A EPA
EPA/635/R-20/424b
External Review Draft
www.epa.gov/iris
Toxicological Review of Perfluorobutanoic Acid (PFBA)
and Related Compound Ammonium
Perfluorobutanoic Acid
(CASRN 375-22-4
CASRN 10495-86-0]
Supplemental Information—Appendices A though F
August 2021
Integrated Risk Information System
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Toxicological Review ofPFBA and Ammonium PFBA
DISCLAIMER
This document is an external review draft for review purposes only. This information is
distributed solely for the purpose of public comment. It has not been formally disseminated by
EPA. It does not represent and should not be construed to represent any Agency determination or
policy. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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CONTENTS
APPENDIX A. SYSTEMATIC REVIEW PROTOCOL FOR THE PFAS IRIS ASSESSMENTS A-l
APPENDIX B. ADDITIONAL DETAILS OF SYSTEMATIC REVIEW METHODS AND RESULTS B-l
APPENDIX C. ADDITIONAL TOXICOKINETIC INFORMATION IN SUPPORT OF DOSE-RESPONSE
ANALYSIS C-l
C.l. USE OF HALF-LIVES OF EXCRETION FOR DOSIMETRIC ADJUSTMENTS C-l
C.2. MIXED MODELING TO ESTIMATE HALF-LIFE IN HUMANS C-7
APPENDIX D. BENCHMARK DOSE MODELING RESULTS D-l
D.l. BENCHMARK DOSE MODELING APPROACHES D-l
D.l.l. Modeling Procedure for Dichotomous Noncancer Data D-l
D.1.2. Modeling Procedure for Continuous Noncancer Data D-l
D.1.3. Modeling Procedure for Continuous Noncancer Developmental Toxicity Data D-2
D.1.4. Modeling Procedure for Dichotomous Noncancer Developmental Toxicity Data D-3
D.1.5. Data Used for Modeling D-3
D.2. RELATIVE LIVER WEIGHT—MALE RATS (Butenhoff et al., 2012; van Otterdijk, 2007) D-16
D.3. RELATIVE LIVER WEIGHT—P0 MICE (Das et al., 2008) D-25
D.4. LIVER HYPERTROPHY—MALE RAT (Butenhoff et al., 2012; van Otterdijk, 2007) D-31
D.5. TOTAL T4—MALE RAT (Butenhoff et al., 2012; van Otterdijk, 2007) D-34
D.6. INCREASED FETAL MORTALITY - MALE AND FEMALE Fi MICE (Das et al., 2008) D-38
D.7. DELAYED EYE OPENING—Fi MALE AND FEMALE MICE (Das et al., 2008) D-45
D.8. VAGINAL OPENING—Fi FEMALE MICE (Das et al., 2008) D-51
D.9. PREPUTIAL SEPARATION—Fi MALE MICE (Das et al., 2008) D-57
D.10. RELATIVE LIVER WEIGHT—MALE HUMANIZED PPARa MICE (Foreman et al., 2009) D-61
APPENDIX E. SUMMARY OF PUBLIC COMMENTS AND EPA'S DISPOSITION E-l
APPENDIX F. QUALITY ASSURANCE FOR THE IRIS TOXICOLOGICAL REVIEW OF
PERFLUOROBUTANOIC ACID AND RELATED COMPOUND AMMONIUM
PERFLUOROBUTANOIC ACID F-l
REFERENCES R-l
This document is a draft for review purposes only and does not constitute Agency policy.
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TABLES
Table B-l. Perfluorobutanoic acid (PFBA) database search strategy B-l
Table B-2. Title/abstract-level screening criteria for the initial literature searches B-4
Table B-3. Example DistillerSR form questions to be used for title/abstract-level and full
text-level screening for literature search updates from 2019 B-6
Table D-l. Sources of data used in benchmark dose modeling of PFBA endpoints D-3
Table D-2. Data received from study authors for Das et al. (2008) on full litter resorptions (FLR) D-4
Table D-3. Data received from study authors for Das et al. (2008) on fetal death (litters without
full litter resorptions) combined with full litter resorptions D-5
Table D-4. Data received from study authors for Das et al. (2008) on delayed eye opening D-8
Table D-5. Data received from study authors for Das et al. (2008) on delayed vaginal opening D-ll
Table D-6. Data received from study authors for Das et al. (2008) on delayed preputial
separation D-14
Table D-7. Dose-response data for relative liver weight in male rats (Butenhoff et al., 2012; van
Otterdijk, 2007) D-16
Table D-8. Benchmark dose results for relative liver weight in male rats—constant variance,
BMR = 10% relative deviation (Butenhoff et al., 2012; van Otterdijk, 2007) D-17
Table D-9. Benchmark dose results for relative liver weight in male rats—nonconstant variance,
BMR = 10% relative deviation (Butenhoff et al., 2012; van Otterdijk, 2007) D-19
Table D-10. Benchmark dose results for relative liver weight in male rats—log-normal
distribution, constant variance, BMR = 10% relative deviation (Butenhoff et al.,
2012; van Otterdijk, 2007) D-20
Table D-ll. Benchmark dose results for relative liver weight in male rats—log-normal
distribution, constant variance, BMR = 1 standard deviation (Butenhoff et al.,
2012; van Otterdijk, 2007) D-24
Table D-12. Dose-response data for relative liver weight in pregnant mice (Das et al., 2008) D-25
Table D-13. Benchmark dose results for relative liver weight in pregnant mice—constant
variance, BMR = 10% relative deviation (Das et al., 2008) D-26
Table D-14. Benchmark dose results for relative liver weight in pregnant mice—constant
variance, BMR = 1 standard deviation (Das et al., 2008) D-30
Table D-15. Dose-response data liver hypertrophy in male rats (Butenhoff et al., 2012; van
Otterdijk, 2007) D-31
Table D-16. Benchmark dose results for liver hypertrophy in rats—BMR = 10% extra risk
(Butenhoff et al., 2012; van Otterdijk, 2007) D-31
Table D-17. Dose-response data for liver hypertrophy (slight severity lesions) in male rats
(Butenhoff et al., 2012; van Otterdijk, 2007) D-34
Table D-18. Benchmark dose results for liver hypertrophy (slight severity lesions) in male
rats—BMR = 10% extra risk (Butenhoff et al., 2012; van Otterdijk, 2007) D-34
Table D-19. Dose-response data for total T4 levels in male rats (Butenhoff et al., 2012; van
Otterdijk, 2007) D-34
Table D-20. Benchmark dose results for total T4 levels in male rats—constant variance,
BMR = 1 standard deviation (Butenhoff et al., 2012; van Otterdijk, 2007) D-35
Table D-21. Benchmark dose results for total T4 levels in male rats—nonconstant variance,
BMR = 1 standard deviation (Butenhoff et al., 2012; van Otterdijk, 2007) D-36
This document is a draft for review purposes only and does not constitute Agency policy.
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Table D-22. Benchmark dose results for total T4 levels in male rats—log-normal distribution,
constant variance, BMR = 1 standard deviation (Butenhoff et al., 2012; van
Otterdijk, 2007) D-37
Table D-23. Dose-response data for increased fetal mortality (Das et al., 2008) D-38
Table D-24. Benchmark dose results for increased fetal mortality (male and female
mice)—BMR = 1% extra risk (Das et al., 2008) D-40
Table D-25. Dose-response data for delayed eye opening in male and female mice (Das et al.,
2008) D-45
Table D-26. Benchmark dose results for delayed eye opening in male and female
mice—constant variance, BMR = 5% relative deviation (Das et al., 2008) D-46
Table D-27. Benchmark dose results for delayed eye opening in male and female
mice—constant variance, BMR = 1 standard deviation (Das et al., 2008) D-50
Table D-28. Dose-response data for delayed vaginal opening in female mice (Das et al., 2008) D-51
Table D-29. Benchmark dose results for delayed vaginal opening in female mice—constant
variance, 5% relative deviation (Das et al., 2008) D-52
Table D-30. Benchmark dose results for delayed vaginal opening in female mice—constant
variance, 1 standard deviation (Das et al., 2008) D-56
Table D-31. Dose-response data for delayed preputial separation in male mice (Das et al., 2008) D-57
Table D-32. Benchmark dose results for delayed preputial separation in male mice—constant
variance, BMR = 5% relative deviation (Das et al., 2008) D-57
Table D-33. Benchmark dose results for delayed preputial separation in male mice—constant
variance, BMR = 1 standard deviation (Das et al., 2008) D-61
Table D-34. Dose-response data for relative liver weight in male humanized PPARa mice
(Foreman et al., 2009) D-61
Table D-35. Benchmark dose results for delayed preputial separation in male
mice—nonconstant variance, BMR = 10% relative deviation (Das et al., 2008) D-62
This document is a draft for review purposes only and does not constitute Agency policy.
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FIGURES
Figure C-l. Mouse AUC after oral doses of PFBA C-l
Figure C-2. Mouse Cmax after oral doses of PFBA C-2
Figure C-3. Rat AUC after oral doses of PFBA C-3
Figure C-4. Rat Cmax after oral doses of PFBA C-4
Figure C-5. Estimated human half-lives versus initial serum concentrations C-5
Figure D-l. Dose-response curve for the Exponential M3 model fit to relative liver weight in
male rats (Butenhoff et al., 2012; van Otterdijk, 2007) D-21
Figure D-2. Dose-response curve for the Exponential M4 model fit to relative liver weight in
pregnant mice (Das et al., 2008) D-27
Figure D-3. Dose-response curve for the Weibull model fit to liver hypertrophy in male rats
(Butenhoff et al., 2012; van Otterdijk, 2007) D-32
Figure D-4. Dose-response curve for the Nested-Logistic model fit to increased fetal mortality in
male and female mice (Das et al., 2008) D-41
Figure D-5. Dose-response curve for the Hill model fit to delayed eye opening in male and
female mice (Das et al., 2008) D-47
Figure D-6. Dose-response curve for the Hill model fit to delayed vaginal opening in female mice
(Das et al., 2008) D-53
Figure D-7. Dose-response curve for the Exponential 3 model fit to delayed preputial separation
in male mice (Das et al., 2008) D-58
This document is a draft for review purposes only and does not constitute Agency policy.
