United States
Environmental Protection
1=1 m m Agency
EPA/690/R-14/012F
Final
7-17-2014
Provisional Peer-Reviewed Toxicity Values for
Perfluorobutane Sulfonate
(CASRN 375-73-5)
and Related Compound
Potassium Perfluorobutane Sulfonate
(CASRN 29420-49-3)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGERS
Evisabel A. Craig, PhD
National Center for Environmental Assessment, Cincinnati, OH
Q. Jay Zhao, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
National Center for Environmental Assessment, Cincinnati, OH
PRIMARY INTERNAL REVIEWERS
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
Suryanarayana Vulimiri, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
1
-------
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iii
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 4
HUMAN STUDIES 7
Oral Exposures 7
Inhalation Exposures 7
ANIMAL STUDIES 7
Oral Exposures 7
Inhalation Exposures 10
OTHER DATA 10
Tests Evaluating Genotoxicity and Mutagenicity 12
Metabolism/Toxicokinetic Studies 12
DERIVATION 01 PROVISIONAL VALUES 12
DERIVATION OF ORAL REFERENCE DOSES 14
Derivation of Subchronic p-RfD 15
Derivation of Chronic Provisional RfD (Chronic p-RfD) 17
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 18
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 19
DERIVATION OF PROVISIONAL CANCER RISK VALUES 19
APPENDIX A. SCREENING PROVISIONAL VALUES 20
APPENDIX B. DATA TABLES 21
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 34
APPENDIX D. REFERENCES 45
li
-------
COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode-of-action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere
Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
POD[adj]
duration-adjusted POD
Number
QSAR
quantitative structure-activity
CBI
covalent binding index
relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEV1
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day
known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase
known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione -S -transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
111
-------
FINAL
7-17-2014
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
PERFLUOROBUTANE SULFONATE (CASRN 375-73-5) AND RELATED COMPOUND
POTASSIUM PERFLUOROBUTANE SULFONATE (CASRN 29420-49-3)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
1
PFBS and related compound
-------
FINAL
7-17-2014
INTRODUCTION
Perfluorobutane sulfonate (PFBS) (CASRN 375-73-5) and its related salt called
potassium perfluorobutane sulfonate (K+PFBS) (CASRN 29420-49-3) are polyfluorinated
compounds (PFCs) manufactured for use in paints, cleaning agents, and water-impermeable
products (Rosal et al.. 2010). Concerns about PFBS and other PFCs stem from the resistance of
these compounds to hydrolysis, photolysis, and biodegradation, which leads to their persistence
in the environment (Sundstrom et al.. 2012). The chemical formula of PFBS is C4HF9O3S and
the chemical formula of K+PFBS is C4F9KO3S. Their respective chemical structures are
presented in Figure 1. K+PFBS differs from PFBS by having a potassium atom. A table of
physicochemical properties for PFBS and K+PFBS is provided below (see Table 1).
F
F F
F F
F
F F
F F
PFBS K+PFBS
Figure 1. Chemical Structures of PFBS and K+PFBS
Table 1. Physicochemical Properties of PFBS (CASRN 375-73-5) and Related Compound
K+PFBS (CASRN 29420-49-3)3
Property (unit)
Value
PFBS (free acid)
K+PFBS (potassium salt)
Boiling point (°C)
200
76-84
Density (g/cm3 at 71°C)
ND
ND
Vapor pressure (mm Hg at 20°C)
ND
9.15 x 10-8
pH (unitless)
ND
ND
Solubility in water (mg/L)
56.6 at 24°C
46.2 at 20°C
Molecular weight (g/mol)
300.10
338.19
Dissociation constant
NA
Fully dissociated in water over
the pH range of 4-9
aNICNAS (2005b).
ND = no data; NA = not applicable.
A summary of available toxicity values for PFBS and related compound K+PFBS from
U.S. EPA and other agencies/organizations is provided in Table 2.
2
PFBS and related compound
-------
FINAL
7-17-2014
Table 2. Summary of Available Toxicity Values for PFBS (CASRN 375-73-5) and
Related Compound K+PFBS (CASRN 29420-49-3)3
Source/Parameter3
Value
(Applicability)
Notes
Reference
Date Accessed
Noncancer
ACGIH
NV
NR
ACGIH (2013)
NA
ATSDR
NV
NR
ATSDR (2013)
NA
Cal/EPA
NV
NR
Cal/EPA (2014a).
2014b)
4-29-2014b
NIOSH
NV
NR
NIOSH (2010)
NA
OSHA
NV
NR
OSHA (2011s).
2006)
NA
IRIS
NV
NR
U.S. EPA
4-29-2014
Drinking water
NV
NR
U.S. EPA (2012a)
NA
HEAST
NV
NR
U.S. EPA (2011a)
NA
CARA HEEP
NV
NR
U.S. EPA (1994)
NA
WHO
NV
NR
WHO
4-29-2014
Cancer
IRIS
NV
NR
U.S. EPA
4-29-2014
HEAST
NV
NR
U.S. EPA (2011a)
NA
IARC
NV
NR
IARC (2013)
NA
NTP
NV
NR
NTP (2011)
NA
Cal/EPA
NV
NR
Cal/EPA (2014b.
(2011)
4-29-2014b
"Sources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical
Assessments and Related Activities; HEAST = Health Effects Assessment Summary Tables; HEEP = Health
and Environmental Effects Profile; IARC = International Agency for Research on Cancer; IRIS = Integrated
Risk Information System; NIOSH = National Institute for Occupational Safety and Health; NTP = National
Toxicology Program; OSHA = Occupational Safety and Health Administration; WHO = World Health
Organization.
bThe Cal/EPA Office of Environmental Health Hazard Assessment (OEHHA) Toxicity Criteria Database
(http://oehha.ca.gov/tcdb/index.asp') was also reviewed and found to contain no information on PFBS.
NA = not applicable; NV = not available; NR = not relevant.
3
PFBS and related compound
-------
FINAL
7-17-2014
Literature searches were conducted on sources published from 1900 through April 2014
for studies relevant to the derivation of provisional toxicity values for PFBS and related
compound K+PFBS. The following databases were searched by chemical name, synonyms, or
CASRN: ACGM, ANEUPL, AT SDR, BIOSIS, Cal/EPA, CCRIS, CDAT, ChemlDplus, CIS,
CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HERO, HMTC,
HSDB, I ARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed, NIOSH, NTIS, NTP, OSHA,
OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology subset), RISKLINE, RTECS,
TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, and
U.S. EPA TSCATS/TSCATS2. The following databases were searched for toxicity values or
exposure limits: ACGM, AT SDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA
HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3 A and 3B provide an overview of the relevant database for PFBS and related
compound K+PFBS and include all potentially relevant repeated-dose, short-term-, subchronic-,
and chronic-duration studies. Principal studies are identified in bold. The phrase "statistical
significance," used throughout the document, indicates ap-value <0.05, unless otherwise noted.
4
PFBS and related compound
-------
FINAL
7-17-2014
Table 3A. Summary of Potentially Relevant Noncancer Data for PFBS (CASRN 375-73-5) and the Related Compound
K+PFBS (CASRN 29420-49-3)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry3
Critical Effects
NO A EL'
BMDL/
BMCLa
LOAEL1
Reference
(Comments)
Notesb
Human
1. Oral (mg/kg-day)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-day)a
Suhch ronic'
10/10, S-D rat, K+PFBS
administered by gavage,
7 days/week, 90 days
0,60, 200, 600
Increased incidence of renal hyperplasia
in males and females
200
78.7
600
Lieder et al.
(2009a)
PR, PS
Chronicd
ND
Developmental
ND
Reproductive
30/30, S-D rat, K+PFBS
administered by gavage,
two-generation reproductive
study
F0 adults: 0, 30,
100, 300, 1,000
F1 adults: 0, 30,
100, 300, 1,000
F0 and F1 adults: increased incidence of
hyperplasia and focal papillary edema in the
kidneys of males and females.
F2 pups: no dose-related effects at the
highest dose tested (1,000 mg/kg-day)
100
26.6 (based
on
increased
incidence
of kidney
hyperplasia
inFO
females)
300
Lieder et al.
f2009M
PR
2. Inhalation (mg/m3)a
ND
aDosimetry: Values expressed in mg/kg-day for oral noncancer effects.
bNotes: PS = principal study; PR = peer reviewed.
°Subchronic = repeated exposure for >90 days < 10% lifespan (based on 70-year typical lifespan).
dChronic = repeated exposure for >10% lifespan.
ND = no data; S-D = Sprague-Dawley.
5
PFBS and related compound
-------
FINAL
7-17-2014
Table 3B. Summary of Potentially Relevant Cancer Data for PFBS (CASRN 375-73-5) and the Related Compound
K+PFBS (CASRN 29420-49-3)
Number of Male/Female,
Strain, Species, Study
BMDL/
Reference
Category
Type, Study Duration
Dosimetry3
Critical Effects
NOAEL
BMCLa
LOAEL1
(Comments)
Notes
Human
1. Oral (mg/kg-day)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-day)
ND
2. Inhalation (mg/m3)
ND
ND = no data.
6
PFBS and related compound
-------
FINAL
7-17-2014
HUMAN STUDIES
Oral Exposures
No studies have been identified for either PFBS or K+PFBS.
Inhalation Exposures
No studies have been identified for either PFBS or K+PFBS.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to K+PFBS were evaluated in one
subchronic-duration and one two-generation reproductive toxicity study. No oral studies in
animals have been identified for PFBS.
Subchronic-duration Studies
Lieder et al. (2009a)
In a peer-reviewed subchronic-duration toxicity study performed by Lieder et al. (2009a).
10 Sprague-Dawley rats/sex/dose were administered K+PFBS daily via gavage for approximately
90 days (90-93 days). Doses of 0, 60, 200, or 600 mg/kg-day K+PFBS were given to rats at
approximately the same time each day. Animals were housed individually in steel,
wire-bottomed cages and fed with Certified Rodent Diet R #5002 (PMI Nutrition International,
Inc, St. Louis, MO) ad libitum throughout the study. K+PFBS (Lot #120k0252, 98.2% pure) was
provided by 3M Company (Maplewood, MN). Dose formulations were prepared by dissolving
K+PFBS in the dosing vehicle, aqueous carboxymethyl cellulose (0.1% CMC, medium
viscosity). The study authors reported using Good Laboratory Practice (GLP) principles as well
as adherence to test guidelines OECD 408 and OPPTS 870.3100.
The rats were observed twice daily during the study: once before dosing and
approximately 1 hour after each dose administration. Detailed clinical observations were
conducted for all rats once before the first dose and at least once weekly thereafter. The eyes of
all rats were examined by a veterinary ophthalmologist prior to the first dose and at termination
of the study. Body weights were recorded prior to treatment, weekly during treatment, and at
sacrifice. Food consumption was determined prior to treatment and weekly during treatment.
