewer
Agreed with
Author
There were no effects of
exposure on clinical
signs, body weight,
hematology and clinical
chemistry parameters,
organ weights (brain,
heart, kidneys, liver,
lungs, trachea, ovaries,
uterus, testis, and
spleen), gross findings,
or microscopic findings
in the brain, heart,
kidneys, liver, lungs
trachea, ovaries, uterus,
testis, or spleen.
Song et al
(2016)
High
Reproductive
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 1000
mg/kg - bw/day
Follicular cell
hypertrophy in thyroid,
decreased T4 levels,
increased prostate gland
weight, decreased
survival
ACC
(2002)
High
25
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Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Reproductive
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL =
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Respiratory
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Respiratory
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0,100, 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
26
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Hexabromocyclododecane (HBCD)
Table 2. Summary of New Animal / In Vivo Data for HBCD
Target
Organ/ System
Study Type
Species/
Strain/Sex
(Number/
group)
Exposure
Route
Doses/
Concentrations
Duration
Author
Reported
Effect Dose/
Concentration/
Result
Reviewer
Reported
Effect Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Skin and
Connective
Tissue
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL = 1000
mg/kg - bw/day
Reviewer
Agreed with
Author
No effects were reported
on neurological/behavior,
body weight, renal,
ocular, gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Skin and
Connective
Tissue
Subchronic
(30-90 days)
Rat Other
Female
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
NOAEL = 1000
mg/kg - bw/day
No effects were reported
on mortality,
neurological/behavior,
body weight,
hematology, renal,
ocular, reproductive,
gastrointestinal,
cardiovascular,
respiratory, or skin
endpoints.
ACC
(2002)
High
Thyroid
Short-term
(1-30 days)
Rat Other
Female
(6/group)
Oral
0, 3, 30 mg/kg-
bw/day
7 days
Not Reported
NOAEL = 30
mg/kg - bw/day
TSH, T3, LH, FSH,
Leptin, and
Cortocosterone levels
Miller et al
Medium
Thyroid
Subchronic
(30-90 days)
Rat Other
Male
(15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 1000
mg/kg - bw/day
Follicular cell
hypertrophy in thyroid,
decreased T4 levels,
increased prostate gland
weight, decreased
survival
ACC
High
Thyroid
Subchronic
(30-90 days)
Rat Other
Female (
15/group)
Oral
0 , 100 , 300 ,
1000 mg/kg-
bw/day
7 days/week
for 90 weeks
NOAEL=
0.048
LOAEL = 300
mg/kg - bw/day
Follicular cell
hypertrophy in thyroid,
decreased T4 levels
ACC
High
27
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Hexabromocyclododecane (HBCD)
1.3 Mechanistic / In Vitro Data Identified from OPPT Literature Search
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
Immune
Short-
term
Human peripheral
blood mononuclear
cells (PBMCs),
monocyte-depleted
peripheral blood
mononuclear cells
(MD-PBMCs), and
natural killer (NK)
cells (4-6 donors, n >
4 replicates)
In vitro
0,0.05,0.1,
0.25,0.5, 1,2.5,
5 nM
24 h, 48 h
and 6 days
No effect up to 5
HM
Cell viability with or
without inhibitors of
NFkB (BAY 11-7085),
MEK !/2 (PD98059), p38
(SB202190), and JNK
(JNKB178D3)
Almughamsi
and Whalen
2016
3350524
(Data not
shown in
report, but
provided in a
supplementary
document
available at
https://Iink.spr
High
inger.com/arti
cle/10.1007%2
Fs0Q2Q4-01S-
1586-6)
Immune
Short-
Human PBMCs,
In vitro
0,0.05,0.1,
24 h, 48 h
LOEC PBMCs
Increased IFN-y
Almughamsi
High
term
MD-PBMCs and NK
cells (4-6 donors, 3
replicates)
0.25,0.5, 1,2.5,
5 nM
and 6 days
and MD-
PBMCs: 0.05
HM
LOEC NK cells:
0.1 nM
(results varied
among donors;
LOEC based on
a significant
effect occurring
in at least one
donor at all
durations)
secretion
and Whalen
2016
3350524
Immune
Short-
Human MD-PBMCs
In vitro
0,0.5, 1,2.5
24 h
Inhibitors of
Increased IFN-y
Almughamsi
High
term
(4 donors, 3
replicates)
HM
NF-kB and MEK
V-i diminished the
ability of HBCD
secretion: effect of
inhibitors of NFkB
(BAY11-7085), MEK !/2
and Whalen
2016
3350524
28
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Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
to increase IFN-y
secretion;
inhibitors of p38
and JNK had no
effect
(PD98059), p38
(SB202190), and JNK
(JNK B178D3)
Immune
Short-
term
Human PBMCs,
MD-PBMCs and NK
cells (3-9 donors,
number of replicates
was not specified)
In vitro
0,0.05,0.1,
0.25,0.5, 1,2.5,
5 nM
24 h, 48 h
and 6 days
LOEC MD-
PBMCs: 5 nM (-
13% of control
cell viability at 6
days);
No effect up to 5
|iIVI in PBMCs
and NK cells;
pathway
inhibitors did not
affect cell
viability
Cell viability with or
without inhibitors of
Caspase 1 (Caspace 1-
inhibitor II), NFkB
(BAY11-7085), MEK !/2
(PD98059), p38
(SB202190), and JNK
(JNKB178D3)
Anisuzzaman
and Whalen
2016
3350463
High
Immune
Short-
term
Human PBMCs,
MD-PBMCs and NK
cells (3-9 donors, 3
replicates)
In vitro
0,0.05,0.1,
0.25,0.5, 1,2.5,
5 nM
24 h, 48 h
and 6 days
LOEC 0.05 nM
for all cell types
(results varied
among donors;
LOEC based on
a significant
effect occurring
in at least one
donor at all
durations)
Increased IL-ip
secretion
Anisuzzaman
and Whalen
2016
3350463
High
Immune
Short-
term
Human MD-PBMCs
(4-9 donors, 3
replicates)
In vitro
0,0.5, 1,2.5
HM
24 h
Inhibitors of
MEK '/2 and p38
reproducibly
diminished the
ability of HBCD
to increase IL-ip
secretion (i.e.,
across donors);
inhibitors of
Caspace 1,
Increased IL-ip
secretion: effect of
inhibitors of Caspace 1
(Caspace 1-inhibitor II),
NFkB (BAY11-7085),
MEK !/2 (PD98059), p38
(SB202190), and JNK
(JNK B178D3)
Anisuzzaman
and Whalen
2016
3350463
High
29
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Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
NFkB and JNK
had no
reproducible
effect onIL-ip
secretion
Immune
Short-
term
Human monocyte-
derived dendritic
cells (7 volunteers, 3
replicates)
In vitro
0,0.1, 1, 10, 20
HM
24 h
No effect up to
20 nM
Cell viability
Canbaz et al.,
2016
3355511
High
Immune
Short-
term
Human monocyte-
derived dendritic
cells (5 volunteers, 3
replicates)
In vitro
0,0.1, 1, 10, 20
HM
24 h
Increased IL-8
LOEC:10 nM
IL-6 and TNFa:
no effect up to
20 uM
Cytokine production (IL-
6, IL-8, TNFa)
Canbaz et al.,
2016
3355511
High
Immune
Short-
term
Human monocyte-
derived dendritic
cells (7 volunteers, 3
replicates)
In vitro
0,0.1, 1, 10, 20
HM
24 h
Increased CD86
LOEC: 10 uM
All other
phenotypes: no
effect up to 20
UM
Expression of
phenotypic cell markers
(CD86, CD80, CD83,
CD40, HLA-DR, CD80 .
CD83+, CD40 )
Canbaz et al.,
2016
3355511
High
Hepatic
Short-
term
Human heptatoma
HepG2 cells (10
replicates)
In vitro
0,0.05,0.5, 1,
5, 10 mg/L
24, 48,
and 72 h
LOEC: 0.05
mg/L at 24 and
72 h (decreased)
Cell viability
Wang et al.,
2016
3350479
High
Hepatic
Short-
term
Human heptatoma
HepG2 cells (6
replicates)
In vitro
0,0.05, 1, 10
mg/L
24 h
LOEC: 0.05
mg/L for
increased
reactive oxygen
species (ROS);
increased
catalase;
decreased long-
chain acyl-CoA
dehydrogenase,
lactate
dehydrogenase,
adenosine-
ROS; oxidative stress
markers (glutathione,
malondialdehyde, total
protein, superoxide
dismutase, catalase);
activity of metabolic
enzymes (metabolomics
analysis)
Wang et al.,
2016
3350479
High
30
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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses/
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