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ABBREVIATIONS AND ACRONYMS
ACO
acyl-CoA oxidase
HAWC
Health Assessment Workspace
ADME
absorption, distribution, metabolism,
Collaborative
and excretion
HED
human equivalent dose
AFFF
aqueous film-forming foam
HERO
Health and Environmental Research
AIC
Akaike's information criterion
Online
ALP
alkaline phosphatase
HISA
highly influential scientific information
ALT
alanine aminotransferase
HPT
hypothalamic-pituitary-thyroid
AST
aspartate aminotransferase
IRIS
Integrated Risk Information System
atm
atmosphere
i.v.
intravenous
ATSDR
Agency for Toxic Substances and
IQ
intelligence quotient
Disease Registry
IQR
interquartile range
AUC
area-under-the-concentration curve
ISI
influential scientific information
BMD
benchmark dose
IUR
inhalation unit risk
BMDL
benchmark dose lower confidence limit
LLOQ
lower limit of quantitation
BMDS
Benchmark Dose Software
LN
log-normal
BMR
benchmark response
LOAEL
lowest-observed-adverse-effect level
BW
body weight
MBq
megabecquerel
Cavg
average concentration
MOA
mode of action
Cmax
maximum concentration
NCEA
National Center for Environmental
CA
Cochran-Armitage
Assessment
CAR
constitutive androstane receptor
NCV
nonconstant variance
CASRN
Chemical Abstracts Service registry
NIOSH
National Institute for Occupational
number
Safety and Health
CDR
Chemical Data Reporting
NIS
sodium-iodide symporter
CI
confidence interval
NOAEL
no-observed-adverse-effect level
CL
clearance
NPL
National Priority List
CLa
clearance in animals
NTP
National Toxicology Program
CLh
clearance in humans
OAT
organic anion transporter
CPAD
Chemical and Pollutant Assessment
OECD
Organisation for Economic Co-
Division
operation and Development
CPHEA
Center for Public Health and
OMB
Office of Management and Budget
Environmental Assessment
ORD
Office of Research and Development
CV
constant variance
OSF
oral slope factor
CYP450
cytochrome P450 superfamily
PC
partition coefficient
DAF
dosimetric adjustment factor
PBPK
physiologically based pharmacokinetic
DNA
deoxyribonucleic acid
PBTK
physiologically based toxicokinetic
DNT
developmental neurotoxicity
PECO
Populations, Exposures, Comparators,
DOD
Department of Defense
Outcomes
EPA
Environmental Protection Agency
PFAA
perfluoroalkyl acid
EOP
Executive Office of the President
PFAS
per- and polyfluoroalkyl substances
ER
extra risk
PFBA
perfluorobutanoic acid
FLR
full-litter resorption
PFBS
perfluorobutane sulfonate
FTOH
fluorotelomer alcohol
PFCA
perfluoroalkyl carboxylic acid
GD
gestation day
PFDA
perfluorodecanoic acid
GFR
glomerular filtration rate
PFHxA
perfluorohexanoic acid
GGT
y-glutamyl transferase
PFHxS
perfluorohexane sulfonate
GRADE
Grading of Recommendations
PFNA
perfluorononanoic acid
Assessment, Development, and
PFOA
perfluorooctanoic acid
Evaluation
PFOS
perfluorooctane sulfonate
GSH
glutathione
PK
pharmacokinetic
PND
postnatal day
This document is a draft for review purposes only and does not constitute Agency policy.
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POD
point of departure
TRI
Toxic Release Inventory
PODhed
human equivalent dose POD
TSCA
Toxic Substances Control Act
PPAR
peroxisome proliferator-activated
TSCATS
Toxic Substances Control Act Test
receptor
Submissions
PQAPP
Programmatic Quality Assurance
TSH
thyroid-stimulating hormone
Project Plan
TSHR
thyroid-stimulating hormone receptor
PT
prothrombin time
UCMR
Unregulated Contaminant Monitoring
PXR
pregnane X receptor
Rule
QA
quality assurance
UDP-GT
uridine 5'-diphospho-
QAPP
Quality Assurance Project Plan
glucuronosyltransferase
QMP
Quality Management Plan
UF
uncertainty factor
RBC
red blood cell
UFa
animal-to-human uncertainty factor
RD
relative deviation
UFc
composite uncertainty factor
RfC
inhalation reference concentration
UFd
database deficiencies uncertainty factor
RfD
oral reference dose
UFh
human variation uncertainty factor
RS
Rao-Scott
UFl
LOAEL-to-NOAEL uncertainty factor
SD
standard deviation
UFs
subchronic-to-chronic uncertainty
S-D
Sprague-Dawley
factor
SE
standard error
Vd
volume of distribution
TD
toxicodynamic
VOC
volatile organic compound
TH
thyroid hormone
WOS
Web of Science
TK
toxicokinetic
TPO
thyroid peroxidase
This document is a draft for review purposes only and does not constitute Agency policy.
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APPENDIX A. SYSTEMATIC REVIEW PROTOCOL
FOR THE PFAS IRIS ASSESSMENTS
1 A single systematic review protocol was used to guide the development of five, separate
2 IRIS PFAS assessments (i.e., PFBA, PFHxA, PFHxS, PFNA, and PFDA). This "systematic review
3 protocol for the PFAS IRIS assessments" was released for public comment and subsequently
4 updated. The updated protocol and prior revisions can be found at the following location:
5
6 http://cfpub.epa.gov/ncea/iris drafts/recordisplay.cfm?deid=345065
This document is a draft for review purposes only and does not constitute Agency policy.
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APPENDIX B. ADDITIONAL DETAILS OF
SYSTEMATIC REVIEW METHODS AND RESULTS
Table B-l. Perfluorobutanoic acid (PFBA) database search strategy
Search
Search strategy
Dates of search
PubMed
Search
terms
375-22-4[rn] OR "Heptafluoro-l-butanoic acid"[tw] OR "Heptafluorobutanoic
acid"[tw] OR "Heptafluorobutyric acid"[tw] OR "Kyselina
heptafluormaselna"[tw] OR "Perfluorobutanoic acid"[tw] OR
"Perfluorobutyric acid"[tw] OR "Perfluoropropanecarboxylic acid"[tw] OR
"2,2,3,3,4,4,4-heptafluoro-Butanoic acid"[tw] OR "Butanoic acid,
2,2,3,3,4,4,4-heptafluoro-"[tw] OR "Butanoic acid, heptafluoro-"[tw] OR
"Perfluoro-n-butanoic acid"[tw] OR "Perfluorobutanoate"[tw] OR
"2,2,3,3,4,4,4-Heptafluorobutanoic acid"[tw] OR "Butyric acid,
heptafluoro-"[tw] OR "Fluorad FC 23"[tw] OR "H 0024"[tw] OR "NSC 820"[tw]
OR «PFBA[tw] OR "FC 23"[tw] OR HFBA[tw]) AND (fluorocarbon*[tw] OR
fluorotelomer*[tw] OR polyfluoro*[tw] OR perfluoro-*[tw] OR
perfluoroa*[tw] OR perfluorob*[tw] OR perfluoroc*[tw] OR perfluorod*[tw]
OR perfluoroe*[tw] OR perfluoroh*[tw] OR perfluoron*[tw] OR
perfluoroo*[tw] OR perfluorop*[tw] OR perfluoros*[tw] OR perfluorou*[tw]
OR perfluorinated[tw] OR fluorinated[tw] OR PFAS[tw] OR PFOS[tw] OR
PFOA[tw]))
No date
limit—7/19/2017
Literature
update
search
terms
(((375-22-4[rn] OR "Heptafluoro-l-butanoic acid"[tw] OR
"Heptafluorobutanoic acid"[tw] OR "Heptafluorobutyric acid"[tw] OR
"Kyselina heptafluormaselna"[tw] OR "Perfluorobutanoic acid"[tw] OR
"Perfluorobutyric acid"[tw] OR "Perfluoropropanecarboxylic acid"[tw] OR
"2,2,3,3,4,4,4-heptafluoro-Butanoic acid"[tw] OR "Butanoic acid,
2,2,3,3,4,4,4-heptafluoro-"[tw] OR "Butanoic acid, heptafluoro-"[tw] OR
"Perfluoro-n-butanoic acid"[tw] OR "Perfluorobutanoate"[tw] OR
"2,2,3,3,4,4,4-Heptafluorobutanoic acid"[tw] OR "Butyric acid,
heptafluoro-"[tw] OR "Fluorad FC 23"[tw] OR "H 0024"[tw] OR "NSC 820"[tw]
OR «PFBA[tw] OR "FC 23"[tw] OR HFBA[tw]) AND (fluorocarbon*[tw] OR
fluorotelomer*[tw] OR polyfluoro*[tw] OR perfluoro-*[tw] OR
perfluoroa*[tw] OR perfluorob*[tw] OR perfluoroc*[tw] OR perfluorod*[tw]
OR perfluoroe*[tw] OR perfluoroh*[tw] OR perfluoron*[tw] OR
perfluoroo*[tw] OR perfluorop*[tw] OR perfluoros*[tw] OR perfluorou*[tw]
OR perfluorinated[tw] OR fluorinated[tw] OR PFAS[tw] OR PFOS[tw] OR
PFOA[tw])) AND ("2017/08/01"[PDAT] : "2018/02/14"[PDAT])
8/1/2017-2/14/2018
This document is a draft for review purposes only and does not constitute Agency policy.
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Search
Search strategy
Dates of search
Web of Science
Search
terms
TS="Heptafluoro-l-butanoic acid" OR TS="Heptafluorobutanoic acid" OR
TS="Heptafluorobutyric acid" ORTS="Kyselina heptafluormaselna" OR
TS="Perfluorobutanoic acid" OR TS="Perfluorobutyric acid" OR
TS="Perfluoropropanecarboxylic acid" OR
TS="2,2,3,3,4,4,4-heptafluoro-Butanoic acid" OR TS="Butanoic acid,
2,2,3,3,4,4,4-heptafluoro-" ORTS="Butanoic acid, heptafluoro-" OR
TS="Perfluoro-n-butanoic acid" ORTS="Perfluorobutanoate" OR
TS="2,2,3,3,4,4,4-Heptafluorobutanoic acid" OR TS="Butyric acid,
heptafluoro-" ORTS="Fluorad FC 23" ORTS="H 0024" ORTS="NSC 820" OR
(TS=(PFBA OR "FC 23" OR HFBA) AND TS=(fluorocarbon* OR fluorotelomer*
OR polyfluoro* OR perfluoro-* OR perfluoroa* OR perfluorob* OR
perfluoroc* OR perfluorod* OR perfluoroe* OR perfluoroh* OR perfluoron*
OR perfluoroo* OR perfluorop* OR perfluoros* OR perfluorou* OR
perfluorinated OR fluorinated OR PFAS OR PFOS OR PFOA))
No date
limit-7/20/2017
Literature
update
search
terms
((TS="Heptafluoro-l-butanoic acid" OR TS="Heptafluorobutanoic acid" OR
TS="Heptafluorobutyric acid" ORTS="Kyselina heptafluormaselna" OR
TS="Perfluorobutanoic acid" ORTS="Perfluorobutyric acid" OR
TS="Perfluoropropanecarboxylic acid" OR
TS="2,2,3,3,4,4,4-heptafluoro-Butanoic acid" OR TS="Butanoic acid,
2,2,3,3,4,4,4-heptafluoro-" ORTS="Butanoic acid, heptafluoro-" OR
TS="Perfluoro-n-butanoic acid" ORTS="Perfluorobutanoate" OR
TS="2,2,3,3,4,4,4-Heptafluorobutanoic acid" OR TS="Butyric acid,
heptafluoro-" ORTS="Fluorad FC 23" ORTS="H 0024" ORTS="NSC 820") OR
TS=(PFBA OR "FC 23" OR HFBA) AND TS=(fluorocarbon* OR fluorotelomer* OR
polyfluoro* OR perfluoro-* OR perfluoroa* OR perfluorob* OR perfluoroc*
OR perfluorod* OR perfluoroe* OR perfluoroh* OR perfluoron* OR
perfluoroo* OR perfluorop* OR perfluoros* OR perfluorou* OR
perfluorinated OR fluorinated OR PFAS OR PFOS OR PFOA)) AND
PY=2017-2018
2017-2018
Toxline
Search
terms
( 375-22-4 [rn] OR "heptafluoro- 1-butanoic acid" OR "heptafluorobutanoic
acid" OR "heptafluorobutyric acid" OR "kyselina heptafluormaselna" OR
"perfluorobutanoic acid" OR "perfluorobutyric acid" OR
"perfluoropropanecarboxylic acid" OR "2,2,3,3,4,4,4-heptafluoro-butanoic
acid" OR "butanoic acid 2 2 3 3 4 4 4-heptafluoro-" OR "butanoic acid
heptafluoro-" OR "perfluoro-n-butanoic acid" OR "perfluorobutanoate" OR
"2,2,3,3,4,4,4-heptafluorobutanoic acid" OR "butyric acid heptafluoro-" OR
"fluorad fc 23" OR "h 0024" OR "nsc 820" OR (( pfba OR "fc 23" OR hfba ) AND
(fluorocarbon* OR fluorotelomer* OR polyfluoro* OR perfluoro* OR
perfluorinated OR fluorinated OR pfas OR pfos OR pfoa ))) AND (ANEUPL
[org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR EPIDEM
[org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKUNE [org] OR
MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] )
AND NOT PubMed [org] AND NOT pubdart [org]
No date
limit-7/20/2017
This document is a draft for review purposes only and does not constitute Agency policy.