Blood was collected on the day following the last administration of the test substance
(Days 91-94 of the study), and the following hematological parameters were evaluated:
erythrocyte count (RBC), hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin
(MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume
(MCV), total leukocyte count (WBC), differential leukocyte count, platelet count (PLAT), mean
platelet volume (MPV), cell morphology, prothrombin time (PT), and activated partial
thromboplastin time (APTT). Two milliliters of blood were processed to obtain serum and
analyze the following clinical chemistry parameters: total protein (TP), triglycerides (TRI),
albumin (A), globulin (G), albumin/globulin ratio (A/G), glucose (GLU), cholesterol (CHOL),
total bilirubin (TBILI), blood urea nitrogen (BUN), creatinine (CREAT), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALK),
calcium (Ca), phosphorus (PHOS), sodium (Na), potassium (K), and chloride (CI). At the
scheduled termination, a gross necropsy of the thoracic, abdominal, and pelvic viscera was
performed. The liver, kidney, spleen, thymus, adrenals, gonads, heart, and brain were weighed.
All tissues from rats in the 0 and 600 mg/kg-day dose groups were histologically examined. In
7
PFBS and related compound
-------
FINAL
7-17-2014
addition, the nasal cavities, nasal turbinates, stomachs, and kidneys of rats in the 60 and
200 mg/kg-day groups were evaluated microscopically.
No treatment-related effects were noted on food consumption, mortality, or behavior.
One male rat in the high-dose group died on Day 85 of the study. However, the study authors
deemed this death to be unrelated to the administration of K+PFBS because the sudden onset of
clinical observations such as urine-stained abdominal fur, decreased motor activity, and
dehydration indicated a possible injury. Body weights for both male and female rats were
similar for all four dose groups throughout the treatment period (see Table B-l). As shown in
Table B-2, males in the 60, 200, and 600 mg/kg-day dose groups showed statistically
significantly decreased (5-17%) absolute and relative spleen weights (spleen-to-body weight
ratio) compared to controls. However, these reductions were not dose dependent and did not
occur in female rats treated with K+PFBS (see Table B-3). No other treatment-related organ
weight effects were observed (see Tables B-2 and B-3). Chloride levels were statistically
significantly increased (3%) in male rats, but not in females, in the 600 mg/kg-day group (see
Table B-4). Also, average total protein and albumin were statistically significantly decreased
(7 and 10%, respectively) in female rats, but not in males, in the 600 mg/kg-day group (see
Table B-4). No other changes in clinical chemistry measurements were reported in male or
female rats. Dose-dependent and statistically significant decreases (5—7.5%) in HGB as well as
HCT levels were observed in males, but not females, in the 200 and 600 mg/kg-day groups (see
Table B-5). There was also a statistically significant decrease {13%) in RBCs in males in the
600 mg/kg-day group (see Table B-5). No other treatment-related changes in hematological
parameters (e.g., MCV, MCH, and MCHC) were reported in males or females; thus, the
biological significance of these small changes in HGB, HCT, and RBC levels is unclear.
Statistically significant histopathological findings included increased incidence of hyperplasia in
the medullary and papillary tubules of the kidneys of both sexes in the 600 mg/kg-day group (see
Table B-6). Hyperplasia and necrosis were also observed in the stomachs of males and females
in the 600 mg/kg-day group (see Table B-6), but the study authors considered this effect to be the
result of repeated gavage dosing. No other biologically significant histopathological findings
were reported. Based on histopathological findings in the kidneys, the high dose of
600 mg/kg-day is considered the lowest-observed-adverse-effect level (LOAEL) and the mid
dose of 200 mg/kg-day is identified as the corresponding no-observed-adverse-effect level
(NOAEL) for both male and female rats.
Chronic-duration Studies
No studies have been identified.
Reproductive Studies
Lieder et al. (2009b)
In a peer-reviewed, two-generation reproductive toxicity study performed by Lieder et al.
(2009b). Sprague-Dawley rats were administered doses of 0, 30, 100, 300, or 1,000 mg/kg-day
K+PFBS (Lot #2, 97.9%) pure) via gavage using formulations that were prepared by dissolving
K+PFBS in aqueous carboxymethyl cellulose with highly purified water. The parental (F0)
generation consisted of 30 rats/sex/group and received daily doses of K+PFBS beginning at
6 weeks of age and lasting until at least 70 days prior to cohabitation. The first generation (Fl)
rats received the same dose as their respective sires and dams beginning at Lactation Day
(LD) 22. Animals were housed individually (except during mating and lactation) in steel,
wire-bottomed cages and fed with Certified Rodent Diet R #5002 (PMI Nutrition International,
8
PFBS and related compound
-------
FINAL
7-17-2014
Inc, St. Louis, MO) ad libitum throughout the study. The study authors reported adherence to
test guidelines OECD 416 and OPPTS 870.3800.
For mating, animals were allowed to cohabitate for a maximum of 14 days. Evidence of
mating was determined by the presence of spermatozoa in a vaginal smear or copulatory plug
and this was considered Gestation Day (GD) 0. For the F0- and Fl-generation rats, clinical
observations, abortions or premature deliveries, and deaths were recorded before dosing and at
60 minutes postdosing. Body weights and food consumption for F0- and Fl-generation rats were
recorded weekly prior to conception; on GDs 0, 7, 10, 14, 18, 21, and 25 (if females did not give
birth); and on LDs 1, 5, 8, 11, 15, and 22. Body weights and food consumption were also
recorded for Fl-generation rats upon attainment of sexual maturation. Second generation (F2)
pup body weights were recorded on LDs 1, 5, 8, 15, and 22. The F0- and Fl-generation rats
were evaluated for duration of gestation, fertility and gestation indices, number and sex of
offspring, number of implantation sites, condition of dams and litters, litter size, viability index,
lactation index, percent survival, and sex ratio. At scheduled termination (after cohabitation for
males and on LD 22 for females), F0- and Fl-generation rats were euthanized by carbon dioxide
(CO2) asphyxiation, necropsied, and examined for gross lesions. The following organs were
individually weighed: brain, kidneys, spleen, ovaries, testes, thymus, liver, adrenal glands,
pituitary, uterus with oviducts and cervix, left epididymis, right epididymis, prostate, and
seminal vesicles. The study authors stated that histopathological evaluations were performed on
the liver and kidneys of all F0 and F1 animals in the control and treatment groups. However,
data were only presented for the 300 and 1,000 mg/kg-day treatment groups. For the pituitary,
adrenal glands, vagina, uterus, cervix, ovaries, right testis, seminal vesicles, right epididymis,
and prostate, histological examinations were only performed on 10 randomly selected rats per
sex from the control and 1,000 mg/kg-day groups. All F2-generation pups culled on LD 22 were
euthanized by CO2 asphyxiation and three randomly selected pups per sex per litter were
examined for gross lesions. The brain, spleen, liver, thymus, and kidneys from one of the three
randomly selected pups per litter were weighed. Fl-generation pups were not examined for
gross lesions.
No biologically significant reproductive effects were observed in F0- or Fl-generation
males following K+PFBS treatment. At the highest dose, there were statistically significant
increases in the percentage of abnormal sperm in F1 animals and decreases in testicular sperm
count in FO-generation males (see Table B-7). However, these effects were not dose dependent
and were observed in only one generation; thus, they were not considered biologically significant
by the study authors. No statistically significant changes in estrous cycling were reported in
F0- or Fl-generation females treated with K+PFBS. No treatment-related weight changes in the
gonads were reported in F0- or Fl-generation males and females. Fertility parameters and
delivery outcomes for F0- and Fl-generation dams remained unaffected by K+PFBS treatment
(see Table B-8). Litter outcomes for Fl- and F2-generation pups such as the mean number of
stillborn pups, mean pup weight at birth, and mean pup weight at weaning did not exhibit
statistically significant changes (see Table B-9). The mean number of live born Fl pups was
statistically significantly decreased in the 30 mg/kg-day group, but this change was not dose
dependent. The viability index in Fl pups and the lactation index in Fl and F2 pups showed
statistically significant changes at various doses but were not dose dependent (see Table B-9).
No significant changes in food consumption were reported in F0- or Fl-generation males.
The terminal body weights of FO-generation males were not affected by K+PFBS treatment (see
9
PFBS and related compound
-------
FINAL
7-17-2014
Table B-10). However, a statistically significant decrease in terminal body weight was noted in
Fl-generation males in the 1,000 mg/kg-day dose group (see Table B-10). Statistically
significant increases in absolute (~12%) and relative (12-21%) liver weight were observed in
FO-generation males in the 300 and 1,000 mg/kg-day dose groups (see Table B-10). In contrast,
Fl-generation males exhibited statistically increased relative liver weight (9%), but not absolute
liver weight, only at the highest dose (see Table B-10). No other statistically significant organ
weight changes were noted in males. With respect to females, the study authors reported
sporadic decreases in food consumption in FO-generation rats in the 300 and 1,000 mg/kg-day
dose groups between GD 10 and GD 14. No changes in food consumption were noted for
Fl-generation females. No statistically significant reductions in body weights were observed in
FO-generation females (see Table B-l 1). Body weight changes in Fl-generation females were
statistically significant but did not reach 10% and were not dose dependent. The organ weights
of F0- and Fl-generation females were not affected by K+PFBS treatment (see Table B-l 1).
Also, no treatment-related changes in body weight or organ weights were observed in
F2-generation pups (data not shown).
There were no treatment-related gross anatomical findings in F0-, F1-, or F2-generation
males and females. Increased incidences of hepatocellular hypertrophy were observed in F0- and
Fl-generation males in the 300 and 1,000 mg/kg-day dose groups (see Table B-12), however
only incidences in the 1,000 mg/kg-day group were statistically significant. Fewer incidences of
these liver effects were observed in Fl-generation males when compared to FO-generation males.
Also, liver effects were not observed in females; thus, the biological significance of the liver
effects in males is unclear. Additional histopathological findings included statistically
significant mild-to-moderate hyperplasia and focal papillary edema in the kidneys of F0- and
Fl-generation males and females in the 300 and 1,000 mg/kg/day dose groups (see Table B-12).
The study authors did not present the incidences of histopathological findings for the
100 mg/kg-day group, although the methods section of the article states that the livers and
kidneys of rats in all dose groups were histologically examined. No histopathological findings
were reported in the F2 generation. Based on kidney histopathology changes observed in F0-
and Fl-generation males and females, 300 mg/kg-day is identified as the LOAEL, with a
corresponding NOAEL of 100 mg/kg-day. No dose-related effects were observed in F1 or
F2 pups, therefore the highest dose of 1,000 mg/kg-day is considered the NOAEL for
reproductive toxicity. Identification of a LOAEL for reproductive toxicity is precluded.
Developmental Studies
No studies have been identified.
Inhalation Exposures
No inhalation studies have been identified on the sub chronic-duration, chronic,
developmental, or reproductive toxicity or on the carcinogenicity of PFBS or K+PFBS in
animals.
OTHER DATA
Other studies that utilized PFBS or K+PFBS are described here. These studies are not
adequate for the determination of provisional reference dose (p-RfD), provisional reference
concentration (p-RfC), provisional oral slope factor (p-OSF), or provisional inhalation unit risk
(p-IUR) values but provide supportive data supplementing a weight-of-evidence approach.
These data may include genotoxicity, metabolism, mechanistic, and other studies (see Table 4).
10
PFBS and related compound
-------
FINAL
7-17-2014
Table 4. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Mutagenicity
test
Salmonella typhimurium (strains TA98 and TA100) and
E. coli (strain pKMlOl) in the presence or absence of S9.
Doses of PFBS were between 0-5,000 |.ig/platc.
Test was negative for TA100 and
pKMlOl strains and equivocal for
TA98 strain.