triphosphate
(ATP), Ca2+-
ATPase, Na+/K+-
ATPase
Hepatic
Short-
term
Human hepatocytes
L02 (6 replicates,
experiments repeated
3 times)
In vitro
0, 10"13, 10"11 M
48 h
LOEC: 1013for
ROS; no effect
up to 10"11 Mfor
cell viability and
DNA single
strand breaks;
CYP2B6
induction (tested
at 10"13 M only)
Cell survival, ROS and
DNA single strand
breaks (comet assay);
expression of metabolic
enzymes (CYP1A1,
CYP1B1, CYP2B6)
An et al.,
2016
3350502
High
Hepatic
Short-
term
Human hepatocytes
L02 (6 replicates,
experiments repeated
3 times)
In vitro
0, 50 nM
48 h
Decreased cell
survival and
increased ROS
and DNA single
strand breaks
Cell survival, ROS and
DNA single strand
breaks (comet assay)
An et al.,
2016
3350502
High
Hepatic
Short-
term
Human hepatocytes
L02 (6 replicates,
experiments repeated
3 times)
In vitro
0, 50 |iIVI with
48h of
pretreatment
with 10"13, 10"11
M
48 h
Pretreatment
with low
concentrations of
HBCD produced
an adaptive
response for cell
survival, ROS
and DNA single-
strand breaks
Cell survival, ROS,
DNA single-strand
breaks (comet assay)
An et al.,
2016
3350502
High
Hepatic
Short-
term
Human hepatocytes
L02 (6 replicates,
experiments repeated
3 times)
In vitro
0, 50 |iIVI with
48h of
pretreatment
with 10"13, 1011
M followed by
a 1-hour
treatment with
PI3K inhibitors
LY294002 (10
UM),
48 h
The adaptive
response for cell
survival, ROS
and DNA single-
strand breaks
was eliminated
by pretreatment
with inhibitors of
PI3K andp38
Cell survival, ROS,
DNA single-strand
breaks (comet assay)
An et al.,
2016
3350502
High
31
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Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
wortmannin
(100 nM), MK-
2206 (10 nM)
or p38 inhibitor
SB203580 (10
UM)
Hepatic
Short-
term
Human liver cells
L02 cells (3
replicates,
experiments repeated
3 times)
In vitro
0, 10"7, 10"6, 10-
5 M
24 and 48
h
LOEC: 10"5 M
for (3- and y-
HBCD at 48 h
No effect up to
10"5 M for (3- and
y-HBCD at 24 h
and a-HBCD at
24 or 48 h
Cell viability
Huang et al.,
2016
3545979
Low
Hepatic
Short-
term
Human hepatoma
cells HepG2 (3
replicates,
experiments repeated
3 times)
In vitro
0, 10"7, 10"6, 10-
5 M
24 and 48
h
LOEC: 10"5 M
for (3- and y-
HBCD at
24 and 48 h and
a-HBCD at 48 h
No effect up to
10"5 M for a-
HBCD at 24 h
Cell viability
Huang et al.,
2016
3545979
Low
Hepatic
Short-
term
Human liver cells
L02 cells (3
replicates,
experiments repeated
3 times)
In vitro
0, 10"7, 10"6, 10"
5 M
24 hours
LOEC (3- and y-
HBCD: 10"5 M
No effect up to
10"5 M for a-
HBCD
ROS
Huang et al.,
2016
3545979
Low
Hepatic
Short-
term
Human hepatoma
cells HepG2 (3
replicates,
experiments repeated
3 times)
In vitro
0, 10"7, 10"6, 10-
5 M
24 hours
LOEC (3- and y-
HBCD: 10"6 M
LOEC for a-
HBCD: 10 "5 M
ROS
Huang et al.,
2016
3545979
Low
Hepatic
Short-
term
Human liver cells
L02 cells (3
replicates,
In vitro
0, 10"7, 10"6, 10-
5 M
24 hours
LOEC a- and (3-
HBCD: 10"6 M
LOEC y-HBCD:
10"5M
DNA single-strand
breaks (comet assay)
Huang et al.,
2016
3545979
Low
32
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Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
experiments repeated
3 times)
Hepatic
Short-
Human hepatoma
In vitro
0, 10"7, 10"6, 10-
24 hours
LOEC (3- and y-
DNA single-strand
Huang et al..
Low
term
cells HepG2 (3
replicates,
experiments repeated
3 times)
5 M
HBCD: 10"5 M
No effect up to
10"5 M for a-
HBCD
breaks (comet assay)
2016
3545979
Cancer and
Short-
Human LNCaP
In vitro
0, 10"8, 10"7,
4 days
Increased cell
Cell
Kim et al..
High
Endocrine
term
prostate cancer cells
(3 replicates)
10"6, 10"5 M
growth at 10"8 M
only
viability/proliferation
2016
3350494
Cancer and
Short-
Human LNCaP
In vitro
10"8 M
6 days
Increased cell
Cell
Kim et al..