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Search
Search strategy
Dates of search
Literature
update
search
terms
@AND+@OR+("heptafluoro-l-butanoic
acid"+"heptafluorobutanoic+acid"+"heptafluorobutyric+acid"+"kyselina+hept
afluormaselna"+"perfluorobutanoic+acid"+"perfluorobutyric+acid"+"perfluor
opropanecarboxylic +acid"+"2 2 3 3 4 4
4-heptafluoro-butanoic+acid"+"butanoic+acid+2 2 3 3 4 4
4-heptafluoro-"+"butanoic+acid+heptafluoro-"+"perfluoro-n-butanoic
acid"+"perfluorobutanoate"+"2 2 3 3 4 4
4-heptafluorobutanoic+acid"+"butyric+acid+heptafluoro-"+"fluorad+fc+23"+"
h0024"+"nsc+820"+@TERM+@rn+375-22-4("pfba"+"fc+23"+"hfba"))+(
fluorocarbon*+
fluorotelomer*+polyfluoro*+perfluoro*+perfluorinated+fluorinated+pfas+pfo
s+pfoa)+@RANGE+yr+2017+2018
2017-2018
TSCATS
Search
terms
375-22-4[rn] AND tscats[org]
No date
limit-7/20/2017
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Table B-2. Title/abstract-level screening criteria for the initial literature
searches
Inclusion criteria
Exclusion criteria
Populations
Humans
Standard mammalian animal models, including rat,
mouse, rabbit, guinea pig, hamster, monkey, dog
Alternative animal models in standard laboratory
conditions (e.g., Xenopus, zebrafish, minipig)
Human or animal cells, tissues, or organs (not whole
animals); bacteria, nonmammalian eukaryotes; other
nonmammalian laboratory species
• Ecological species
Exposures
Exposure is to PFBA
• Study population is not exposed to PFBA
Exposure via oral, inhalation, dermal, intraperitoneal,
or intravenous injection routes
• Exposure is to a mixture only
Exposure is measured in air, dust, drinking water,
diet, gavage, injection or via a biomarker of exposure
(PFBA levels in whole blood, serum, plasma, or
breastmilk)
Outcomes
Studies that include a measure of one or more health
effect endpoints, including but not limited to, effects
on reproduction, development, developmental
neurotoxicity, liver, thyroid, immune system, nervous
system, genotoxicity, and cancer
In vivo or in vitro studies related to toxicity
mechanisms, physiological effects/adverse outcomes,
and studies useful for elucidating toxic modes of
action (MOAs)
Qualitative or quantitative description of absorption,
distribution, metabolism, excretion, toxicokinetic or
toxicodynamic models (e.g., PBPK, PBTK, PBTK/TD)
Studies addressing risks to infants, children, pregnant
women, occupational workers, the elderly, and any
other susceptible or differentially exposed
populations
This document is a draft for review purposes only and does not constitute Agency policy.
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Inclusion criteria
Exclusion criteria
Other
Structure and physiochemical properties
Not on topic, including:
Reviews and regulatory documents
• Abstract only, inadequately reported
abstract, or no abstract and not
considered further because study was
not potentially relevant
• Bioremediation, biodegradation, or
chemical or physical treatment of PFBA,
including evaluation of wastewater
treatment technologies and methods for
remediation of contaminated water and
soil
• Ecosystem effects
• Studies of environmental fate and
transport of PFBA in environmental
media
• Analytical methods for
detecting/measuring PFAS compounds in
environmental media and use in sample
preparations and assays
• Studies describing the manufacture and
use of PFBA
• Not chemical specific (studies that do
not involve testing of PFBA)
• Studies that describe measures of
exposure to PFBA without data on
associated health effects
MOA = mode of action; PBPK = physiologically based pharmacokinetic; PBTK = physiologically based toxicokinetic;
TD = toxicodynamic.
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Table B-3. Example DistillerSR form questions to be used for title/abstract-level and full text-level screening for
literature search updates from 2019
Used in title/abstract and full-text screening
Used in full text screening only
Question
Source of
study if not
identified
from database
search?
Does the
article meet
PECO criteria?
If meets PECO,
what type of
evidence?
If supplemental, what
type of information?
Which PFAS
did the study
report?
If meets PECO, which
health outcome(s) apply?
If meets PECO and
endocrine
outcome, which
endocrine tags
apply?
Answer
options
(can select
multiple
options)
• Source other
than HERO
database
search
• Yes
• No
• Unclear
• Tag as
potentially
relevant
supplemental
information
• Human
• Animal (mam-
malian
models)
• In vitro or
in silico
genotoxicity
• PBPKorPK
model
• In vivo mechanistic or
MOA studies,
including non-PECO
routes of exposure
(e.g., injection) and
populations
(e.g., nonmammalian)
• In vitro or in silico
studies
(nongenotoxicity)
• ADME/toxicokinetic
(excluding models)
• Exposure assessment
or characterization (no
health outcome)
• PFAS mixture study
(no individual PFAS
comparisons)
• Human case reports or
case series
• Ecotoxicity studies
• PFBA
• PFHxA
• PFHxS
• PFNA
• PFDA
• General toxicity, including
body weight, mortality,
and survival
• Cancer
• Cardiovascular, including
serum lipids
• Endocrine (hormone)
• Gastrointestinal
• Genotoxicity
• Growth (early life) and
development
• Hematological, including
nonimmune/hepatic/
renal clinical chemistry
measures
• Hepatic, including liver
measures and serum
markers (e.g., ALT; AST)
• Immune/
inflammation
• Adrenal
• Sex hormones
(e.g., androgen;
estrogen;
progesterone)
• Neuroendocrine
• Pituitary
• Steroidogenesis
• Thyroid
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Used in title/abstract and full-text screening
Used in full text screening only
Question
Source of
study if not
identified
from database
search?
Does the
article meet
PECO criteria?
If meets PECO,
what type of
evidence?
If supplemental, what
type of information?
Which PFAS
did the study
report?
If meets PECO, which
health outcome(s) apply?
If meets PECO and
endocrine
outcome, which
endocrine tags
apply?
• Environmental fate or
occurrence (including
food)
• Manufacture,
engineering, use,
treatment,
remediation, or
laboratory methods
• Other assessments or
records with no
original data
(e.g., reviews,
editorials,
commentaries)
• Musculoskeletal
• Nervous system,
including behavior and
sensory function
• Nutrition and metabolic
• Ocular
• PBPK or PK model
• Renal, including urinary
measures (e.g., protein)
• Reproductive
• Respiratory
• Skin and connective
tissue effects
ADME = absorption, distribution, metabolism, and excretion; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HERO = Health and
Environmental Research Online; MOA = mode of action; PBPK = physiologically based pharmacokinetic; PECO = Populations, Exposures, Comparators, and
Outcomes; PFAS = per- and polyfluoroalkyl substance; PFBA = perfluorobutanoic acid; PFDA = perfluorodecanoic acid; PFHxA = perfluorohexanoic acid;
PFHxS = perfluorohexanesulfonate; PFNA = perfluorononanoic acid; PK = pharmacokinetic.
This document is a draft for review purposes only and does not constitute Agency policy.
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APPENDIX C. ADDITIONAL TOXICOKINETIC
INFORMATION IN SUPPORT OF DOSE-RESPONSE
ANALYSIS
C.l. USE OF HALF-LIVES OF EXCRETION FOR DOSIMETRIC
ADJUSTMENTS
1 The pharmacokinetics of PFBA have only been measured after direct administration of
2 PFBA in single-exposure/single-day studies in animals (Chang etal.. 20081. For the mouse, Chang
3 etal. f20081 performed 24-hour toxicokinetic studies after 10, 30, and 100 mg/kgoral doses.
4 Based on the area-under-the-concentration-curve (AUC) and maximum concentration (Cmax), the
5 data also appear approximately linear below 3 0 mg/kg but show some saturation above that dose
6 rate (see Figure C-l, Figure C-2).
9000
0000
7000
— 6000
E
£ 5000
— 4000
D
<¦ 3000
2000
1000
0
9 Male
+ Fen ale
0
I
~
20
Mouse 24-h AUC
after oral doses of
)
40 60
Dose (mg/kg)
80
100
Figure C-l. Mouse AUC after oral doses of PFBA.
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350
300
250
•|2t>0
| 150
u
• Male
+ Fan ale
100
5
I
Mouse Cmax after
oral doses of PFBA
}
}
50
0
0
20
40 60
Dose (mg/kg)
SO
100
Figure C-2. Mouse Cmax after oral doses of PFBA.
Chang etal. f20081 reported serum and liver concentrations in male rats and serum
concentrations in female rats given a 3-300 mg/kg oral dose ofPFBA at 24 hours after dosing.
Although the time point for these measurements is not ideal given the short half-life of PFBA, the
data indicate that the dosimetry is approximately linear up to 100 mg/kg in male rats and up to
30 mg/kg in female rats (see Figure C-3, Figure C-4). Tissue levels then appear to saturate or
decline; this might be due to incomplete absorption at higher doses, saturable renal resorption, or
both, whereby excretion is more rapid for concentrations above the level of saturable resorption in
the kidney. With the half-life in female rats being ~3 hours, the female serum 24-hour data are
particularly subject to experimental noise, but at least provide an indication that use of the half-life
measured using a 30 mg/kg dose is applicable to BMD levels from bioassays at or below this dose
rate.
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72
to 60
° 48
E
36
s
o
£ 24
c
OJ
u
312
0
• Serum
+ Liver
f i
*
0
¦i x
Male rat tissue
concentrations 24 h after
an oral dose of PFBA
50 100 150 200
Dose (mg/kg)
250
300
Figure C-3. Rat AUC after oral doses of PFBA.
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E
1
e
o
%
Ol
0.4
0.35
0.3
0.25
0.2
0.15
o
u 0.1
0.05
0
Female rat serum
concentration 24 h after
j
an oral dose of PFBA
i
L
!
-1
«
r
-
*
0 50 100 150 200
Dose (mg/kg)
250
300
Figure C-4. Rat Cmax after oral doses of PFBA.
1 For the human data analyzed by Chang etal. f20081. detailed toxicokinetic parameters are
2 not available, but one can evaluate the relationship between the initial concentration and ti/2. Here
3 we only consider data for subjects in which the final concentration is greater than the limit of
4 quantification to avoid statistical artifacts due to limited observational data. Although the lower
5 half-life of the subject with the highest initial concentration indicates a possible negative trend, the
6 half-life is in the range of subjects with lower initial concentrations. Thus, these data do not show a
7 clear dose dependence for half-life and are interpreted as only showing interindividual variation
8 (see Figure C-5). The human data appear consistent with first-order clearance across the range of
9 concentrations observed.
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160
140
120
i 100
Ol
= SO
<•1
« 60
40
20
0
t
Human half-life vs. initial concentration
*
• •
•
•
•
•
•
} 20 40 60 SO
Initial concentration (ng/ml)
Figure C-5. Estimated human half-lives versus initial serum concentrations.
Chang etal. f20081 only evaluated one PFBA dose in monkeys, so determining whether the
biphasic clearance pattern is due to the classical distinction between distribution and excretion
phases or a nonlinearity in clearance is not possible. The data show linear clearance from 1-7 or
10 days after the i.v. dose was given, however, when serum concentrations were below 100 ng/mL.