There is no in vitro evidence of
PFBS mutagenicity.
NTP (2005s)
Genotoxicity test
Human hepatoma (HepG2) cells were treated with
0.4 |_lM to 2 mM PFBS. Intracellular ROS production
was measured by use of 2',7'-dichlorofluorescein
diacetate and DNA damage was measured with the comet
assay.
The amount of ROS and DNA
strand breaks remained unaffected
by PFBS treatment.
PFBS did not generate ROS or
DNA damage in human liver cells.
Eriksen et al.
(2010s)
Metabolism/
toxicokinetic
Blood and urine samples were collected from the
following species: Sprague-Dawley rats (3M/3F) treated
with a single intravenous (i.v.) or oral (gavage) dose of
30 mg K+PFBS/kg body weight; cynomolgus monkeys
(3M/3F) treated with a single i.v. dose of 10 mg
K+PFBS/kg body weight; and human workers (5M/1F)
engaged in the production of K+PFBS prior to study
initiation but not during 6 mo of follow-up.
The mean terminal serum
elimination half-life of K+PFBS is
3.96-4.51 hours in rats,
83.2-95.2 hours in monkeys, and
25.8 days in humans.
K+PFBS appears to be eliminated
at a slower rate in humans than in
monkeys or rats.
Olsen et al.
(2009)
11
PFBS and related compound
-------
FINAL
7-17-2014
Tests Evaluating Genotoxicity and Mutagenicity
PFBS was negative for mutagenicity in E. Coli strain pKMlOl and Salmonella
typhimurium strain TA100 CNTP. 2005). Mutagenicity test results were equivocal in
S. typhimurium strain TA98. PFBS did not generate reactive oxygen species (ROS) or oxidative
DNA damage in HepG2 cells (Eriksen et al.. 2010) (see Table 4).
Metabolism/Toxicokinetic Studies
Olsen et al. (2009) evaluated the toxicokinetics of K+PFBS in Sprague-Dawley rats,
cynomolgus monkeys, and humans. The following parameters were evaluated: (1) elimination of
K+PFBS after intravenous (i.v.) dosing in rats and monkeys; (2) oral uptake and elimination of
K+PFBS in rats; and (3) human serum K+PFBS elimination in a group of workers with
occupational exposure. In rats, the mean terminal serum K+PFBS elimination half-lives, after
i.v. administration of 30 mg/kg K+PFBS, were 4.51 ± 2.22 hours for males and 3.96 ± 0.21 hours
for females. Although there was no statistical difference between the terminal serum half-lives
in male and female rats, clearance was statistically significantly greater in female rats
(469 ± 40 mL/hour) than in male rats (119 ± 34 mL/hour). These differences were not observed
between male and female monkeys. For rats receiving an oral dose, terminal serum K+PFBS
elimination half-lives were 4.68 ± 0.43 hours for males and 7.42 ± 0.79 hours for females. In
monkeys, the mean terminal serum elimination half-lives, after i.v. administration of 10 mg/kg
K+PFBS, were 95.2 ± 27.1 hours in males and 83.2 ± 41.9 hours in females. Based on estimates
obtained for the volume of distribution in rats and monkeys, K+PFBS appears to be primarily
distributed in the extracellular space. Among 6 human subjects (5 male, 1 female) followed up
to 180 days after cessation of further K+PFBS work-related activity, the geometric mean serum
elimination half-life for K+PFBS was 25.8 days (95% confidence interval = 16.6-40.2). These
findings indicate that K+PFBS is eliminated at a slower rate from human serum than from that of
rats or monkeys. Urine appeared to be a major route of elimination in all three species tested.
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
12
PFBS and related compound
-------
FINAL
7-17-2014
Table 5. Summary of Noncancer Provisional Reference Values for PFBS (CASRN 375-73-5) and Related Compound
K+PFBS (CASRN 29420-49-3)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
PODa
UFc
Principal Study
Subchronic p-RfD (mg/kg-day) for K+PFBS (salt)
Rat/F
Increased incidence of
kidney hyperplasia.
2 x KT1
BMDLio
18.9
100
Lieder et al. (2009a)
Subchronic p-RfD (mg/kg-day) for PFBS (free acid)
Rat/F
Increased incidence of
kidney hyperplasia.
2 x KT1
BMDLio
18.9
100
Lieder et al. (2009a)
Chronic p-RfD (mg/kg-day) forK+PFBS (salt)
Rat/F
Increased incidence of
kidney hyperplasia.
2 x 10-2
BMDLio
18.9
1,000
Lieder et al. (2009a)
Chronic p-RfD (mg/kg-day) for PFBS (free acid)
Rat/F
Increased incidence of
kidney hyperplasia.
2 x 10-2
BMDLio
18.9
1,000
Lieder et al. (2009a)
Subchronic p-RfC (mg/m3) forK+PFBS
NDr
Subchronic p-RfC (mg/m3) for PFBS
NDr
Chronic p-RfC (mg/m3) for K+PFBS
NDr
Chronic p-RfC (mg/m3) for PFBS
NDr
aHED expressed in mg/kg-day.
NDr = not determined.
Table 6. Summary of Provisional Cancer Values for PFBS (CASRN 375-73-5) and Related Compound
K+PFBS (CASRN 29420-49-3)
Toxicity Type
p-OSF
p-IUR
Species/Sex
NDr
Tumor Type
Cancer Value
Principal Study
NDr
NDr = not determined.
13
PFBS and related compound
-------
FINAL
7-17-2014
DERIVATION OF ORAL REFERENCE DOSES
The database of oral toxicity studies for PFBS and the related compound K+PFBS
includes one subchronic-duration study and one reproductive toxicity study, both of which were
conducted in rats using the potassium salt (K+PFBS). From the subchronic-duration rat study by
Lieder et al. (2009a). a NOAEL of 200 mg/kg-day and a LOAEL of 600 mg/kg-day were
identified for both males and females based on histopathological findings in the kidneys (mild to
moderate hyperplasia). No treatment-related effects were reported in the liver. Although a
statistically significant decrease in hematocrit and hemoglobin levels was observed at
200 mg/kg-day in male rats, these effects were considered mild, were not accompanied by bone
marrow abnormalities or any other hematological changes, and were only observed in males.
Thus, the biological relevance of these hematological findings is uncertain. The Lieder et al.
(2009a) study was peer-reviewed, used GLP guidelines, and met the standards of study design
and performance with regards to the number of animals used, examination of potential toxicity
endpoints, and presentation of information.
The reproductive toxicity study in rats by Lieder et al. (2009b) identified a NOAEL of
100 mg/kg-day and a LOAEL of 300 mg/kg-day in F0- and Fl-generation animals based on
increased incidences and severity of kidney histopathology observed in both sexes. Although
increased liver weights and hepatocellular hypertrophy were noted in males, these hepatic effects
were not observed in females and no increased response was seen in Fl-generation males when
compared to FO-generation males. Furthermore, no liver changes in either sex were observed in
the subchronic-duration study by Lieder et al. (2009a); thus, the biological relevance of liver
effects in males of the reproductive toxicity study is not clear. Hematological parameters were
not assessed in this study. There were no abnormal clinical or necropsy observations in the
F2 generation. This report was peer-reviewed, employed an adequate number of animals, and
was performed according to U.S. EPA guidelines.
Both the subchronic-duration study by Lieder et al. (2009a) and the reproductive toxicity
study by Lieder et al. (2009b) in rats suggest the kidney as a major target organ of K+PFBS
toxicity, with kidney effects (hyperplasia) observed both in males and females. Thus, increased
incidence of kidney hyperplasia is selected as the critical effect. Benchmark dose (BMD)
analyses were conducted on the kidney hyperplasia data from males and females for both studies
using the U.S. EPA's Benchmark Dose Software (BMDS version 2.3). Results of BMD
modeling are summarized in Appendix C. BMD modeling of the kidney hyperplasia data was
performed using a benchmark response (BMR) of 10%. For kidney hyperplasia data from the
subchronic-duration study by Lieder et al. (2009a). the Exponential model provided the best fit
with a BMDLio of 96.7 mg/kg-day for males and a BMDLio of 78.7 mg/kg-day for females (see
Tables C-l and C-2). Kidney hyperplasia data from the reproductive study by Lieder et al.
(2009b) provided a BMDLio of 73.2 mg/kg-day and a BMDLio of 126 mg/kg-day for FO-
generation and Fl-generation males, respectively (see Tables C-3 and C-4). The reproductive
toxicity study also provided a BMDLio of 26.6 mg/kg-day for FO-generation females and a
BMDLio of 52.4 mg/kg-day for Fl-generation females (see Tables C-5 and C-6) for kidney
hyperplasia, which are lower than the BMDLs obtained with data from the subchronic-duration
study. However, the analyses from the reproductive toxicity study provide less reliable BMD
estimates because they do not contain a data point near the BMR (unlike the subchronic-duration
study), which is recommended for adequate BMD modeling (U.S. EPA. 2012b). Therefore, the
BMDLio of 78.7 mg/kg-day based on increased incidence of kidney hyperplasia in females from
14
PFBS and related compound
-------
FINAL
7-17-2014
the sub chronic-duration study is selected as the point of departure (POD) for derivation of the
subchronic p-RfD.
Derivation of Subchronic p-RfD
The U.S. EPA endorses a hierarchy of approaches to derive human equivalent oral
exposures from data from laboratory animal species, with the preferred approach being
physiologically based toxicokinetic modeling. Another approach may include using
chemical-specific information, including what is known about the toxicokinetics and
toxicodynamics of the chemical, to derive chemical-specific adjustments. In lieu of
chemical-specific information to derive human equivalent oral exposures, U.S. EPA endorses
body-weight scaling to the 3/4 power (i.e., BW3/4) as a default to extrapolate toxicologically
equivalent doses of orally administered agents from all laboratory animals to humans for the
purpose of deriving an RfD under certain exposure conditions (U.S. EPA. 2011b). More
specifically, the use of BW3 4 scaling for deriving an RfD is recommended when the observed
effects are associated with the parent compound or a stable metabolite but not for portal-of-entry
effects or developmental endpoints. Although the pharmacokinetic study by Olsen et al. (2009)
suggests a longer half-life for K+PFBS in humans than in rats, these results were obtained by
single-dose administration and it is uncertain whether this reflects the compound's half-life after
repeated dosing. Furthemore, clearance is a more relevant parameter than serum half-life to
determine chemical elimination, but no information on the clearance rate in humans is provided
by Olsen et al. (2009). Thus, due to a lack of definitive information regarding potential
pharmacokinetic differences between species, the use of BW3 4 scaling to obtain a human
equivalent dose (HED) is considered appropriate in this case.
Following U.S. EPA guidance, the POD for the rat subchronic-duration study is
converted to an HED through an application of a dosimetric adjustment factor (DAF) derived as
follows:
DAF = (BWa1/4 - BWh1/4)
Where:
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a BWa of 0.25 kg for rats and a standard BWh of 70 kg for humans the resulting
DAF is 0.24. Applying this DAF to the BMDLio obtained from modeling the kidney hyperplasia
data from the K+PFBS rat subchronic-duration study yields a BMDLiohed as follows:
BMDLiohed for K+PFBS = BMDLio (mg/kg-day) x DAF
= 78.7 (mg/kg-day) x 0.24
= 18.9 mg/kg-day
The subchronic p-RfD for K+PFBS, based on the BMDLiohed of 18.9 mg/kg-day for
kidney hyperplasia in female rats, is derived as follows:
15
PFBS and related compound
-------
FINAL
7-17-2014
Subchronic p-RfD for K+PFBS = BMDLiohed ^ UFc
= 18.9 mg/kg-day -MOO
= 2 x 10"1 mg/kg-day
The data for K+PFBS can be used to derive a subchronic p-RfD for the free acid (PFBS),
as K+PFBS is fully dissociated in water at the environmental pH range of 4-9 (NICNAS. 2005a).