High
Endocrine
term
prostate cancer cells
(3 replicates)
(co-treated with
Casodex, a non-
steroidal anit-
androgen 10"
9M)
growth blocked
by anti-androgen
viability/proliferation
2016
3350494
Cancer and
Short-
Human LNCaP
In vitro
10"8 M
3 and 5
Enhanced cell
Cell mobility/migration
Kim et al.,
High
Endocrine
term
prostate cancer cells
(3 replicates)
days
migration
2016
3350494
Cancer and
Short-
Human LNCaP
In vitro
10"8 M
24 and 48
Increased mRNA
mRNA and protein
Kim et al..
High
Endocrine
term
prostate cancer cells
(3 replicates)
h
and protein
expression of
cyclinDl;
increased protein
expression of
cyclin E;
decreased
mRNA and
protein
expression of
p27; decreased
protein levels of
bax
expression of cell cycle
(cyclin D1, cyclin E,
p21, p27), apoptosis
(BCL-2, bax) and
metastasis (cathepsin D)
related genes
2016
3350494
Respiratory
Short-
Human bronchial
In vitro
0,0.01,0.1, 1,
24 h
Increased cell
Cell viability/
Koike et al..
High
term
epithelial cells
10 iig/mL
number at 0.1
and 1 ng/mL;
proliferation
2016
3350501
33
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Hexabromocyclododecane (HBCD)
Ta
)le 3. Summary of New Mechanistic / In Vitro Data for HBCD
Target
Organ/
System
Study
Type
Species/
Strain/Cell type
(Number/
Group)
Exposure
Route
Doses /
Concentrations
Duration
Effect
Dose/
Concentration/
Result
Effect Measured
Reference
Data
Quality
Evaluation
(BEAS-2B) (3
replicates)
decreased cell
number at 10
Hg/mL
Respiratory
and Immune
Short-
term
Human bronchial
epithelial cells
(BEAS-2B) (3
replicates)
In vitro
0,0.01, 1, 10
Hg/mL
24 h
LOEC: 10
Hg/mL for
increased
expression of
ICAM-1, IL-6
and IL-8
Expression of
proinflammatory
proteins (ICAM-1, IL-6
and IL-8)
Koike et al.,
2016
3350501
High
Respiratory
and Immune
Short-
term
Human bronchial
epithelial cells
(BEAS-2B) (3
replicates)
In vitro
0, 3 iig/mL in
the presence of
protein kinase
inhibitors (10
(iM) following
lh pretreatment
24 h
Protein kinase
inhibitors
eliminated the
HBCD increases
in IL-6 and IL-8
Change in IL-6 and IL-8
expression by inhibitors
of p38 (SB203580),
MEK (PD98059) and
EGF receptor-selective
tyrosine kinase
(AG1478)
Koike et al.,
2016
3350501
High
Respiratory
and Immune
Acute
Human bronchial
epithelial cells
(BEAS-2B) (3
replicates)
In vitro
0, 1,3, 10
Hg/mL
24 h
LOAEL: 3
Hg/mL
(increased)
EGF production
Koike et al.,
2016
3350501
High
Respiratory
and Immune
Acute
Human bronchial
epithelial cells
(BEAS-2B) (3
replicates)
In vitro
0, 10 ng/mL
15
minutes
Increased
EGF receptor
phosphorylation
Koike et al.,
2016
3350501
High
Respiratory
Acute
Human bronchial
epithelial cells
(BEAS-2B) (3
replicates)
In vitro
0, 10 ng/mL
1-24 hours
Increased
activation of
NFkB and AP-1;
no change in
STAT
Activation of nuclear
transcription factors
NFkB, AP-1, and
STAT
Koike et al.,
2016
3350501
High
34
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Hexabromocyclododecane (HBCD)
1.4 Epidemiological Study Data
Table 4. Summary of Epidemiological Study Data for HBCD
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Neurological/Beha
vior
Reaction time, errors of
omission, errors of
commission, digit symbol total
latency, forward digit span,
backward digit span, and finger
tapping
High school students
(n=515), 13.6-17 years of age
from two industrial areas or
from the general Flemish
population
Serum HBCD (median
-------
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Hexabromocyclododecane (HBCD)
Table 4. Summary of Epidemiological Study Data for HBCD
Target Organ/
System
Outcome/ Endpoint
Study Population
Exposure
Results
Reference
Data Quality
Evaluation
Thyroid
Free T3, free T4, TSH
High school students (n=515)
age 13.6-17 years of age from
two industrial areas (163
from Genk, 178 from Menen)
or from the general Flemish
population (n=174)
Serum HBCD (median
------- |