Thus, interpreting these data as showing linear kinetics for serum concentrations below 100 ng/mL
under long-term exposure conditions seems reasonable. Because the highest initial condition of the
human subjects in Chang etal. (20081 was 72 ng/mL, to the extent that kinetics in monkeys can be
extrapolated to humans, the results for monkeys confirm the conclusion that human kinetics are
also reasonably assumed linear below ~100 ng/mL. This is approximately 1,000-fold below the
range of linearity in mice and rats, however, so uncertainty exists as to whether the range of linear
kinetics in humans and monkeys extends into the range of rodent-based points of departure.
Russell etal. (20151 attempted to evaluate the kinetics ofPFBA as a metabolite of
6:2 fluorotelomer alcohol (FTOH) during a 1-day inhalation study (6-hour exposure, 24-hour
observation) and at the end of 23 days of exposure. The half-life of PFBA, however, could not be
estimated from the single-day data for male rats and could be estimated only for the high-level
exposure in female rats, with yields ofPFBA 0.2% in males and not detectable or 0.02% in females.
Also, three metabolic intermediates occur between 6:2 FTOH and PFBA, but the model appears to
have assumed direct, instantaneous transformation through the first two steps. Assumptions about
the volume of distribution were made by Russell etal. (20151. These simplifications in the model
likely explain the large discrepancy between the PFBA half-life determined from the single-day
exposure 6:2 FTOH for female rats (19 hours) and the half-life obtained for direct exposure to PFBA
(1.4-hour average) by Chang etal. f20081. Russell etal. f20151 used only male rats in the 2 3-day
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6:2 FTOH inhalation study, from which they estimated a half-life of 27.7 hours, over three times
higher than the average obtained by Chang etal. f20081. The discrepancy also could be due to an
underestimation of the metabolic yield from the 1-day experiments. In summary, whereas Russell
etal. f20151 described measurements ofPFBA in male rats from 23 days of exposure to 6:2 FTOH,
the results for female rats after a single exposure are completely inconsistent with the results of
(Chang etal.. 2008). Therefore, the conclusions from the multiday study are considered too
unreliable to be used.
The other long-term data available on internal dosimetry are from the bioassays (Butenhoff
etal.. 2012: Das etal.. 2008: van Otterdiik. 20071. Serum concentrations in nonpregnant female
mice after 17 days of exposure (24 hours after the last dose) are 2.0 ± 1.0 and 2.4 ± 1.7 [ig/mL, and
for pregnant mice are 3.8 ± 1.0 and 4.4 ± 0.7 [ig/mL, for the 35- and 175-mg/kg dose groups,
respectively fDas etal.. 20081. For female mice dosed with 30- and 100-mg/kg PFBA, Chang et al.
(2008) reported 4.1 ± 1.7 and 6.4 ± 3.9 |J.g/mL in serum 24 hours after the dose; using linear
extrapolation based on the difference in dose, one might expect 4.8 and 11.2 |J.g/mL at 24 hours
after doses of 35 and 175 mg/kg, given these data. Although the concentrations in the Das etal.
f20081 study are somewhat lower than these projections, the difference, especially at the low dose,
is within the range of uncertainty and precision expected for PK analysis.
Of note is that, given an average clearance of 28 mL/kg-hour obtained by Chang et al.
(2008) after 10- and 30-mg/kg doses, the predicted average serum concentrations for a 35-mg/kg
dose is 52 [ig/mL. This average concentration reflects the much higher concentrations expected in
the first few hours after each dose.
For male rats. Butenhoff et al. (2012) measured end-of-treatment serum levels of 38 ± 23
and 52 ± 25 |ig/mL after 28 and 90 days, respectively, at 30 mg/kg-day; we presume these
measurements were made 24 hours after the last dose. The corresponding values reported by
Chang etal. f20081 for a 30-mg/kg oral dose in the dose-range and time-course studies are 16 ± 3
and 29 ± 13 [ig/mL, respectively. Although again, some discrepancy is found between the
short-term PK data and the bioassay measurements, the difference is that it is roughly within a
factor of 2, which is acceptable for PK analysis and does not indicate a strong time dependence in
the PK. One should keep in mind that the estimated clearance and half-life values are based on
multiple time points at which the serum concentration is measured, while the comparisons above
use only a single time point, 24 hours after dosing, when the result will be sensitive to experimental
variation.
Given these data and results, the half-life or clearance ofPFBA measured in single-day
exposures by Chang etal. (2008) will be assumed to predict dosimetry after repeated exposures
that occur in bioassays. This is a common assumption for chemicals with relatively short half-lives
because pharmacokinetic studies are typically confined to a single day or less. Clearance in rats and
mice might include a slower beta phase, like that observed in monkeys. If a slow clearance phase
exists, internal dose from long-term exposure will be higher than is effectively estimated using the
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clearance rate determined from single-day exposures, which would increase the HED compared
with the current prediction. Using an animal-human ratio of clearance values to estimate the HED
relies only on the assumptions that the average serum concentration (Cavg) is predictive of systemic
effects in adults and that the relationship between Cavg and dose rate is linear with the
proportionality determined by the clearance values estimated here (i.e., the clearance from
single-day experiments is predictive of bioassay conditions).
The human half-life estimates were from subjects who had been occupationally exposed to
PFBA, with the duration of the PK observation 7-10 days. Thus, those results are reasonably
expected to represent clearance under (subsequent to) chronic exposure conditions. The primary
uncertainty in predicting human clearance comes from assuming a volume of distribution equal to
that estimated for monkeys, which is thought modest given the physiological similarity between
monkeys and humans. Thus, the overall uncertainty from using the animal-human clearance ratio
to predict the HED for systemic effects in adults appears modest, especially compared to the case
where PK data such as used here are not available.
Because developmental effects are usually presumed to depend on peak concentration
rather than average concentration, it must be noted that use of the clearance ratio to estimate HEDs
for those endpoints also involves an assumption that the absorption rate in humans is similar to
that of animals. For PFBA, the absorption rate in mice and rats is fairly rapid, with the peak
concentration occurring 0.6-4 hours after bolus oral doses (Chang etal.. 2008). That absorption in
humans would be faster than in rodents seems unlikely, and exposures are more likely spread out
over the day than in the animal bioassays. Therefore, the most likely case is that the peak
concentration in humans exposed at the HED will be lower than the peak concentration in mice or
rats at the corresponding dose rate. Thus, although this assumption creates uncertainty in the dose
extrapolation, the result is not expected to underpredict human health risks.
C.2. MIXED MODELING TO ESTIMATE HALF-LIFE IN HUMANS
A linear mixed-effects model was additionally used to estimate a ti/2 for PFBA according to
methods described in Li etal. (2018). Briefly, linear mixed-effect models are extensions of simple
linear models that use the best linear unbiased prediction estimator to estimate random and fixed
effects for clustered data. One important consequence of clustering is that measurements of serum
PFBA units within the same person (cluster) are more similar than measurements on serum PFBA
in different people (i.e., other clusters). Failure to account for the intracluster correlation would
result in misleading inferences. Each individual in Chang etal. (2008) was assumed to have been
selected randomly from a larger population. Below is the mixed model formula used for estimating
the half-life of serum PFBA:
Serum PFBA^- = (apop + at) + (fcpop + kt) x ttJ + Ei} (C-l)
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where PFBA,y is the natural logarithm of the serum PFBA concentrations measured at the jth time
point for the ith subject, crpop is the population mean (also known as the fixed intercept for the
population); ai ~ N (0, o2a) is a random intercept for the ith subject; /fpop is the fixed slope for the
population (also known as the average excretion rate constant for serum PFBA for the whole
population); ki ~ N (0, a2k) is the random slope for the ith subject that allows the excretion rate to
vary by individuals; t,y represents the observation time for the jth measurement of serum PFBA for
ith subject; and £,y ~ N (0, a2e) is the random-error effect (residual) for jth measurement of ith
subject Of note, the small sample sizes (due to the exclusion of the only two subjects identified as
females) limited our ability to draw clear conclusions in gender-stratified comparisons.
The half-life of serum PFBA for the study population (ti/2,pop) then was estimated as:
^1/2, pop
ln(2)
fcpop
(C-2)
The mixed-effects model estimated /fpop to be -0.010, therefore resulting in an estimated ti/2
of 67.9 hours. This value matches very closely to the median value calculated when not taking
clustering into account, and therefore was used in estimation of clearance in humans.
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APPENDIX D. BENCHMARK DOSE MODELING
RESULTS
D.l. BENCHMARK DOSE MODELING APPROACHES
As discussed in Section 5 of the body of the Toxicological Review, the endpoints selected for
benchmark dose (BMD) modeling were relative liver weight, liver hypertrophy, total T4, and
thyroid follicular hypertrophy incidence from Butenhoff etal. f20121 and relative liver weight, full
litter resorption, delayed eye opening, delayed vaginal opening and delayed preputial separation
from Das etal. (2008). The animal doses in the study were used in the BMD modeling and then
converted to human equivalent doses (HEDs) using the ratio of animal-to-human clearance values;
the modeling results are presented in this appendix.
D.l.l. Modeling Procedure for Dichotomous Noncancer Data
BMD modeling of dichotomous noncancer data was conducted using EPA's Benchmark Dose
Software (BMDS, version 3.1.2). For these data, the Gamma, Logistic, Log-Logistic, Log-Probit,
Multistage, Probit, Weibull, and Dichotomous Hill models available within the software were fit
using a benchmark response (BMR) of 10% extra risk (see Toxicological Review, Section 4.2.1 for
justification of selected BMRs). The Multistage model is run for all polynomial degrees up to n - 2,
where n is the number of dose groups including control. Adequacy of model fit was judged on the
basis ofx2 goodness-of-fit p-value (p >0.1), scaled residuals at the data point (except the control)
closest to the predefined benchmark response (absolute value <2.0), and visual inspection of the
model fit. In the cases where no best model was found to fit to the data, a reduced data set without
the high-dose group was further attempted for modeling and the result presented with that of the
full data set In cases where a model with several parameters equal to the number of dose groups
was fit to the data set, all parameters were estimated, and no p-value was calculated, that model
was not considered for estimating a point of departure (POD) unless no other model provided
adequate fit. Among all models providing adequate fit, the benchmark dose lower confidence limit
(BMDL) from the model with the lowest Akaike's information criterion (AIC) was selected as a
potential POD when BMDL values were sufficiently close (within threefold). Otherwise, the lowest
BMDL was selected as a potential POD.
D.l.2. Modeling Procedure for Continuous Noncancer Data
BMD modeling of continuous noncancer data was conducted using EPA's Benchmark Dose
Software (BMDS, version 3.1.2). For these data, the Exponential, Hill, Polynomial, and Power
models available within the software are fit using a BMR of 1 standard deviation (SD) when no
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toxicological information was available to determine an adverse level of response. When
toxicological information was available, the BMR was based on relative deviation, as outlined in the
Benchmark Dose Technical Guidance fU.S. EPA. 20121 (see Toxicological Review, Section 5.2.1 for
justification for using BMRs); when a BMR based on relative deviation was used, modeling results
using BMRs based on SD are included for reference. An adequate fit is judged on the basis ofx2
goodness-of-fitp-value (p > 0.1), scaled residuals at the data point (except the control) closest to
the predefined benchmark response (absolute value <2.0), and visual inspection of the model fit In
addition to these three criteria for judging adequacy of model fit, a determination is made on
whether the variance across dose groups is homogeneous. If a homogeneous variance model is
deemed appropriate based on the statistical test provided by BMDS (i.e., Test 2), the final BMD
results are estimated from a homogeneous variance model. If the test for homogeneity of variance
is rejected (p < 0.05), the model is run again while modeling the variance as a power function of the
mean to account for this nonhomogeneous variance. If this nonhomogeneous variance model does
not adequately fit the data (i.e., Test 3; p < 0.05), alternative approaches were assessed on a
case-by-case basis. For example, in cases where neither variance model fit, or constant variance did
not fit (with adequate Test-4 p-value) and nonconstant variance did fit (with inadequate Test-4
p-value), the log-normal distribution was attempted.