In order to calculate the subchronic p-RfD for the free acid, the subchronic p-RfD for the
potassium salt is adjusted to compensate for differences in molecular weight between K+PFBS
(338.19) and PFBS (300.10). The subchronic p-RfD for PFBS (free acid) is calculated as
follows:
Subchronic p-RfD = p-RfD for K+PFBS salt x (MW free acid ^ MW salt)
for PFBS (free acid) = 2 x 10_1 mg/kg-day x (300.10 338.19)
= 2 x 10_1 mg/kg-day x (0.89)
= 2 x 10"1 mg/kg-day
Table 7 summarizes the uncertainty factors for the subchronic p-RfDs for PFBS and
K+PFBS.
Table 7. Uncertainty Factors for the Subchronic p-RfD for PFBS (CASRN 375-73-5) and
the Related Compound K+PFBS (CASRN 29420-49-3)
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for uncertainty in characterizing the toxicodynamic
differences between mice and humans following oral K+PFBS/PFBS exposure. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent dose (HED) through
application of a dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of
Bodv Weight3/4 as the Default Method in Derivation of the Oral Reference Dose ('U.S. EPA. 2011b).
UFd
3
A UFd of 3 is applied because the database includes one acceptable two-generation reproductive
toxicity studv in rats (Licdcr et al.. 2009b). but there is no acceptable developmental toxicity study
via the oral route.
UFh
10
A UFh of 10 is applied for inter-individual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of K+PFBS/PFBS in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because a subchronic-duration study was selected as the principal study.
UFC
100
Composite Uncertainty Factor = UFA x UFD x UFH x UFL x UFS
The confidence in the subchronic p-RfD for PFBS and K+PFBS is medium as explained
in Table 8 below.
16
PFBS and related compound
-------
FINAL
7-17-2014
Table 8. Confidence Descriptors for Subchronic p-RfD for PFBS (CASRN 375-73-5) and
the Related Compound K+PFBS (CASRN 29420-49-3)
Confidence Categories
Designation3
Discussion
Confidence in study
H
Confidence in the kev studv is hieh. Lieder et al. (2009a)
utilized an adequate subchronic-duration study design in rats.
This study is also peer-reviewed, and experiments were
performed according to GLP guidelines.
Confidence in database
M
The database includes one subchronic-duration study in rats
Lieder et al. (2009a) and one reproductive toxicity studv in
rats (Lieder et al.. 2009b). However, no developmental
toxicity studies have been identified.
Confidence in subchronic p-RfDb
M
The overall confidence in the subchronic p-RfD is medium.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
There are no chronic-duration studies available for PFBS and K+PFBS. Therefore, based
on the same database and similar considerations, the chronic p-RfD for K+PFBS is derived as
follows using the BMDLiohed of 18.9 mg/kg-day for increased incidence of kidney hyperplasia
in female rats from the subchronic-duration study by Lieder et al. (2009a) as the POD:
Chronic p-RfD for K+PFBS = BMDLiohed UFc
= 18.9 mg/kg-day ^ 1,000
= 2 x 10"2 mg/kg-day
The chronic p-RfD for PFBS (free acid) is calculated using the ratio of molecular
weights, as follows:
Chronic p-RfD = p-RfD for salt x (MW free acid ^ MW salt)
for PFBS (free acid) = 2 x 10~2 mg/kg-day x (300.10 338.19)
= 2 x 10~2 mg/kg-day x (0.89)
= 2 x 10"2 mg/kg-day
Table 9 summarizes the uncertainty factors for the chronic p-RfD for PFBS and K+PFBS.
17
PFBS and related compound
-------
FINAL
7-17-2014
Table 9. Uncertainty Factors for the Chronic p-RfD for PFBS (CASRN 375-73-5) and the
Related Compound K+PFBS (CASRN 29420-49-3)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicodynamic
differences between mice and humans following oral K+PFBS/PFBS exposure. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent dose (HED) through
application of a dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use
ofBodv Weight3/4 as the Default Method in Derivation of the Oral Reference Dose fU.S. EPA.
2011b).
UFd
3
A UFd of 3 is applied because the database includes one acceptable two-generation reproductive
toxicity studv in rats (Lieder et al.. 2009b). but there is no acceptable developmental toxicity
study via the oral route.
UFh
10
A UFh of 10 is applied for inter-individual variability to account for human-to-human variability
in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of K+PFBS/PFBS in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
10
A UFS of 10 is applied to extrapolate from less than chronic-duration exposure.
UFC
1,000
Composite Uncertainty Factor = UFA x UFD x UFH x UFL x UFS
The confidence in the chronic p-RfD for PFBS and K+PFBS is medium as explained in
Table 10 below.
Table 10. Confidence Descriptors for Chronic p-RfD for PFBS (CASRN 375-73-5) and
the Related Compound K+PFBS (CASRN 29420-49-3)
Confidence Categories
Designation"
Discussion
Confidence in study
H
Confidence in the kev studv is hieh. Lieder et al. (2009a) utilized
an adequate subchronic-duration study design in rats. This study is
also peer-reviewed, and experiments were performed according to
GLP guidelines.
Confidence in database
M
The database includes one subchronic-duration studv in rats Lieder
et al. (2009a) and one reproductive toxicity studv in rats Lieder et
al. (2009b). However, no developmental toxicity or chronic-
duration studies have been identified.
Confidence in chronic p-RfDb
M
The overall confidence in the subchronic p-RfD is medium.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No suitable published studies investigating the effects of subchronic- or chronic-duration
inhalation toxicity of PFBS and the related compound K+PFBS in humans or animals have been
identified.
18
PFBS and related compound
-------
FINAL
7-17-2014
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 11 identifies the cancer weight-of-evidence (WOE) descriptor for PFBS and the
related compound K+PFBS.
Table 11. Cancer WOE Descriptor for PFBS (CASRN 375-73-5) and the Related
Compound K+PFBS (CASRN 29420-49-3)
Possible WOE
Descriptor
Designation
Route of Entry
(oral, inhalation, or
both)
Comments
"Carcinogenic to
Humans "
NS
NA
There are no human carcinogenicity data identified
to support this descriptor.
"Likely to Be
Carcinogenic to Humans "
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
This descriptor is selected due to the lack of any
information on carcinogenicity of PFBS and the
related compound K+PFBS.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
Although the genotoxicity studies were negative or
equivocal, there are no data to indicate that PFBS
or K+PFBS is not carcinogenic.
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER RISK VALUES
The lack of data on the carcinogenicity of PFBS and the related compound K+PFBS
precludes the derivation of quantitative estimates for either oral (p-OSF) or inhalation (p-IUR)
exposure.
19
PFBS and related compound
-------
FINAL
7-17-2014
APPENDIX A. SCREENING PROVISIONAL VALUES
No screening values for PFBS or the related compound K+PFBS are identified.
20
PFBS and related compound
-------
FINAL
7-17-2014
APPENDIX B. DATA TABLES
Table B-l. Body Weight Data on Sprague-Dawley Rats Exposed to K+PFBS via Gavage
for 90 Daysa'b
Dose
(mg/kg-day)
Number of
animals (M/F)
Body weight at Day 1(g)
Terminal body weight (g)
Males
Females
Males
Females
0
10/10
192.1 ±7.3
161.5 ±9.6
510.9 ±47.0
276.5 ± 24.0
60
10/10
192.9 ±6.8 (100)
161.0 ±7.7 (100)
482.6 ±60.4 (94.5)
286.0 ±21.5 (103)
200
10/10
190.0 ±7.2 (98.9)
157.9 ± 11.2(97.8)
479.6 ± 30.3 (93.9)
284.8 ± 30.1 (103)
600°
10/10
193.1 ±7.2 (101)
158.1 ± 10.9(97.9)
485.3 ±49.4(95.0)c
264.6 ± 19.5 (95.7)
aValues obtained from Lieder et al. (2009a'). Table 1, page 47.
bData are presented as mean values ± SD (% of control); % of control calculated by U.S. EPA.
Terminal body weights for this dose in males exclude the value for one rat found dead on Day 85 of study.
Table B-2. Selected Organ Weight Data on Male Sprague-Dawley Rats Exposed to
K+PFBS via Gavage for 90 Daysa'b'c
Dose in mg/kg-day (Number of animals)
Organ measurement
0 (TV = 10)
60 (N = 10)
200 (N = 10)
600 (N= 9d)
Absolute liver weight (g)
14.48 ± 1.76
13.83 ±2.67 (95.5)
13.50 ± 1.28 (93.2)
14.78 ± 1.78 (102)
Relative liver weight (%)
2.832 ±0.198
2.846 ± 0.273 (100)
2.814 ±0.175 (99.4)
3.049 ±0.220 (108)
Absolute kidney weight (g)
4.18 ±0.48
4.15 ±0.55 (99.3)
3.93 ±0.30 (94.0)
4.18 ±0.33 (100)
Relative kidney weight (%)
0.818 ±0.058
0.859 ±0.053 (105)
0.818 ±0.053 (100)
0.864 ± 0.049 (106)
Absolute spleen weight (g)
0.93 ±0.13
0.77 ±0.10** (82.8)
0.83 ± 0.06* (89.2)
0.80 ±0.11** (86.0)
Relative spleen weight (%)
0.181 ±0.018
0.158 ±0.015**
(87.3)
0.172 ±0.017 (95.0)
0.163 ±0.020* (90.1)
aValues obtained from Lieder et al. (2009a'). Table 2, page 48.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA. Relative weights denote
organ weight to terminal body weight ratios.
Dosage occurred on Days 1 through 90, 91, 92, or 93 of study.
dExcludes values for one rat found dead on Day 85 of study.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
21
PFBS and related compound
-------
FINAL
7-17-2014
Table B-3. Selected Organ Weight Data on Female Sprague-Dawley Rats Exposed to
K+PFBS via Gavage for 90 Daysa'b'c
Dose in mg/kg-day (Number of animals)
Organ measurement
0 (TV = 10)
60 (N = 10)
200 (N = 10)
600 (N = 10)
Absolute liver weight (g)
7.71 ±0.78
8.30 ±0.72 (108)
8.23 ±0.91 (107)
7.79 ±0.36 (101)
Relative liver weight (%)
2.788 ±0.152
2.902 ±0.154 (104)
2.890 ±0.100 (104)
2.951 ±0.204 (106)
Absolute kidney weight (g)
2.34 ±0.22
2.40 ±0.30 (103)
2.40 ±0.18 (103)
2.39 ±0.41 (102)
Relative kidney weight (%)
0.847 ± 0.069
0.838 ±0.071 (98.9)
0.846 ±0.059 (99.9)
0.906 ±0.150 (107)
Absolute spleen weight (g)
0.58 ±0.09
0.59 ±0.11 (102)
0.57 ±0.07 (98.3)
0.65 ±0.11 (112)
Relative spleen weight (%)
0.209 ±0.033
0.208 ±0.037 (99.5)
0.202 ± 0.030 (96.7)
0.248 ±0.046 (119)
aValues obtained from Lieder et al. (2009a'). Table 3, page 48.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA. Relative weights denote
organ weight to terminal body weight ratios.