In cases where a model with several parameters equal to the number of dose groups was fit
to the data set, all parameters were estimated, and no p-value was calculated, that model was not
considered for estimating a POD unless no other model provided adequate fit. Among all models
providing adequate fit, the BMDL from the model with the lowest AIC was selected as a potential
POD when BMDL estimates differed by less than threefold. When BMDL estimates differed by
greater than threefold, the model with the lowest BMDL was selected to account for model
uncertainty.
D.1.3. Modeling Procedure for Continuous Noncancer Developmental Toxicity Data
For continuous developmental toxicity data, data for individual animals were requested
from the study authors when possible. The use of individual animal data allows for the correct
measure of variance to be calculated. When a biological rationale for selecting a benchmark
response level is lacking, a BMR equal to 0.5 SD was used. The use of 1 SD for the BMR for
continuous endpoints is based on the observation that shifting the distribution of the control group
by 1 SD results in ~10% of the animal data points falling beyond an adversity cutoff defined at the
~1.5 percentile (Crump. 1995). This approximates the 10% extra risk commonly used as the BMR
for dichotomous endpoints. Thus, the use of 0.5 SD for continuous developmental toxicity
endpoints approximates the extra risk commonly used for dichotomous developmental toxicity
endpoints.
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D.1.4. Modeling Procedure for Dichotomous Noncancer Developmental Toxicity Data
For dichotomous developmental toxicity data, data for individual animals were requested
from the study authors when possible. This allowed the use of the nested logistic model, which
statistically accounts for intralitter similarity (the propensity of littermates to respond more like
one another than pups from another litter) by estimating intralitter correlation and using
litter-specific covariates. Judging model fit for this model is identical to the procedure used for
regular dichotomous models.
D.1.5. Data Used for Modeling
The source of the data used for modeling is provided in Table D-l. For endpoints from the
Das etal. (2008) study, the study authors kindly provided individual dam-level data to facilitate
modeling and to provide corrected data where needed. These data also are included in full in the
tables below.
Table D-l. Sources of data used in benchmark dose modeling of PFBA
endpoints
Endpoint/Reference
Reference
Location
HAWC link
Relative liver weight
Butenhoff et al.
(2012)
Appendix 1, page 37 (van
Otterdiik, 2007)
https://hawcprd. eoa.gov/ani/endDoint/
100507453/
Relative liver weight
Das et al. (2008)
Figure 2, page 175
https://hawcprd. eoa.gov/ani/endDoint/
100507508/
Liver hypertrophy
Butenhoff et al.
(2012)
Table 9, page 523
httos://hawcord. eoa.gov/ani/endooint/
100507383/
Total T4
Butenhoff et al.
(2012)
Table 8, page 522
httos://hawcord. eoa.gov/ani/endooint/
100507375/
Full litter resorption
Das et al. (2008)
Table D-2
Fetal mortality (full
litter resorptions
combined with fetal
death from litters
without full litter
resorptions)
Das et al. (2008)
Table D-3
Eyes opening
Das et al. (2008)
Table D-4
Vaginal opening
Das et al. (2008)
Table D-5
Preputial separation
Das et al. (2008)
Table D-6
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-2. Data received from study authors for Das etal. (2008)
on full litter resorptions (FLR)
Dose (mg/kg-day)
Number of implants FLR
0
8
0
18
35
2
175
2
175
2
175
9
175
5
350
3
350
2
350
13
350
13
350
3
350
14
350
13
This document is a draft for review purposes only and does not constitute Agency policy.
D-4 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-3. Data received from study authors for Das etal. (2008) on fetal
death (litters without full litter resorptions) combined with full litter
resorptions
Dose (mg/kg-day)
Number of implants
Number of dead
Dam weight on GDI (litter-
specific covariate)
0
16
1
30
0
16
1
28.2
0
11
2
27.7
0
11
0
27.4
0
12
3
25.9
0
11
0
24.1
0
15
0
29.2
0
14
1
28
0
12
3
27.1
0
14
0
26.8
0
16
1
26.6
0
13
2
25.1
0
17
3
30.1
0
14
0
29
0
6
0
27.5
0
9
2
28.1
0
6
0
26.9
0
13
1
26.7
0
11
0
23.3
0
8
8
25.8
0
18
18
31.4
35
15
3
28.1
35
13
0
29.3
35
13
0
27.4
35
14
1
27
35
15
2
26.9
35
13
2
25.7
35
12
4
31.6
This document is a draft for review purposes only and does not constitute Agency policy.
D-5 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Number of implants
Number of dead
Dam weight on GDI (litter-
specific covariate)
35
13
0
29.2
35
14
1
27.7
35
16
0
27.5
35
13
2
28.1
35
7
3
25.5
35
15
1
30.3
35
13
0
27.5
35
14
1
28.1
35
13
1
27.9
35
11
0
26.4
35
10
1
27.4
35
13
1
27.9
35
13
0
26.1
35
13
1
24.8
35
12
1
24.8
35
2
2
23.1
175
14
1
28.1
175
15
0
27.5
175
14
0
27.4
175
14
1
27.5
175
15
2
29.4
175
14
1
27.5
175
15
0
26
175
16
2
26.2
175
11
0
23.4
175
16
3
29.1
175
11
0
28.2
175
13
0
25.8
175
11
2
26.8
175
15
1
26.9
175
14
1
25
This document is a draft for review purposes only and does not constitute Agency policy.
D-6 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Number of implants
Number of dead
Dam weight on GDI (litter-
specific covariate)
175
13
1
26.7
175
2
2
25.5
175
2
2
25.4
175
9
9
29
175
5
5
25
350
7
2
29.2
350
12
1
26.3
350
16
3
27.4
350
11
0
25.1
350
14
2
25.3
350
12
1
29.5
350
16
2
28.8
350
17
2
26.2
350
12
2
26.2
350
16
0
27.3
350
9
3
27.6
350
13
0
27.7
350
13
0
27.4
350
13
1
26.4
350
7
1
24.6
350
3
3
21.5
350
2
2
23
350
13
13
25.8
350
13
13
24.6
350
3
3
25.1
350
14
14
28.2
350
13
13
29.2
350
1
1
25.4
This document is a draft for review purposes only and does not constitute Agency policy.
D-7 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-4. Data received from study authors for Das etal. (2008)
on delayed eye opening
Dose (mg/kg-day)
Average day of eye opening
0
16.27
0
15.57
0
15.22
0
15.27
0
14.55
0
14.91
0
17.64
0
15.69
0
15.00
0
17.57
0
17.71
0
14.91
0
16.50
0
17.58
0
16.50
0
16.25
0
15.20
0
17.25
0
18.00
0
18.00
35
16.00
35
17.31
35
18.00
35
17.23
35
17.23
35
16.82
35
18.78
35
17.31
35
17.57
35
17.53
35
18.00
This document is a draft for review purposes only and does not constitute Agency policy.
D-8 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of eye opening
35
15.25
35
17.00
35
17.82
35
18.09
35
17.70
35
16.11
35
18.29
35
17.50
35
17.55
35
17.60
35
17.78
175
17.69
175
17.67
175
15.71
175
17.77
175
16.91
175
18.00
175
17.69
175
17.27
175
17.17
175
17.64
175
18.00
175
18.00
175
18.09
175
18.88
175
18.00
175
18.00
175
18.20
350
15.00
350
18.64
350
17.85
350
17.64
350
18.00
This document is a draft for review purposes only and does not constitute Agency policy.
D-9 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of eye opening
350
17.36
350
17.85
350
17.93
350
18.00
350
18.00
350
18.00
350
18.60
350
18.00
350
18.09
350
18.00
This document is a draft for review purposes only and does not constitute Agency policy.
D-10 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-5. Data received from study authors for Das etal. (2008)
on delayed vaginal opening
Dose (mg/kg-day)
Average day of vaginal opening
0
32.40
0
27.00
0
30.80
0
30.20
0
34.17
0
33.67
0
30.33
0
28.00
0
30.14
0
33.67
0
28.00
0
31.90
0
32.50
0
34.00
0
29.25
0
28.00
0
29.33
0
35.57
0
34.83
35
28.20
35
34.00
35
37.25
35
34.00
35
31.00
35
31.20
35
35.67
35
34.25
35
35.38
35
30.00
35
31.50
35
31.20
This document is a draft for review purposes only and does not constitute Agency policy.
D-ll DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of vaginal opening
35
33.50
35
32.50
35
37.67
35
35.00
35
35.20
35
33.00
35
34.50
35
38.50
35
34.30
175
31.60
175
29.40
175
33.67
175
31.67
175
34.20
175
34.50
175
37.00
175
32.22
175
38.00
175
34.50
175
34.33
175
34.67
175
37.86
175
33.00
175
36.50
175
35.33
175
39.25
350
35.00
350
36.00
350
33.80
350
33.00
350
32.00
350
31.17
350
33.57
This document is a draft for review purposes only and does not constitute Agency policy.
D-12 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of vaginal opening
350
34.10
350
33.33
350
38.70
350
36.33
350
36.00
350
37.25
350
35.00
350
38.50
This document is a draft for review purposes only and does not constitute Agency policy.
D-13 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-6. Data received from study authors for Das etal. (2008)
on delayed preputial separation
Dose (mg/kg-day)
Average day of preputial separation
0
29.00
0
28.20
0
28.20
0
28.00
0
31.80
0
29.20
0
28.71
0
30.00
0
31.00
0
28.29
0
30.00
0
29.80
0
31.00
0
29.50
0
29.00
0
31.00
0
29.67
35
27.40
35
33.40
35
28.20
35
31.80
35
30.00
35
31.33
35
35.50
35
30.22
35
33.17
35
30.00
35
29.00
35
30.14
35
30.29
35
29.80
This document is a draft for review purposes only and does not constitute Agency policy.
D-14 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of preputial separation
35
30.43
35
30.00
35
27.50
35
28.20
35
28.57
35
29.25
35
30.17
175
26.60
175
28.80
175
30.50
175
31.71
175
31.11
175
32.33
175
28.00
175
31.00
175
35.00
175
30.60
175
30.13
175
29.50
175
30.00
175
31.60
175
31.00
175
30.17
175
31.50
350
28.00
350
31.80
350
31.50
350
32.40
350
31.83
350
30.80
350
31.17
350
33.80
350
34.00
This document is a draft for review purposes only and does not constitute Agency policy.
D-15 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
Average day of preputial separation
350
30.33
350
30.00
350
33.17
350
32.00
350
32.80
D.2. RELATIVE LIVER WEIGHT-MALE RATS fButenhoffet al..2012:
van Otterdiik. 200711
Table D-7. Dose-response data for relative liver weight in male rats
(Butenhoff et al.. 2012: van Otterdijk. 2007)
Dose (mg/kg-day)
n
Mean
SD
0
10
2.11
0.13
1.2
10
2.29
0.14
6
10
2.26
0.16
30
10
2.8
0.32
'Throughout this document, if a model was selected as appropriately fitting the modeled data, that model's
entries in the tables are in green shaded cells and the text is bolded.
This document is a draft for review purposes only and does not constitute Agency policy.
D-16 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-8. Benchmark dose results for relative liver weight in male
rats—constant variance, BMR = 10% relative deviation (Butenhoff etal.. 2012:
van Otterdijk. 2007)
Models
Restriction3
10% Relative
deviation
p-Value
AIC
BMDS
classification13
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
11.3634
9.4685
0.1720
-8.8244
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Modeled control response
SD > 11.51 actual response
SD
Exponential 3
(CV—normal)
Restricted
11.3634
9.4572
0.1720
-8.8244
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Modeled control response
SD > 11.51 actual response
SD
Exponential 4
(CV—normal)
Restricted
10.4110
4.8569
0.0584
-6.7628
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Goodness-of-fit
p-value < 0.1
Modeled control response
SD > 11.51 actual response
SD
Exponential 5
(CV—normal)
Restricted
10.4033
4.8563
0.0584
-6.7621
Questionable
Constant variance test
failed (Test 2 p-
value < 0.05)
Goodness-of-fit
p-value < 0.1
Modeled control response
SD > 11.51 actual response
SD
Hill
(CV—normal)
Restricted
6.6152
6.0656
NA
-4.1913
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Modeled control response
SD > 11.51 actual response
SD
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
This document is a draft for review purposes only and does not constitute Agency policy.
D-17 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Models
Restriction3
10% Relative
deviation
p-Value
AIC
BMDS
classification13
BMDS notes
BMD
BMDL
Constant variance
Polynomial
(3 degree)
(CV—normal)
Restricted
12.8952
8.4671
0.0624
-6.8714
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Goodness-of-fit
p-value < 0.1
Modeled control response
SD > 11.51 actual response
SD
Polynomial
(2 degree)
(CV—normal)
Restricted
12.1463
8.4560
0.0611
-6.8370
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Goodness-of-fit
p-value < 0.1
Modeled control response
SD > 11.51 actual response
SD
Power
(CV—normal)
Restricted
10.4151
8.4328
0.1668
-8.7631
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Modeled control response
SD > 11.51 actual response
SD
Linear
(CV—normal)
Unrestricted
10.4151
8.4328
0.1668
-8.7631
Questionable
Constant variance test
failed (Test 2
p-value < 0.05)
Modeled control response
SD > 11.51 actual response
SD
a"Restriction" column denotes the restriction status of applied models.
^'Classification" column denotes whether a model can be considered for model selection purposes. See BMDS
User Guide: https://www.epa.gov/bmds.
This document is a draft for review purposes only and does not constitute Agency policy.
D-18 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-9. Benchmark dose results for relative liver weight in male
rats—nonconstant variance, BMR = 10% relative deviation (Butenhoff et al..
2012: van Otterdijk. 2007)
Models
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Nonconstant variance
Exponential 2
(NCV—normal)
Restricted
11.3982
9.0908
0.0362
-15.2001
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 3
(NCV—normal)
Restricted
11.3962
9.0911
0.0362
-15.2001
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 4
(NCV—normal)
Restricted
10.5179
5.2058
0.0096
-13.1325
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 5
(NCV—normal)
Restricted
10.5091
5.2055
0.0096
-13.1313
Questionable
Goodness-of-fit
p-value < 0.1
Hill
(NCV—normal)
Restricted
11.1854
7.9783
0.0090
-13.0126
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial
(3 degree)
(NCV—normal)
Restricted
12.7313
8.1751
0.0104
-13.2674
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial
(2 degree)
(NCV—normal)
Restricted
11.9089
8.1513
0.0100
-13.2065
Questionable
Goodness-of-fit
p-value < 0.1
Power
(NCV—normal)
Restricted
10.5174
8.1228
0.0350
-15.1326
Questionable
Goodness-of-fit
p-value < 0.1
Linear
(NCV—normal)
Unrestricted
10.5179
8.1236
0.0350
-15.1326
Questionable
Goodness-of-fit
p-value < 0.1
This document is a draft for review purposes only and does not constitute Agency policy.
D-19 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-10. Benchmark dose results for relative liver weight in male
rats—log-normal distribution, constant variance, BMR = 10% relative
deviation (Butenhoff et al.. 2012: van Otterdijk. 2007)
Models3
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Log-normal distribution, constant variance
Exponential 2
(CV—log-normal)
Restricted
11.5672
9.5455
0.1004
-14.1752
Viable-
Alternate
Modeled control
response SD >| 1.51
actual response SD
Exponential 3
(CV—log-normal)
Restricted
11.5672
9.6019
0.1004
-14.1752
Viable-
Recommended
Lowest AIC
Modeled control
response SD > 11.51
actual response SD
Exponential 4
(CV—log-normal)
Restricted
10.6449
5.1404
0.0311
-12.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >11.51
actual response SD
Exponential 5
(CV—log-normal)
Restricted
10.6419
5.1401
0.0311
-12.1239
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Hill
(CV—log-normal)
Restricted
10.5728
4.9799
0.0976
-14.1178
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Polynomial
(3 degree)
(CV—log-normal)
Restricted
12.6948
8.5635
0.0328
-12.2144
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >11.51
actual response SD
Polynomial
(2 degree)
(CV—log-normal)
Restricted
11.9903
8.5515
0.0321
-12.1783
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
This document is a draft for review purposes only and does not constitute Agency policy.
D-20 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Models3
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Log-normal distribution, constant variance
Power
(CV—log-normal)
Restricted
10.6452
8.5334
0.0979
-14.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Linear
(CV—log-normal)
Unrestricted
10.6452
8.5334
0.0979
-14.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Frequentist Exponential Degree 3 Model with BMRof 0.1 Rel. Dev. for the BMD and 0.95
Lower Confidence Limit for the BMDL
3.1
Dose
Figure D-l. Dose-response curve for the Exponential M3 model fit to relative
liver weight in male rats (Butenhoff et al.. 2012: van Otterdijk. 2007).
This document is a draft for review purposes only and does not constitute Agency policy.
D-21 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Exponential degree 3 vl.l
Dataset Name
Butenhoff_90_Lweight_rel
User notes
[Add user notes here]
Dose-Response Model
M[dose] = a * exp(±l * (b * dose)Ad)
Variance Model
Var[i] = alpha
Model Options
BMR Type
Rel. Dev.
BMRF
0.1
Tail Probability
-
Confidence Level
0.95
Distribution Type
Log-normal
Variance Type
Constant
Model Data
Dependent Variable
[Dose]
Independent Variable
[Mean]
Total # of Observations
4
Adverse Direction
Automatic
This document is a draft for review purposes only and does not constitute Agency policy.
D-22 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Model Results
Benchmark Dose
BMD
11.56718731
BMDL
9.60187006
BMDU
14.67526197
AIC
-14.17517344
Test 4 P-value
0.100441772
D.O.F.
2
Model Parameters
# of Parameters
4
Variable
Estimate
a
2.171112769
b
0.0082397
d
Bounded
log-alpha
-5.045994496
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
GSD
Calc'd GSD
Observed
SD
Scaled
Residual
0
10
2.171112769
2.10600663
2.11
1.08352413
1.063487
0.13
-0.17835832
1.2
10
2.192686432
2.28573248
2.29
1.08352413
1.062982
0.14
0.284010771
6
10
2.281146197
2.25435749
2.26
1.08352413
1.073268
0.16
-0.061715421
30
10
2.779944166
2.78189148
2.8
1.08352413
1.120657
0.32
0.058533184
Likelihoods of Interest
# of
Model
Log Likelihood*
Parameters
AIC
A1
12.38576382
5
-14.771528
A2
15.32442666
8
-14.648853
A3
12.38576382
5
-14.771528
fitted
10.08758672
3
-14.175173
R
-8.71328445
2
21.4265689
* Includes additive constant of -70.8323. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
-2*Log( Likelihood
Test
Ratio)
Test df
p-value
1
48.07542222
6
<0.0001
2
5.877325671
3
0.11773355
3
5.877325671
3
0.11773355
4
4.596354207
2
0.10044177
This document is a draft for review purposes only and does not constitute Agency policy.
D-23 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-ll. Benchmark dose results for relative liver weight in male
rats—log-normal distribution, constant variance, BMR = 1 standard deviation
(Butenhoff et al.. 2012: van Otterdijk. 2007)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Log-normal distribution, constant variance
Exponential 2
(CV—log-normal)
Restricted
9.7357
7.6047
0.1004
-14.1752
Viable-
Alternate
Modeled control
response SD >11.51
actual response SD
Exponential 3
(CV—log-normal)
Restricted
9.7356
7.6049
0.1004
-14.1752
Viable-
Recommended
Lowest AIC
Modeled control
response SD > 11.51
actual response SD
Exponential 4
(CV—log-normal)
Restricted
8.8962
0.0000
0.0311
-12.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Exponential 5
(CV—log-normal)
Restricted
8.8943
6.9746
0.0311
-12.1239
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Hill
(CV—log-normal)
Restricted
8.8323
4.0523
0.0976
-14.1178
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >11.51
actual response SD
Polynomial
(3 degree)
(CV—log-normal)
Restricted
10.7197
6.8148
0.0328
-12.2144
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Polynomial
(2 degree)
(CV—log-normal)
Restricted
10.1369
6.8036
0.0321
-12.1783
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
Power
(CV—log-normal)
Restricted
8.8972
6.7871
0.0979
-14.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >11.51
actual response SD
This document is a draft for review purposes only and does not constitute Agency policy.
D-24 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Log-normal distribution, constant variance
Linear
(CV—log-normal)
Unrestricted
8.8972
6.7871
0.0979
-14.1242
Questionable
Goodness-of-fit
p-value <0.1
Modeled control
response SD >| 1.51
actual response SD
D.3. RELATIVE LIVER WEIGHT-Po MICE fDas etal.. 20081
Table D-12. Dose-response data for relative liver weight in pregnant mice
(Das etal.. 2008)
Dose (mg/kg-day)
n
Mean
SD
0
6
8.04
0.66
35
6
8.76
1.37
175
7
10.28
0.75
350
6
10.65
0.62
This document is a draft for review purposes only and does not constitute Agency policy.
D-25 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-13. Benchmark dose results for relative liver weight in pregnant
mice—constant variance, BMR = 10% relative deviation (Das et al.. 2008)
Models
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
130.2877
98.9543
0.0486
73.1479
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 3
(CV—normal)
Restricted
130.2877
99.1362
0.0486
73.1479
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 4
(CV—normal)
Restricted
36.1911
15.1545
0.8612
69.1285
Viable-
recommended
Lowest AIC
Exponential 5
(CV—normal)
Restricted
39.4346
15.2398
NA
71.0979
Questionable
df = 0, saturated
model
(goodness-of-fit p-
value cannot be
calculated)
Hill
(CV—normal)
Restricted
38.7873
12.3846
NA
71.0979
Questionable
df = 0, saturated
model
(goodness-of-fit p-
value cannot be
calculated)
Polynomial (3
degree)
(CV—normal)
Restricted
115.5880
84.4884
0.0736
72.3159
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial (2
degree)
(CV—normal)
Restricted
115.5878
84.4883
0.0736
72.3159
Questionable
Goodness-of-fit
p-value < 0.1
Power
(CV—normal)
Restricted
115.5870
84.4876
0.0736
72.3159
Questionable
Goodness-of-fit
p-value < 0.1
Linear
(CV—normal)
Unrestricted
115.5882
84.4875
0.0736
72.3159
Questionable
Goodness-of-fit
p-value < 0.1
This document is a draft for review purposes only and does not constitute Agency policy.
D-26 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Frequentist Exponential Degree 4 Model with BMR of 0.1 Rel. Dev. for the BMD and 0.95
Lower Confidence Limit for the BMDL
i CS—1
Estimated Probability
Response at BMD
O Data
BMD
BMDL
Dose
Figure D-2. Dose-response curve for the Exponential M4 model fit to relative
liver weight in pregnant mice (Das etal.. 20081.
This document is a draft for review purposes only and does not constitute Agency policy.
D-27 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Exponential degree 4 vl.l
Dataset Name
Das_p_Lweight_rel
User notes
[Add user notes here]
Dose-Response Model
M[dose] = a * [c-(c-l) * exp(-b * dose)]
Variance Model
Var[i] = alpha
Model Options
BMR Type
Rel. Dev.