Dosage occurred on Days 1 through 90, 91, 92, or 93 of study.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
22
PFBS and related compound
-------
FINAL
7-17-2014
Table B-4. Selected Clinical Chemistry Data on Male and Female Sprague-Dawley Rats
Exposed to K+PFBS via Gavage for 90 Daysa'b'c
Dose in mg/kg-day (Number of animals)
Measurement
0 (TV = 10)
60 (TV =10)
200 (N = 10)
600 (N = 9d'e)
Males
Total protein (g/dL)
6.6 ±0.33
6.5 ±0.15 (98.5)
6.4 ±0.19 (97.0)
6.5 ±0.50 (98.5)
Albumin (g/dL)
4.1 ± 0.17
4.1 ±0.19 (100)
4.0 ±0.11 (97.6)
4.0 ± 0.26 (97.6)
Blood urea nitrogen (mg/dL)
15 ± 1.4
14 ± 1.5 (93.0)
14 ±2.2 (93.0)
15 ± 1.4(100)
Creatinine (mg/dL)
0.3 ±0.05
0.2 ± 0.05 (66.7)
0.3 ±0.06 (100)
0.3 ±0.05 (100)
ALT (U/L)
42 ±5.8
45 ±7.1 (107)
41 ±4.6 (97.6)
43 ±7.8 (102)
AST (U/L)
84 ± 11.2
90 ± 10.9(107)
88 ±7.5 (105)
91 ± 12.7(112)
ALK (U/L)
94 ± 15.0
90 ± 12.0(95.7)
96 ± 12.1 (102)
107 ± 12.7 (114)
Chloride (mmol/L)
98 ±2.0
100 ± 1.2(102)
100 ± 1.4(102)
101 ±1.7** (103)
Females
Total protein (g/dL)
7.2 ±0.40
7.2 ±0.34 (100)
7.1 ±0.40 (98.6)
6.7 ±0.23* (93.1)
Albumin (g/dL)
4.9 ±0.38
4.8 ±0.29 (98.0)
4.7 ±0.31 (95.9)
4.4 ±0.23* (89.8)
Blood urea nitrogen (mg/dL)
16 ± 1.9
16 ± 1.6(100)
15 ± 1.8(93.8)
16 ±2.9 (100)
Creatinine (mg/dL)
0.4 ±0.05
0.4 ±0.04 (100)
0.3 ±0.05 (75.0)
0.4 ±0.05 (100)
ALT (U/L)
44 ± 11.6
55 ±23.6 (125)
49 ±30.7 (111)
44 ± 13.3 (100)
AST (U/L)
85 ± 15.8
95 ±25.8 (112)
94 ± 51.0 (111)
96 ± 19.6(113)
ALK (U/L)
44 ± 8.0
46 ± 13.3 (105)
45 ± 12.1 (102)
59 ± 18.2(134)
Chloride (mmol/L)
101 ±2.5
101 ±2.3 (101)
102 ±2.2 (101)
102 ±1.1 (101)
"Values obtained from Lieder et al. (2009a'). Table 4, page 49.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA.
Dosage occurred on Days 1 through 90, 91, 92, or 93 of study.
dExcludes values for one male rat found dead on Day 85 of study.
"Excludes one female rat that did not have sufficient sample volume.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
23
PFBS and related compound
-------
FINAL
7-17-2014
Table B-5. Selected Hematology Data on Male and Female Sprague-Dawley Rats Exposed
to K+PFBS via Gavage for 90 Daysa'b'c
Dose in mg/kg-day (Number of animals)
Measurement
0 (TV = 10)
60 (N = 10)
200 (N = 10)
600 (N = 9d)
Males
WBC (103/mm3)
17.0 ±3.66
15.4 ± 3.50 (90.6)
14.7 ±2.31 (86.5)
15.2 ±2.80 (89.4)
RBC (106/mm3)
7.76 ± 0.469
7.62 ± 0.443 (98.2)
7.55 ± 0.282 (97.3)
7.19 ±0.481* (92.7)
HGB (g/dL)
16.4 ±0.96
16.0 ±0.41 (97.6)
15.6 ±0.48* (95.1)
15.5 ±0.78* (94.5)
HCT (%)
44.2 ±2.32
42.7 ± 1.44 (96.6)
41.9 ± 1.50* (94.8)
40.9 ±2.24** (92.5)
MCV (|am3)
57.0 ± 1.25
56.2 ±2.12 (98.6)
55.6 ± 1.38 (97.5)
57.0 ±2.08 (100)
MCH (pg)
21.2 ±0.53
21.1 ± 1.18(99.5)
20.7 ±0.51 (97.6)
21.6 ± 1.01 (102)
MCHC (%)
37.2 ±0.50
37.5 ± 1.11 (101)
37.2 ±0.69 (100)
37.8 ±0.96 (102)
Females
WBC (103/mm3)
12.2 ±3.95
11.5 ±3.10 (94.3)
12.1 ± 3.77 (99.2)
13.5 ±3.94 (111)
RBC (106/mm3)
7.17 ± 0.315
6.95 ± 0.226 (96.9)
7.16 ±0.309 (99.9)
6.95 ± 0.297 (96.9)
HGB (g/dL)
15.9 ±0.61
15.8 ±0.57 (99.4)
15.6 ±0.69 (98.1)
15.3 ±0.82 (96.2)
HCT (%)
43.3 ± 1.85
42.1 ± 1.56 (97.2)
42.7 ±2.14 (98.6)
41.2 ± 1.71 (95.1)
MCV (|am3)
60.5 ± 1.08
60.6 ± 1.47(100)
59.5 ± 1.50 (98.3)
59.2 ± 1.21 (97.9)
MCH (pg)
22.2 ± 0.64
22.7 ±0.65 (102)
21.8 ±0.61 (98.2)
22.0 ±0.75 (99.1)
MCHC (%)
36.7 ±0.69
37.4 ±0.54* (102)
36.7 ±0.51 (100)
37.1 ±0.70 (101)
aValues obtained from Lieder et al. (2009a'). Table 5, page 49.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA.
Dosage occurred on Days 1 through 90, 91, 92, or 93 of study.
dExcludes values for one rat found dead on Day 85 of study.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
24
PFBS and related compound
-------
FINAL
7-17-2014
Table B-6. Incidences of Selected Histopathological Findings in Male and Female
Sprague-Dawley Rats Exposed to K+PFBS via Gavage for 90 Daysa'b
Dose in mg/kg-day (Number of animals)
Observation
o
II
O
60 (N = 10)
200 (N = 10)
600 (N = 10)
Males
Kidney
Hyperplasia, tubular/ductal epithelium papilla
1
0
0
g**
Edema, focal papillary
0
0
0
3
Necrosis, papillary
0
0
0
1
Basophilia, tubular, multifocal
1
0
0
3
Hyaline droplets, cortical tubules
2
0
0
1
Mineralization, multifocal
0
0
0
0
Mononuclear cell infiltration
1
2
4
0
Stomach
Dilation, mucosal glands
2
1
2
1
Necrosis, limiting ridge
0
2
2
g**
Hyperplasia/hyperkeratosis, limiting ridge
0
0
0
5*
Females
Kidney
Hyperplasia, tubular/ductal epithelium papilla
0
0
1
6*
Edema, focal papillary
0
0
0
3
Necrosis, papillary
0
0
0
0
Basophilia, tubular, multifocal
0
0
0
1
Hyaline droplets, cortical tubules
0
0
0
1
Mineralization, multifocal
5
5
2
2
Mononuclear cell infiltration
0
3
0
2
Stomach
Dilation, mucosal glands
0
3
0
0
Necrosis, limiting ridge
1
0
1
9**
Hyperplasia/hyperkeratosis, limiting ridge
0
0
0
7**
aValues obtained from Lieder et al. (2009a'). Table 6, page 50.
bValues expressed as number of animals with lesions.
* Significantly different from controls (p < 0.05, Fisher's Exact test), independently calculated by U.S. EPA.
**Significantly different from controls (p < 0.01, Fisher's Exact test), independently calculated by U.S. EPA.
25
PFBS and related compound
-------
FINAL
7-17-2014
Table B-7. Sperm Analysis of F0- and Fl-Generation Male Sprague-Dawley Rats Exposed
to K+PFBS via Gavagea'b
Dose in mg/kg-day
Parameter
Generation
0
30
100
300
1,000
Motility
F0
O
¦rf m
-H II
£ ^
95 ± 5 (99.0)
[# = 30]
94 ± 12 (97.9)
[#=30]
95 ± 4 (99.0)
[#=30]
95 ± 5 (99.0)
[#=28]
F1
92 ± 10
[# = 28]
92 ± 10 (100)
[TV = 26]
94 ± 6 (102)
[#=29]
95 ±3 (103)
[#=27]
92 ± 10 (100)
[#=27]
Morphology
(% abnormal)
F0
1.7 ± 1.5
[# = 30]
2.0 ± 1.3 (118)
[#=30]
1.6 ± 1.0 (94.1)
[#=30]
1.5 ±0.6 (88.2)
[#=30]
2.0 ±0.6 (118)
[#=29]
F1
1.5 ±0.7
[# = 29]
1.3 ±0.6 (86.7)
[#=27]
1.4 ±0.5 (93.3)
[#=29]
1.5 ±0.6 (100)
[#=27]
1.9 ±0.5* (127)
[#=29]
Testicular
sperm count
(io6/g)
F0
148 ±39
[# = 30]
136 ±34 (91.9)
[#=30]
146 ± 36 (98.6)
[#=30]
132 ±21(89.2)
[#=30]
122 ± 36* (82.4)
[#=29]
F1
124 ±33
[# = 29]
109 ±34 (87.9)
[#=27]
107 ±29 (86.3)
[#=29]
110 ±24 (88.7)
[#=27]
107 ± 32 (86.3)
[#=27]
Epididymal
sperm count
(io6/g)
F0
1,030 ±209
[# = 30]
1,033 ±226 (100)
[#=30]
957 ±217
(92.9)
[#=30]
1,019 ± 181
(98.9)
[#=30]
969 ±275 (94.1)
[#=29]
F1
837 ±237
[# = 29]
770 ± 282 (92.0)
[#=27]
840 ±262 (100)
[#=29]
857 ± 222 (102)
[#=27]
928 ±273 (111)
[#=27]
aValues obtained from Lieder et al. (2009b'). Table 1, page 35.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA.
* Significantly different from controls, p < 0.05.
N = number of animals examined.