BMRF
0.1
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Constant
Model Data
Dependent Variable
[Dose]
Independent Variable
[Mean]
Total # of Observations
4
Adverse Direction
Automatic
This document is a draft for review purposes only and does not constitute Agency policy.
D-28 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
#NAME?
Benchmark Dose
BMD
36.19110286
BMDL
15.15446485
BMDU
87.70968183
AIC
69.12846157
Test 4 P-value
0.861196136
D.O.F.
1
Model Parameters
#of Parameters
4
Variable
Estimate
a
8.018710905
b
0.009531749
c
1.342753894
log-alpha
-0.39273843
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
6
8.018710905
8.04
8.04
0.82170879
0.66
0.66
0.063462168
35
6
8.798356028
8.76
8.76
0.82170879
1.37
1.37
-0.114338192
175
7
10.24876199
10.28
10.28
0.82170879
0.75
0.75
0.100580637
350
6
10.66937939
10.65
10.65
0.82170879
0.62
0.62
-0.057769406
Likelihoods of Interest
# of
Model
Log Likelihood*
Parameters
AIC
A1
-30.54894422
5
71.0978884
A2
-27.8068244
8
71.6136488
A3
-30.54894422
5
71.0978884
fitted
-30.56423079
4
69.1284616
R
-42.8486201
2
89.6972402
* Includes additive constant of -22.97346. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
-2*Log(Likelihood
Test
Ratio)
Test df
p-value
1
30.08359139
6
<0.0001
2
5.484239634
3
0.13958431
3
5.484239634
3
0.13958431
4
0.030573129
1
0.86119614
This document is a draft for review purposes only and does not constitute Agency policy.
D-29 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-14. Benchmark dose results for relative liver weight in pregnant
mice—constant variance, BMR = 1 standard deviation (Das et al.. 2008)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
141.5518
104.9937
0.0524
73.6332
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 3
(CV—normal)
Restricted
141.5511
104.9942
0.0524
73.6331
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 4
(CV—normal)
Restricted
37.2658
16.6945
0.5517
70.0879
Viable-
recommended
Lowest AIC
Exponential 5
(CV—normal)
Restricted
40.3641
16.7699
NA
71.7337
Questionable
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Hill
(CV—normal)
Restricted
39.5789
13.8731
NA
71.7337
Questionable
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Polynomial
(3 degree)
(CV—normal)
Restricted
124.9178
90.1236
0.0725
72.9822
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial
(2 degree)
(CV—normal)
Restricted
124.9176
90.1235
0.0725
72.9822
Questionable
Goodness-of-fit
p-value < 0.1
Power
(CV—normal)
Restricted
124.9169
90.1256
0.0725
72.9822
Questionable
Goodness-of-fit
p-value < 0.1
Linear
(CV—normal)
Unrestricted
124.9180
90.1238
0.0725
72.9822
Questionable
Goodness-of-fit
p-value < 0.1
This document is a draft for review purposes only and does not constitute Agency policy.
D-30 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
D.4. LIVER HYPERTROPHY-MALE RAT rButenhoff et al.. 2012: van
Otterdiik. 20071
Table D-15. Dose-response data liver hypertrophy in male rats
(Butenhoff et al.. 2012: van Otterdijk. 2007)
Dose (mg/kg-day)
n
Incidence
0
10
0
1.2
10
0
6
10
0
30
10
9
Table D-16. Benchmark dose results for liver hypertrophy in
rats—BMR = 10% extra risk (Butenhoff et al.. 2012: van Otterdijk. 2007)
Models
Restriction
10% Extra risk
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Gamma
Restricted
16.2946
5.3859
1.0000
8.5017
Viable—alternate
Log-logistic
Restricted
23.5001
5.4486
1.0000
10.5017
Viable—alternate
Multistage 3rd
Restricted
10.8404
5.0184
0.9796
8.8673
Viable—alternate
Multistage 2nd
Restricted
6.8934
3.6966
0.8078
10.2814
Viable—alternate
Multistage 1st
Restricted
2.4428
1.4091
0.0817
18.5672
Questionable
Goodness-of-fit
p-value < 0.1
Weibull
Restricted
25.2757
5.3801
1.0000
8.5017
Viable-
recommended
Lowest AIC
Dichotomous Hill
Unrestricted
23.4994
5.8336
0.9995
12.5017
Viable—alternate
Logistic
Unrestricted
23.4727
8.4278
1.0000
8.5017
Viable—alternate
Log-pro bit
Unrestricted
20.1374
5.4722
1.0000
10.5017
Viable—alternate
Probit
Unrestricted
21.2661
7.6123
1.0000
10.5017
Viable—alternate
This document is a draft for review purposes only and does not constitute Agency policy.
D-31 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Frequentist Weibull Model with BMR of 10% Extra Risk for the BMD and 0.95 Lower
Confidence Limit for the BMDL
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0®-
e-
-e-
15
Dose
Estimated Probability
Response at BMD
O Data
BMD
BMDL
Figure D-3. Dose-response curve for the Weibull model fit to liver
hypertrophy in male rats (Butenhoff et al.. 2012: van Otterdijk. 20071.
This document is a draft for review purposes only and does not constitute Agency policy.
D-32 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Weibull vl.l
Dataset Name
Butenhoff_90_Lhypertrophy
User notes
[Add user notes here]
Dose-Response Model
P[dose] = g+ (l-g)*[l-exp(-b*doseAa)]
Model Options
RiskType
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
Dose
Independent Variable
Incidence
Total # of Observations
4
Model Results
Benchmark Dose
BMD
25.27565904
BMDL
5.380065202
BMDU
26.31774355
AiC
8.501660382
P-value
1
D.O.F.
3
Chi2
4.56905E-07
Model Parameters
#of Parameters
3
Variable
Estimate
g
Bounded
a
Bounded
b
5.94337E-27
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.523E-08
1.523E-07
0
10
-0.00039
1.2
1.523E-08
1.523E-07
0
10
-0.00039
6
1.52306E-08
1.52306E-07
0
10
-0.00039
30
0.899999999
8.999999992
9
10
8.003 E-09
Analysis of Deviance
Model
Log Likelihood
#of Parameters
Deviance
Test d.f.
P Value
Full Model
-3.250829734
4
-
-
-
Fitted Model
-3.250830191
1
9.1381E-07
3
1
Reduced Model
-21.32655363
1
36.1514478
3
<0.0001
This document is a draft for review purposes only and does not constitute Agency policy.
D-33 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-17. Dose-response data for liver hypertrophy (slight severity lesions)
in male rats (Butenhoff et al.. 2012: van Otterdijk. 2007)
Dose (mg/kg-day)
n
Incidence
0
10
0
1.2
10
0
6
10
0
30
10
4
Table D-18. Benchmark dose results for liver hypertrophy (slight severity
lesions) in male rats—BMR = 10% extra risk (Butenhoff et al.. 2012: van
Otterdijk. 2007)
Models
Restriction
10% Extra risk
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Gamma
Restricted
23.1357
5.6717
1.0000
15.4602
Viable—alternate
Log-logistic
Restricted
27.1575
5.5461
1.0000
17.4602
Viable—alternate
Multistage 3rd
Restricted
17.7871
5.5407
0.9978
15.5422
Viable—alternate
Multistage 2nd
Restricted
13.9892
5.1121
0.8984
17.8741
Viable—alternate
Multistage 1st
Restricted
8.1158
3.9098
0.5376
19.5942
Viable-
recommended
Lowest BMDL
Weibull
Restricted
27.4811
5.6718
1.0000
17.4602
Viable—alternate
Dichotomous
Hill
Unrestricted
27.1562
5.2830
0.9995
19.4602
Viable—alternate
BMD:BMDL ratio > 5
Logistic
Unrestricted
26.9449
13.6106
1.0000
15.4602
Viable—alternate
Log-Pro bit
Unrestricted
24.8237
5.3131
1.0000
17.4602
Viable—alternate
Probit
Unrestricted
25.5166
12.1561
1.0000
17.4602
Viable—alternate
D.5. TOTAL T4—MALE RAT fButenhoff et al.. 2012: van Otterdiik.
20071
Table D-19. Dose-response data for total T4 levels in male rats
(Butenhoff et al.. 2012: van Otterdijk. 2007)
Dose (mg/kg-day)
n
Mean
SD
0
10
5.27
0.71
1.2
10
5.97
1.08
6
9
4.46
0.88
30
9
3.23
0.55
This document is a draft for review purposes only and does not constitute Agency policy.
D-34 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-20. Benchmark dose results for total T4 levels in male rats—constant
variance, BMR = 1 standard deviation (Butenhoff et al.. 2012: van Otterdijk.
20071
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
9.2322
6.5166
0.0138
104.3816
Questionable
Goodness-of-fit
p-value <0.1
Exponential 3
(CV—normal)
Restricted
9.2324
6.5166
0.0138
104.3816
Questionable
Goodness-of-fit
p-value <0.1
Exponential 4
(CV—normal)
Restricted
4.9496
2.5239
0.0075
104.9572
Questionable
Goodness-of-fit
p-value <0.1
Exponential 5
(CV—normal)
Restricted
5.7655
3.5138
NA
103.5642
Questionable
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Hill
(CV—normal)
Restricted
5.5394
3.2999
NA
103.5644
Questionable
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Polynomial
(3 degree)
(CV—normal)
Restricted
11.5906
8.7704
0.0090
105.2374
Questionable
Goodness-of-fit
p-value <0.1
Polynomial
(2 degree)
(CV—normal)
Restricted
11.5906
8.7704
0.0090
105.2374
Questionable
Goodness-of-fit
p-value <0.1
Power
(CV—normal)
Restricted
11.5906
8.7706
0.0090
105.2374
Questionable
Goodness-of-fit
p-value <0.1
Linear
(CV—normal)
Unrestricted
11.5906
8.7704
0.0090
105.2374
Questionable
Goodness-of-fit
p-value <0.1
This document is a draft for review purposes only and does not constitute Agency policy.
D-35 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-21. Benchmark dose results for total T4 levels in male
rats—nonconstant variance, BMR = 1 standard deviation (Butenhoffetal..
2012: van Otterdijk. 2007)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Nonconstant variance
Exponential 2
(NCV—normal)
Restricted
11.3786
7.8978
0.0182
102.5921
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 3
(NCV—normal)
Restricted
11.3789
7.8977
0.0182
102.5921
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 4
(NCV—normal)
Restricted
5.8707
2.9606
0.0104
103.1558
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 5
(NCV—normal)
Restricted
5.8297
3.9098
NA
102.1810
Questionable
df = 0, saturated
model (goodness-of-fit
p-value cannot be
calculated)
Hill
(NCV—normal)
Restricted
5.8562
3.7033
NA
102.1809
Questionable
df = 0, saturated
model (goodness-of-fit
p-value cannot be
calculated)
Polynomial
(3 degree)
(NCV—normal)
Restricted
13.7327
10.1890
0.0130
103.2666
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial
(2 degree)
(NCV—normal)
Restricted
13.7329
10.1889
0.0130
103.2666
Questionable
Goodness-of-fit
p-value < 0.1
Power
(NCV—normal)
Restricted
13.7325
10.1890
0.0130
103.2666
Questionable
Goodness-of-fit
p-value < 0.1
Linear
(NCV—normal)
Unrestricted
13.7332
10.1889
0.0130
103.2666
Questionable
Goodness-of-fit
p-value < 0.1
This document is a draft for review purposes only and does not constitute Agency policy.