26
PFBS and related compound
-------
FINAL
7-17-2014
Table B-8. Delivery Outcomes of F0- and Fl-Generation Sprague-Dawley Dams Exposed
to K+PFBS via Gavage1'
Dose in mg/kg-day
Parameter
Generation
0
30
100
300
1,000
Number of
dams delivering
F0
26
29
29
29
25
F1
24
26
28
25
27
Length of
gestation, days
(mean ± SD)
F0
22.7 ±0.5
22.8 ±0.4
22.8 ±0.5
22.8 ±0.4
22.7 ±0.4
F1
22.7 ±0.5
22.8 ±0.5
22.6 ±0.5
22.6 ±0.5
22.8 ±0.4
Deliveries (%)
F0
100
100
100
100
100
F1
100
100
100
100
100
Percentage with
live-born pupsb
F0
100
100
100
100
100
F1
100
100
100
100
100
Number with
stillborn pups0
F0
2
5
1
4
2
F1
5
1
5
5
1
Mean
implantation
sites
(mean ± SD)
F0
15.2 ± 1.8
14.6 ±3.0
14.3 ±2.3
14.7 ± 1.7
14.0 ±2.3
F1
14.3 ±2.3
14.6 ±2.3
15.2 ±2.0
15.2 ±2.8
15.3 ±2.0
Mean pups
delivered
(mean ± SD)
F0
14.2 ±2.2
13.9 ±3.0
13.8 ±3.0
14.0 ±2.0
13.6 ±2.3
F1
13.2 ±2.3
13.8 ±2.2
14.1 ±2.3
14.0 ±2.1
14.0 ±2.1
"Values obtained from Lieder et al. (2009b'). Table 6, page 37.
bIndicates the number of dams producing a litter containing at least one live-born pup.
Indicates the number of dams with at least one stillborn pup.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
27
PFBS and related compound
-------
FINAL
7-17-2014
Table B-9. Litter Outcomes for Fl- and F2-Generation Pups Exposed to K+PFBS via
Gavage"
Dose in mg/kg-day
Parameter
Generation
0
30
100
300
1,000
Number of
litters
delivered
Fl
26
29
29
29
25
F2
24
26
28
25
27
Mean (± SD)
live-born (TV)
Fl
14.2 ±2.2
13.5 ±2.8**
13.7 ±3.0
13.8 ±2.0
13.5 ±2.3
F2
13.0 ±2.3
13.6 ±2.3
13.9 ±2.4
13.6 ±2.6
14.0 ±2.0
Mean (± SD)
stillborn (N)
Fl
0.1 ±0.3
0.2 ±06
0.1 ±0.4
0.1 ±04
0.1 ± 0.3
F2
0.2 ±0.4
0.1 ±0.6
0.2 ±0.5
0.4 ± 1.0
0.0 ±0.2
Mean (± SD)
pup weight at
birth
Fl
6.4 ±0.4
6.5 ±0.5
6.6 ±0.5
6.4 ±0.4
6.3 ±0.5
F2
6.3 ±0.6
6.4 ±0.5
6.4 ±0.4
6.2 ±0.5
6.2 ±0.8
Mean (± SD)
pup weight at
weaning (g)
Fl
40.2 ±5.6
40.2 ±6.8
40.8 ±7.8
39.2 ± 5.9b
39.3 ±4.4
F2
36.4 ± 7.7°
39.4 ±7.3
37.1 ±5.1
36.3 ±6.6
35.0 ± 5.6d
Viability index
(%)e
Fl
98.1
96.7*
98.2
99.2
99.4*
F2
95.5
96.9
97.2
96.8
95.8
Lactation
index (%)f
Fl
99.4
98.7
97 4**
97 7**
99.7
F2
97.0
96.5
98.2
97.3
93.1*
"Values obtained from Lieder et al. (2009b'). Table 7, page 38.
biV = 28. Excludes values for litters with no surviving pups.
°N= 23. Excludes values for litters with no surviving pups.
d Y = 25. Excludes values for litters with no surviving pups.
"(Number of pups alive on Day 4/number of pups alive on Day 1) x 100
f(Number of pups alive on Day 21/number of pups alive on Day 4) x 100
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
28
PFBS and related compound
-------
FINAL
7-17-2014
Table B-10. Selected Organ Weight Data on F0- and Fl-Generation Male
Sprague-Dawley Rats Exposed to K+PFBS via Gavagea'b
Dose in mg/kg-day
Measurement
Generation
0
30
100
300
1,000
Terminal body
weight (g)
F0
552 ± 56
[# = 30]
569 ± 53 (103)
[# = 30]
570 ±45 (103)
[#=30]
572 ± 69 (104)
[#=30]
551 ±46 (99.8)
[#=29]
F1
594 ± 45
[TV = 29]
583 ±61 (98.1)
[TV = 27]
593 ±73 (99.8)
[#=29]
598 ±65 (101)
[#=27]
549 ± 38**(92.4)
[#=27]
Absolute liver
weight (g)
F0
19.2 ±2.4
[# = 30]
20.0 ±2.9
(104)
[# = 30]
20.5 ±2.4
(107)
[#=30]
21.5 ±
2.9**(112)
[#=30]
2.7 ± 2.8°
[#=29]
F1
20.6 ±2.5
[# = 29]
20.1 ±2.7
(97.6)
[TV = 27]
21.2 ±4.4
(98.1)
[#=29]
21.7 ±3.2 (105)
[#=27]
21.1 ±2.2 (102)
[#=27]
Relative liver
weight (%)
F0
3.4 ±0.3
[# = 30]
3.5 ±0.4 (103)
[TV= 30]
3.6 ±0.3 (106)
[#=30]
3.8 ± 0.3**(112)
[#=30]
4.1 ± 0.4**(121)
[#=29]
F1
3.5 ±0.4
[# = 29]
3.4 ±0.3 (97.1)
[# = 27]
3.5 ±0.4 (100)
[#=29]
3.6 ±0.3 (103)
[#=27]
3.8 ± 0.3**(109)
[#=27]
Absolute left
kidney weight
(g)
F0
2.10 ±0.21
[# = 30]
2.17 ±0.20
(103)
[TV= 30]
2.18 ±0.20
(104)
[#=30]
2.20 ±0.28 (105)
[#=30]
2.20 ±0.26 (105)
[#=29]
F1
2.04 ±0.21
[# = 29]
2.06 ±0.23
(101)
[#=27]
2.08 ±0.20
(102)
[#=29]
2.14 ±0.24 (105)
[#=27]
1.97 ±0.16
(96.6)
[#=27]
Relative left
kidney weight
(%)
F0
0.375 ±
0.034
[# = 30]
0.382 ±0.035
(102)
[#=30]
0.383 ±0.032
(102)
[#=30]
0.385 ±0.042
(103)
[#=30]
0.400 ± 0.047
(107)
[#=29]
F1
0.344 ±
0.030
[# = 29]
0.352 ±0.021
(102)
[#=27]
0.353 ±0.033
(103)
[#=29]
0.358 ±0.038
(104)
[#=27]
0.357 ±0.029
(104)
[#=29]
Absolute right
kidney weight
(g)
F0
2.15 ±0.22
[# = 30]
2.18 ±0.21
(101)
[#=30]
2.20 ±0.21
(102)
[#=30]
2.21 ±0.28 (103)
[#=30]
2.22 ±0.25 (103)
[#=29]
F1
2.05 ±0.20
[# = 29]
2.08 ±0.22
(101)
[#=27]
2.09 ±0.20
(102)
[#=28]
2.14 ±0.25 (104)
[#=27]
2.00 ±0.18
(97.6)
[#=27]
Relative right
kidney weight
(%)
F0
0.383 ±
0.041
[# = 30]
0.384 ±0.034
(100)
[#=30]
0.385 ±0.033
101)
[#=30]
0.387 ±0.042
(101)
[#=30]
0.403 ± 0.040
(105)
[#=29]
F1
0.346 ±
0.030
[TV = 29]
0.356 ±0.020
(103)
[#=27]
0.356 ±0.029
(103)
[#=28]
0.359 ±0.040
(104)
[#=27]
0.364 ±0.032
(105)
[#=27]
29
PFBS and related compound
-------
FINAL
7-17-2014
Table B-10. Selected Organ Weight Data on F0- and Fl-Generation Male
Sprague-Dawley Rats Exposed to K+PFBS via Gavagea'b
Dose in mg/kg-day
Measurement
Generation
0
30
100
300
1,000
Absolute
spleen weight
(g)
F0
0.86 ±0.13
[TV = 30]
0.92 ±0.18
(107)
[TV = 30]
0.89 ± 0.11
(103)
[TV= 30]
0.88 ±0.19 (102)
[TV= 30]
0.86 ±0.09 (100)
[TV = 29]
F1
0.90 ±0.19
[TV = 29]
0.88 ±0.08
(97.8)
[TV = 27]
0.87 ±0.17
(96.7)
[TV = 29]
0.84 ±0.14
(93.3)
[TV = 27]
0.79 ±0.12
(87.8)
[TV = 27]
Relative spleen
weight (%)
F0
0.153 ±
0.023
[TV = 30]
0.161 ±0.030
(105)
[TV= 30]
0.156 ±0.017
(102)
[TV= 30]
0.153 ±0.025
(100)
[TV= 30]
0.157 ±0.019
(103)
[TV = 29]
F1
0.151 ±
0.033
[TV = 29]
0.151 ±0.018
(100)
[TV = 27]
0.147 ±0.025
(97.4)
[TV = 29]
0.141 ±0.024
(93.4)
[TV = 27]
0.144 ±0.023
(95.4)
[TV = 27]
aValues obtained from Lieder et al. (2009b'). Table 11, page 40.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA. Relative weights denote
organ weight to terminal body weight ratios. TV = number of animals measured.
°This appears to be a typographical error in the original publication.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
30
PFBS and related compound
-------
FINAL
7-17-2014
Table B-ll. Selected Organ Weight Data on F0- and Fl-Generation Female
Sprague-Dawley Rats Exposed to K+PFBS via Gavagea'b'c
Dose in mg/kg-day
Measurement
Generation
0
30
100
300
1,000
Terminal body
weight (g)
F0
346 ± 23
[TV = 26]
343 ±26 (99.1)
[TV = 29]
351 ±23 (101)
[TV = 29]
344 ± 30 (99.4)
[TV = 28]
336 ±22 (97.1)
[TV = 25]
F1
331 ±29
[TV = 23]
350 ±33* (106)
[TV = 26]
353 ±26**
(107)
[TV = 28]
347±16*
(105)
[TV = 25]
348 ±23*
(105)
[TV = 25]
Absolute left
kidney weight
(g)
F0
141 ±0.12
[TV = 26]
1.42 ±0.15
(101)
[TV = 29]
1.41 ± 0.15
(100)
[TV = 29]
1.48 ±0.18
(105)
[TV = 28]
1.42 ±0.17
(101)
[TV = 25]
F1
1.51 ± 0.16
[TV= 23]
1.51 ± 0.13
(100)
[TV = 26]
1.52 ±0.14
(101)
[TV = 28]
1.52 ±0.18
(101)
[TV = 25]
1.48 ±0.16
(98.0)
[TV = 25]
Relative left
kidney weight
(%)
F0
0.407 ±
0.032
[TV = 26]
0.416 ±0.035
(102)
[TV = 29]
0.402 ±0.034
(98.8)
[TV = 29]
0.430 ±0.055
(106)
[TV = 28]
0.422 ±0.051
(104)
[TV = 25]
F1
0.462 ±
0.092
[TV= 23]
0.434 ±0.039
(93.9)
[TV = 26]
0.433 ±0.032
(93.7)
[TV = 28]
0.438 ±0.046
(94.8)
[TV = 25]
0.428 ± 0.047
(92.6)
[TV = 25]
Absolute right
kidney weight
(g)
F0
1.41 ±0.13
[TV = 26]
1.39 ±0.14
(98.6)
[TV = 29]
1.42 ±0.16
(101)
[TV = 29]
1.44 ±0.19
(102)
[TV = 28]
1.40 ±0.15
(99.3)
[TV = 25]
F1
1.55 ±0.18
[TV= 23]
1.58 ±0.13
(102)
[TV = 26]
1.57 ±0.14
(101)
[TV = 28]
1.57 ±0.18
(101)
[TV = 25]
1.56 ±0.18
(101)
[TV = 25]
Relative right
kidney weight
(%)
F0
0.406 ±
0.035
[TV = 26]
0.407 ±0.036
(100)
[TV = 29]
0.406 ±0.036
(100)
[TV = 29]
0.420 ±0.053
(103)
[TV = 28]
0.418 ±0.044
(103)
[TV = 25]
F1
0.474 ±
0.101
[TV= 23]
0.454 ± 0.042
(95.8)
[TV = 26]
0.446 ± 0.024
(94.0)
[TV = 28]
0.454 ± 0.046
(95.8)
[TV = 25]
0.450 ± 0.048
(94.9)
[TV = 25]
Absolute
spleen weight
(g)
F0
0.74 ±0.15
[TV = 26]
0.70 ±0.12
(94.6)
[TV = 29]
0.71 ±0.16
(95.9)
[TV = 29]
0.74 ± 0.23
(100)
[TV = 28]
0.67 ±0.12
(90.5)
[TV = 25]
F1
0.62 ±0.12
[TV= 23]
0.70 ±
0.11*(113)
[TV = 26]
0.70 ±
0.13 *(113)
[TV = 28]
0.71 ±0.11*
(115)
[TV = 25]
0.67 ±0.09
(108)
[TV = 25]
31
PFBS and related compound
-------
FINAL
7-17-2014
Table B-ll. Selected Organ Weight Data on F0- and Fl-Generation Female
Sprague-Dawley Rats Exposed to K+PFBS via Gavagea'b'c
Dose in mg/kg-day
Measurement
Generation
0
30
100
300
1,000
Relative spleen
weight (%)
F0
0.213 ±
0.045
[TV = 26]
0.206 ±0.033
(96.7)
[TV = 29]
0.202 ± 0.043
(94.8)
[TV = 29]
0.215 ±0.061
(101)
[TV = 28]
0.198 ±0.036
(93.0)
[TV = 25]
F1
0.186 ±
0.034
[TV = 23]
0.201 ±0.030
(108)
[TV = 26]
0.198 ±0.035
(106)
[TV = 28]
0.204 ±0.035
(110)
[TV = 25]
0.193 ±0.027
(104)
[TV = 25]
aValues obtained from Lieder et al. (2009b'). Table 12, page 41.
bValues expressed as mean ± SD (% of control); % of control calculated by U.S. EPA. Relative weights denote
organ weight to terminal body weight ratios. TV = number of animals measured.
°Study authors did not provide liver weight measurements for females but stated that "with the exception of splenic
weights, all organ weights were similar to control values" in female rats.
* Significantly different from controls, p < 0.05.
**Significantly different from controls, p < 0.01.
32
PFBS and related compound
-------
FINAL
7-17-2014
Table B-12. Incidences of Selected Histopathological Findings on F0- and Fl-Generation
Male and Female Sprague-Dawley Rats Exposed to K+PFBS via Gavagea'b
Dose in mg/kg-day (Number of animals)
Organ
Observation
Generation
0 (N=30)
300 (TV =30)
1,000 (TV =30)
Males
Kidney
Papillary epithelial tubular/ductal
hyperplasia
F0
0
9** (7+; 2++)
19** (9+; 9++;
1+++)
F1
3(3+)
5 (4+; 1++)
21** (8+; 13++)
Focal papillary edema
F0
1(1+)
2(2+)
6 (5+; 1++)
F1
1(1+)
0
9* (9+)
Focal necrosis of the papilla
F0
0
0
1 (1++)
F1
0
2(2+)
0
Focal cortical tubular dilation
F0
0
0
1(1+)
F1
0
0
1(1+)
Liver
Hepatocellular hypertrophy
F0
0
3(3+)
26** (25+; 1++)
F1
0
3(3+)
14** (13+; 1++)
Females
Kidney
Papillary epithelial tubular/ductal
hyperplasia
F0
3 (1+; 2++)
16** (7+;
8++; 1+++)
21** (9+; 12++)
F1
2(2+)
13** (7+;
5++; 1+++)
15** (7+; 7++;
1+++)
Focal papillary edema
F0
1(1+)
8* (7+; 1++)
7* (7+)
F1
0
7* (6+; 1++)
4 (3+; 1++)
Focal necrosis of the papilla
F0
0
3 (1+; 2++)
0
F1
0
1 (1++)
1 (1++)
Focal cortical tubular dilation
F0
0
1 (+++)
1 (1++)
F1
1 (1++)
1(1+)
0
Liver
Hepatocellular hypertrophy
F0
0
0
0
F1
0
0
0
"Values obtained from Lieder et al. (2009b'). Table 10, page 40.
bValues expressed as number of animals with lesions (degree of severity: + = minimal severity, ++ = mild severity,
+++ = moderate severity).
* Significantly different from controls (p < 0.05, Fisher's Exact test), independently calculated by U.S. EPA.
**Significantly different from controls (p < 0.01, Fisher's Exact test), independently calculated by U.S. EPA.
33
PFBS and related compound
-------
FINAL
7-17-2014
APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE FOR DICHOTOMOUS DATA
The benchmark dose (BMD) modeling of dichotomous data was conducted with EPA's
BMD Software (version 2.3). For these data, all of the dichotomous models (i.e., Gamma,
Multistage, Logistic, Log-logistic, Probit, Log-probit, Weibull, and Quantal-linear models)
available within the software were fit using a 10% benchmark response (BMR). An adequate fit
was judged based on the %2 goodness-of-fitp-value (p> 0.1), magnitude of the scaled residuals
in the vicinity of the BMR, and visual inspection of the model fit. Among all models providing
adequate fit, the benchmark dose lower confidence limit (BMDL) from the model with the
lowest Akaike's Information Criteria (AIC) was selected as a potential point of departure (POD)
from which to derive the reference dose (RfD).
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN MALE RATS TREATED
WITH K+PFBS FOR 90 DAYS VIA GAVAGE
Table C-l. Model Predictions for Increased Incidence of Kidney Hyperplasia in Male
Sprague-Dawley Rats Treated with K+PFBS
Model
/>-Valuc"
AIC for Fitted
Model
BMDio
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
0.3057
30.45
240
110
Logistic
0.3372
29.14
192
119
Log-logistic
0.3059
30.46
242
115
Log-probit
0.305
30.45
233
116
Multistage 2
0.3812
29.33
167
85.6
Multistage 3
0.5824
28.48
245
96.7
Lowest AIC, best fitting
Probit
0.271
29.47
170
109
Weibull
0.3069
30.47
256
107
Quantal-linear
0.0636
34.08
71.0
40.9
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
34
PFBS and related compound
-------
FINAL
7-17-2014
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN FEMALE RATS
TREATED WITH K+PFBS FOR 90 DAYS VIA GAVAGE
Table C-2. Model Predictions for Increased Incidence of Kidney Hyperplasia in Female
Sprague-Dawley Rats Treated with K+PFBS
Model
/j-Valuc"
AIC for Fitted
Model
BMD io
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
0.9716
24.06
211
81.3
Logistic
0.7182
24.86
288
179
Log-logistic
0.9692
24.07
210
84.8
Log-probit
0.9925
23.98
204
103
Multistage 2
0.9926
22.15
204
78.7
Lowest AIC, best fitting
Multistage 3
0.953
24.14
212
78.3
Probit
0.7868
24.62
264
165
Weibull
0.9533
24.13
215
79.7
Quantal-linear
0.6045
24.53
97.9
55.1
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
35
PFBS and related compound
-------
FINAL
7-17-2014
BMD Output for Multistage 2 Model for Increased Incidence of Kidney Hyperplasia in
Female Rats after Exposure to K+PFBS via Gavage for 90 days
Multistage Model with 0.95 Confidence Level
Multistage
BMDL
0 100 200 300 400 500 600
dose
14:37 08/13 2013
Multistage Model
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
36
PFBS and related compound
-------
FINAL
7-17-2014
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 3.43191e-005
Beta(2) = 2.50059e-006
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(2)
Beta (2) 1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Estimate
0
0
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
2.52309e-006 *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-9.98095
-10. 0729
-18.5491
# Param's Deviance Test d.f. P-value
4
1 0.183913 3 0.9801
1 17.1362 3 0.0006626
AIC:
22.1458
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
60.0000
200.0000
600.0000
Chi^2 = 0.09
0.0000
0.0090
0.0960
0.5968
d.f. = 3
0.000 0.000 10
0.090 0.000 10
0.960 1.000 10
5.968 6.000 10
P-value = 0.992 6
0. 000
-0.302
0. 043
0. 021
37
PFBS and related compound
-------
FINAL
7-17-2014
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 204.349
BMDL = 78.7178
BMDU = 291.15
Taken together, (78.7178, 291.15 ) is a 90 % two-sided confidence
interval for the BMD
38 PFBS and related compound
-------
FINAL
7-17-2014
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN FO-GENERATION MALE
RATS TREATED WITH K+PFBS VIA GAVAGE—REPRODUCTIVE STUDY
Table C-3. Model Predictions for Increased Incidence of Kidney Hyperplasia in F0 Male
Sprague-Dawley Rats Treated with K+PFBS in Reproductive Study
Model
/>-Valuca
AIC for
Fitted
Model
BMDio
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
0.9188
78.2
99.5
73.2
Lowest AIC, best fitting
Logistic
0.0191
87.7
276
208
Log-logistic
1
80.1
93.5
45.6
Log-probit
0.5914
79.1
168
127
Multistage 2
0.9188
78.2
99.5
73.2
Lowest AIC, best fitting
Multistage 3
0.9188
78.2
99.5
73.2
Lowest AIC, best fitting
Probit
0.0233
87.0
257
197
Weibull
0.9188
78.2
99.5
73.2
Lowest AIC, best fitting
Quantal-linear
0.9188
78.2
99.5
73.2
Lowest AIC, best fitting
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
39
PFBS and related compound
-------
FINAL
7-17-2014
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN Fl-GENERATION MALE
RATS TREATED WITH K+PFBS VIA GAVAGE—REPRODUCTIVE STUDY
Table C-4. Model Predictions for Increased Incidence of Kidney Hyperplasia in F1 Male
Sprague-Dawley Rats Treated with K+PFBS in Reproductive Study
Model
/>-Valuca
AIC for
Fitted
Model
BMD io
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
NA
89.19
340
140
Does not meet goodness-of-fit criteria
Logistic
0.6206
87.43
265
199
Log-logistic
NA
89.19
339
156
Does not meet goodness-of-fit criteria
Log-probit
NA
89.19
333
173
Does not meet goodness-of-fit criteria
Multistage 2
0.832
87.24
311
126
Lowest AIC, best fitting
Multistage 3
NA
89.19
348
122
Does not meet goodness-of-fit criteria
Probit
0.5219
87.60
242
186
Weibull
NA
89.19
346
137
Does not meet goodness-of-fit criteria
Quantal-linear
0.0675
90.81
119
82.8
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
NA = y2-tcst for fit is not valid; AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower
confidence limit (95%) on the benchmark dose.
40
PFBS and related compound
-------
FINAL
7-17-2014
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN FO-GENERATION
FEMALE RATS TREATED WITH K+PFBS VIA GAVAGE—REPRODUCTIVE STUDY
Table C-5. Model Predictions for Increased Incidence of Kidney Hyperplasia in F0
Female Sprague-Dawley Rats Treated with K+PFBS in Reproductive Study
Model
/>-Value"
AIC for
Fitted
Model
BMD io
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
0.0968
104
79.6
56.4
Does not meet goodness-of-fit criteria
Logistic
0.01
109
173
131
Does not meet goodness-of-fit criteria
Log-logistic
0.4561
102
44.7
26.6
Lowest AIC, best fitting
Log-probit
0.0449
105
132
93.2
Does not meet goodness-of-fit criteria
Multistage 2
0.0968
104
79.6
56.4
Does not meet goodness-of-fit criteria
Multistage 3
0.0968
104
79.6
56.4
Does not meet goodness-of-fit criteria
Probit
0.0106
108
169
131
Does not meet goodness-of-fit criteria
Weibull
0.0968
104
79.6
56.4
Does not meet goodness-of-fit criteria
Quantal-linear
0.0968
104
79.6
56.4
Does not meet goodness-of-fit criteria
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
41
PFBS and related compound
-------
FINAL
7-17-2014
INCREASED INCIDENCE OF KIDNEY HYPERPLASIA IN Fl-GENERATION
FEMALE RATS TREATED WITH K+PFBS VIA GAVAGE—REPRODUCTIVE STUDY
Table C-6. Model Predictions for Increased Incidence of Kidney Hyperplasia in F1
Female Sprague-Dawley Rats Treated with K+PFBS in Reproductive Study
Model
/>-Value"
AIC for
Fitted
Model
BMD io
(mg/kg-day)
BMDLio
(mg/kg-day)
Conclusions
Gamma
0.036
106
135
89.9
Does not meet goodness-of-fit criteria
Logistic
0.008
109
280
206
Does not meet goodness-of-fit criteria
Log-logistic
0.112
104
89.0
52.4
Lowest AIC, best fitting
Log-probit
0.0055
109
229
150
Does not meet goodness-of-fit criteria
Multistage 2
0.036
106
135
89.9
Does not meet goodness-of-fit criteria
Multistage 3
0.036
106
135
89.9
Does not meet goodness-of-fit criteria
Probit
0.0087
108
266
198
Does not meet goodness-of-fit criteria
Weibull
0.036
106
135
89.9
Does not meet goodness-of-fit criteria
Quantal-linear
0.036
106
135
89.9
Does not meet goodness-of-fit criteria
"Values <0.10 fail to meet conventional goodness-of-fit criteria.
AIC = Akaike's Information Criteria; BMD = benchmark dose; BMDL = lower confidence limit (95%) on the
benchmark dose.
42
PFBS and related compound
-------
FINAL
7-17-2014
Log-Logistic Model for Increased Incidence of Kidney Hyperplasia in FO-Generation
Female Rats after Oral Gavage Exposure to K+PFBS in Reproductive Study
Log-Logistic Model with 0.95 Confidence Level
0.9
o.e
0.7
o.e
O.E
0.4
0.3
0.2
0.1
Log-Leg btic
/
/
-r- /
/
/
BMDL
BMD
_i_
200
-------
FINAL
7-17-2014
Log-Logistic Model for Increased Incidence of Kidney Hyperplasia in Fl-Generation
Female Rats after Oral Gavage Exposure to K+PFBS in Reproductive Study
Log-Log isfc Model with 0.55 Con idenoe Level
0.7
0.6
0.4
0.3
02
0.1
Log-Log Etc
BMCL It,ID
200
400
800
wo
1000
dose
15:17 07,'31 2013
44
PFBS and related compound
-------
FINAL
7-17-2014
APPENDIX D. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2013). 2013 TLVs and
BEIs. Based on documentation of the threshold limit values for chemical substances and
physical agents and biological exposure indices. Cincinnati, OH.
AT SDR (Agency for Toxic Substances and Disease Registry). (2013). Minimal risk levels
(MRLs) for hazardous substances. Atlanta, GA: Agency for Toxic Substnaces and
Disease Registry. Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp
Cal/EPA (California Environmental Protection Agency). (2011). Hot spots unit risk and cancer
potency values. Appendix A. Sacramento, CA: Office of Environmental Health Hazard
Assessment, http://www.oehha.ca.gov/air/hot spots/tsd052909.html
Cal/EPA (California Environmental Protection Agency). (2012). OEHHA toxicity criteria
database. Sacramento, CA: Office of Environmental Health Hazard Assessment.
http ://www. oehha. ca. gov/tcdb/
Cal/EPA (California Environmental Protection Agency). (2014a). All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as of January 2014. Sacramento, CA: Office
of Environmental Health Hazard Assessment, http://www.oehha.ca.gov/air/allrels.html
Cal/EPA (California Environmental Protection Agency). (2014b). Chemicals known to the state
to cause cancer or reproductive toxicity, April 18, 2014. (Proposition 65 list).
Sacramento, CA: Office of Environmental Health Hazard Assessment.
http://oehha.ca.gov/prop65/prop65 list/files/P65single04182014.pdf
Eriksen. KT; Raaschou-Nielsen. O; S0rensen. M; Roursgaard. M; Loft S: Mjaller. P. (2010).
Genotoxic potential of the perfluorinated chemicals PFOA, PFOS, PFBS, PFNA and
PFHxA in human HepG2 cells. Mutat Res 700: 39-43.
http://dx.doi.Org/10.1016/i.mrgentox.2010.04.024
IARC (International Agency for Research on Cancer). (2013). Monographs on the evaluation of
carcinogenic risks to humans. Lyon, France.
http://monographs.iarc.fr/ENG/Monographs/voll03/monol03-B02-B03.pdf
Lieder. PH; Chang. SC: York. RG: Butenhoff JL. (2009a). Toxicological evaluation of
potassium perfluorobutanesulfonate in a 90-day oral gavage study with Sprague-Dawley
rats. Toxicology 255: 45-52. http://dx.doi.Org/10.1016/i.tox.2008.10.002
Lieder. PH: York. RG: Hakes. DC: Chang. SC: Butenhoff. JL. (2009b). A two-generation oral
gavage reproduction study with potassium perfluorobutanesulfonate (K+PFBS) in
Sprague Dawley rats. Toxicology 259: 33-45. http://dx.doi.Org/10.1016/i.tox.2009.01.027
NICNAS (National Industrial Chemicals Notification and Assessment Scheme). (2005a).
Existing chemical hazard assessment report. Potassium perfluorbutane sulfonate.
Canberra, Australia: Commonwealth of Australia, Australian Government Publishing.
http://www.nicnas.gov.au/ data/assets/pdf file/0004/4927/Potassium Perfluorobutane
Sulfonate PDF.pdf
NICNAS (National Industrial Chemicals Notification and Assessment Scheme). (2005b).
Potassium perfluorbutane sulfonate. Existing hazardous assessment report. Canberra,
Australia: Commonwealth of Australia, Australian Government Publishing.
NIOSH (National Institute for Occupational Safety and Health). (2010). NIOSH pocket guide to
chemical hazards. Index of chemical abstracts service registry numbers (CAS No.).
Atlanta, GA: Center for Disease Control and Prevention, U.S. Department of Health,
Education and Welfare, http://www.cdc.gov/niosh/npg/npgdcas.html
45
PFBS and related compound
-------
FINAL
7-17-2014
NTP (National Toxicology Program). (2005). Perfluorobutane sulfonate. Genetic toxicology -
bacterial mutagenicity. Chemical effects in biological systems (CEBS). (Study ID
A32037). Research Triangle Park, NC: National Institutes of Environmental Sciences,
National Institutes of Health.
http://tools.niehs.nih. gov/cebs3/ntpViews/?activeTab=detail&studvNumber=A32037
NTP (National Toxicology Program). (2011). Report on carcinogens: Twelfth edition (12th ed.).
Research Triangle Park, NC. http://ntp.niehs.nih.gov/ntp/roc/twelfth/rocl2.pdf
01 sen. GW: Chang. SC: Noker. PE; Gorman. GS: Ehresman. DJ; Lieder. PH; Butenhoff JL.
(2009). A comparison of the pharmacokinetics of perfluorobutanesulfonate (PFBS) in
rats, monkeys, and humans. Toxicology 256: 65-74.
http://dx.doi.Org/10.1016/i.tox.2008.l 1.008
OSHA (Occupational Safety & Health Administration). (2006). Table Z-l limits for air
contaminants. Occupational Safety and Health Administration.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p
id=9992
OSHA (Occupational Safety & Health Administration). (2011). Air contaminants: occupational
safety and health standards for shipyard employment, subpart Z, toxic and hazardous
substances. (OSHA Standard 1915.1000). Washington, DC: U.S. Department of Labor.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p
id=l0286
Rosal. R; Rodea-Palomares. I: Boltes. K; Fernandez-Pinas. F; Leganes. F; Petre. A. (2010).
Ecotoxicological assessment of surfactants in the aquatic environment: Combined
toxicity of docusate sodium with chlorinated pollutants. Chemosphere 81: 288-293.
http://dx.doi.Org/10.1016/i.chemosphere.2010.05.050
Sundstrom. M; Bogdanska. J: Pham. HV; Athanasios. V: Nobel. S: Mcalees. A: Eriksson. J:
Depierre. JW; Bergman. A. (2012). Radiosynthesis of perfluorooctanesulfonate (PFOS)
and perfluorobutanesulfonate (PFBS), including solubility, partition and adhesion studies.
Chemosphere 87: 865-871. http://dx.doi.org/10.1016/i.chemosphere.2012.01.027
U.S. EPA (U.S. Environmental Protection Agency). (1994). Chemical assessments and related
activities (CARA) [EPA Report], (600/R-94/904; OHEA-I-127). Washington, DC.
http://nepis. epa.gov/Exe/ZyPURL. cgi?Dockev=6000 lG8L.txt
U.S. EPA (U.S. Environmental Protection Agency). (201 la). Health Effects Assessment
Summary Tables (HEAST). Available online at http://epa-heast.ornl.gov/
U.S. EPA (U.S. Environmental Protection Agency). (201 lb). Recommended use of body weight
3/4 as the default method in derivation of the oral reference dose [EPA Report],
(EPA/100/R11/0001). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum, http://www.epa.gov/raf/publications/interspecies-extrapolation.htm
U.S. EPA (U.S. Environmental Protection Agency). (2012a). 2012 Edition of the drinking water
standards and health adivsories. (EPA/822/S-12/001). Washington, DC: Office of Water.
http://water.epa.gov/action/advisories/drinking/upload/dwstandards2012.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012b). Benchmark dose technical
guidance. (EPA/100/R-12/001). Washington, DC: Risk Assessment Forum.
http://www.epa.gov/raf/publications/pdfs/benchmark dose guidance.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012c). Integrated risk information system
(IRIS). Available online at http://dx.doi.Org/10.l 177/1091581812466418
WHO (World Health Organization). (2012). Online catalog for the Environmental Health
Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/en/
46
PFBS and related compound
------- |