D-36 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-22. Benchmark dose results for total T4 levels in male
rats—log-normal distribution, constant variance, BMR = 1 standard deviation
(Butenhoff et al.. 2012: van Otterdijk. 2007)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Log-normal distribution, constant variance
Exponential 2
(CV—log-normal)
Restricted
12.0074
7.6347
0.0223
98.5676
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 3
(CV—log-normal)
Restricted
12.0074
7.6347
0.0223
98.5676
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 4
(CV—log-normal)
Restricted
5.7060
2.5325
0.0200
98.3698
Questionable
Goodness-of-fit
p-value < 0.1
Exponential 5
(CV—log-normal)
Restricted
5.9263
3.4425
NA
97.5382
Questionable
df = 0, saturated
model (goodness-of-fit
p-value cannot be
calculated)
Hill
(CV—log-normal)
Restricted
Questionable
df = 0, saturated
model (goodness-of-fit
p-value cannot be
calculated)
Polynomial
(3 degree)
(CV—log-normal)
Restricted
Questionable
Goodness-of-fit
p-value < 0.1
Polynomial
(2 degree)
(CV—log-normal)
Restricted
Questionable
Goodness-of-fit
p-value < 0.1
Power
(CV—log-normal)
Restricted
-
-
-
-
Questionable
Goodness-of-fit
p-value < 0.1
Linear
(CV—log-normal)
Unrestricted
-
-
-
-
Questionable
Goodness-of-fit
p-value < 0.1
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
D.6. INCREASED FETAL MORTALITY - MALE AND FEMALE Fi MICE
fDas etai.. 20081
Table D-23. Dose-response data for increased fetal mortality fDas et al.. 20081
Dose (mg/kg-day)
n (No. of implants)
No. of dead fetuses/neonates
by PND 21
Litter-specific covariate
(Maternal weight on GDI)
0
16
1
30
0
16
1
28.2
0
11
2
27.7
0
11
0
27.4
0
12
3
25.9
0
11
0
24.1
0
15
0
29.2
0
14
1
28
0
12
3
27.1
0
14
0
26.8
0
16
1
26.6
0
13
2
25.1
0
17
3
30.1
0
14
0
29
0
6
0
27.5
0
9
2
28.1
0
6
0
26.9
0
13
1
26.7
0
11
0
23.3
0
8
8
25.8
0
18
18
31.4
35
15
3
28.1
35
13
0
29.3
35
13
0
27.4
35
14
1
27
35
15
2
26.9
35
13
2
25.7
35
12
4
31.6
This document is a draft for review purposes only and does not constitute Agency policy.
D-38 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
n (No. of implants)
No. of dead fetuses/neonates
by PND 21
Litter-specific covariate
(Maternal weight on GDI)
35
13
0
29.2
35
14
1
27.7
35
16
0
27.5
35
13
2
28.1
35
7
3
25.5
35
15
1
30.3
35
13
0
27.5
35
14
1
28.1
35
13
1
27.9
35
11
0
26.4
35
10
1
27.4
35
13
1
27.9
35
13
0
26.1
35
13
1
24.8
35
12
1
24.8
35
2
2
23.1
175
14
1
28.1
175
15
0
27.5
175
14
0
27.4
175
14
1
27.5
175
15
2
29.4
175
14
1
27.5
175
15
0
26
175
16
2
26.2
175
11
0
23.4
175
16
3
29.1
175
11
0
28.2
175
13
0
25.8
175
11
2
26.8
175
15
1
26.9
175
14
1
25
This document is a draft for review purposes only and does not constitute Agency policy.
D-39 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Dose (mg/kg-day)
n (No. of implants)
No. of dead fetuses/neonates
by PND 21
Litter-specific covariate
(Maternal weight on GDI)
175
13
1
26.7
175
2
2
25.5
175
2
2
25.4
175
9
9
29
175
5
5
25
350
7
2
29.2
350
12
1
26.3
350
16
3
27.4
350
11
0
25.1
350
14
2
25.3
350
12
1
29.5
350
16
2
28.8
350
17
2
26.2
350
12
2
26.2
350
16
0
27.3
350
9
3
27.6
350
13
0
27.7
350
13
0
27.4
350
13
1
26.4
350
7
1
24.6
350
3
3
21.5
350
2
2
23
350
13
13
25.8
350
13
13
24.6
350
3
3
25.1
350
14
14
28.2
350
13
13
29.2
Table D-24. Benchmark dose results for increased fetal mortality (male and
female mice)—BMR = 1% extra risk (Das etal.. 2008)
Models
Restriction
1% Extra risk
p-Value
AIC
BMDS notes
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
BMD
BMDL
BMDS
classification
Nested logistic
(lsc+ilc+)
Restricted
19.5989
5.7383
Infinity
0.2633
Viable-
Recommended
Lowest AIC
BMDL 3x lower
than lowest non-
zero dose
Nested logistic
(Isc+ilc-)
Restricted
326.9633
170.7455
Infinity
<0.0001
Questionable
Goodness of fit p-
value < 0.1
Nested logistic
(lsc-ilc+)
Restricted
50.4014
10.1822
Infinity
0.0833
Questionable
Goodness of fit p-
value < 0.1
BMDL 3x lower
than lowest non-
zero dose
Nested logistic
(Isc-ilc-)
Restricted
191.2272
81.9934
Infinity
<0.0001
Questionable
Goodness of fit p-
value < 0.1
Frequentist Nested Logistic Model with BMR of 0.01 Std. Dev. for the BMDand 0.95
Lower Confidence Limit for the BMDL
0.6
Dose
Figure D-4. Dose-response curve for the Nested-Logistic model fit to increased
fetal mortality in male and female mice (Das etal.. 2008).
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Nested Logistic_lsc+ilc+_ v2.2
Dataset Name
Das FLR Fetal Death
User notes
[Add user notes here]
Dose-Response Model
P[dose] = alpha + thetal*Rij + [1 - alpha -
thetal*Rij]/[l+exp(-beta-theta2*Rij-rho*log(dose))]
Model Options
Risk Type
Extra Risk
BMR
0.01
Confidence Level
0.95
Litter Specific Covariate
Overall Mean
Intralitter Correlation
Estimate
Background
Estimate
Model Data
Dependent Variable
Dose
Independent Variable
Incidence
Total # of Observations
87
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D-42 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Model Results
Benchmark Dose
BMD
19.59891366
BMDL
5.738265629
BMDU
-
AIC
688.92042
P-value
0.263333333
D.O.F.
78
Chi2
96.74138773
Model Parameters
# of Parameters
9
Va riable
Estimate
alpha
-0.5312932
beta
16.8290783
thetal
0.024711312
theta2
-0.913645475
rho
1.08467654
phil
0.368252856
phi2
0.135465621
phi3
0.509745798
phi4
0.576861839
Bootstrap Results
# Iterations
1000
Bootstrap Seed
1599045577
Log-likelihood
-335.46021
Observed Chi-square
96.74138773
Combined P-value
0.263333333
Bootstrap Runs
Run
Bootstrap Chi-square Percentiles
P-Value
50th
90th
95th
99th
1
0.285
85.65851617
109.848694
117.6
134.18995
2
0.258
85.12942257
110.722914
119.0851
131.33939
3
0.247
85.05473338
108.751327
115.9296
137.48443
Combined
0.263333333
85.30000651
109.644757
117.9646
135.17128
Scaled Residuals
Minimum scaled residual for dose group nearest the BMD
-0.50395
Minimum ABS(scaled residual) for dose group nearest the BMD
0.503952
Average Scaled residual for dose group nearest the BMD
-0.50395
Average ABS(scaled residual) for dose group nearest the BMD
0.503952
Maximum scaled residual for dose group nearest the BMD
-0.50395
Maximum ABS(scaled residual) for dose group nearest the BMD
0.503952
This document is a draft for review purposes only and does not constitute Agency policy.
D-43 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Litter Data
Dose
Lit. Spec. Cov.
Est. Prob.
Litter Size
Expected
Observed
Scaled Residua
0
23.3
0.044480361
11
0.489284
0
-0.330689547
0
24.1
0.06424941
11
0.706744
0
-0.401615664
0
25.1
0.088960722
13
1.156489
2
0.353012617
0
25.8
0.10625864
8
0.850069
8
4.33673202
0
25.9
0.108729771
12
1.304757
3
0.699492477
0
26.6
0.126027689
16
2.016443
1
-0.299772055
0
26.7
0.12849882
13
1.670485
1
-0.238711127
0
26.8
0.130969952
14
1.833579
0
-0.603802545
0
26.9
0.133441083
6
0.800646
0
-0.570250323
0
27.1
0.138383345
12
1.6606
3
0.498243205
0
27.4
0.145796738
11
1.603764
0
-0.633212408
0
27.5
0.14826787
6
0.889607
0
-0.606305933
0
27.7
0.153210132
11
1.685311
2
0.121734257
0
28
0.160623525
14
2.248729
1
-0.377819018
0
28.1
0.163094657
9
1.467852
2
0.241698202
0
28.2
0.165565788
16
2.649053
1
-0.434253259
0
29
0.185334837
14
2.594688
0
-0.741848906
0
29.2
0.190277099
15
2.854156
0
-0.756724162
0
30
0.210046149
16
3.360738
1
-0.567256611
0
30.1
0.21251728
17
3.612794
3
-0.138387912
0
31.4
0.244641985
18
4.403556
18
2.76675012
35
23.1
0.420439493
2
0.840879
2
1.558208765
35
24.8
0.193667312
12
2.324008
1
-0.612920728
35
24.8
0.193667312
13
2.517675
1
-0.657368032
35
25.5
0.160429819
7
1.123009
3
1.435714172
35
25.7
0.15539473
13
2.020131
2
-0.009511434
35
26.1
0.149721705
13
1.946382
0
-0.933727752
35
26.4
0.148530963
11
1.633841
0
-0.902727468
35
26.9
0.150776303
15
2.261645
2
-0.110930327
35
27
0.151716296
14
2.124028
1
-0.503951928
35
27.4
0.156698447
13
2.03708
0
-0.959178264
35
27.4
0.156698447
10
1.566984
1
-0.331093052
35
27.5
0.158199979
16
2.5312
0
-0.995853056
35
27.5
0.158199979
13
2.0566
0
-0.964622031
35
27.7
0.16145156
14
2.260322
1
-0.550928027
35
27.9
0.164988496
13
2.14485
1
-0.527947549
35
27.9
0.164988496
13
2.14485
1
-0.527947549
35
28.1
0.168763344
15
2.53145
3
0.189788804
35
28.1
0.168763344
14
2.362687
1
-0.585185094
35
28.1
0.168763344
13
2.193923
2
-0.088622513
35
29.2
0.192293335
13
2.499813
0
-1.08570969
35
29.3
0.194583201
13
2.529582
0
-1.093706422
35
30.3
0.218173919
15
3.272609
1
-0.834803748
35
31.6
0.249793258
12
2.997519
4
0.423637452
175
23.4
0.753292803
11
8.286221
0
-2.346999161
175
25
0.450913899
14
6.312795
1
-1.033293673
175
25
0.450913899
5
2.254569
5
1.415449135
175
25.4
0.381299381
2
0.762599
2
1.466122666
175
25.5
0.365523168
2
0.731046
2
1.516399081
175
25.8
0.322690467
13
4.194976
0
-0.932876612
175
26
0.298046899
15
4.470703
0
-0.884741991
175
26.2
0.276550941
16
4.424815
2
-0.460908554
175
26.7
0.235805287
13
3.065469
1
-0.505849379
175
26.8
0.229690589
11
2.526596
2
-0.152863219
175
26.9
0.2241858
15
3.362787
1
-0.512836334
175
27.4
0.204707536
14
2.865906
0
-0.687383811
175
27.5
0.202204115
14
2.830858
1
-0.441145101
175
27.5
0.202204115
14
2.830858
1
-0.441145101
175
27.5
0.202204115
15
3.033062
0
-0.683561326
175
28.1
0.194568014
14
2.723952
1
-0.421446879
175
28.2
0.194300585
11
2.137306
0
-0.659587572
175
29
0.199087513
9
1.791788
9
2.670218904
175
29.1
0.200338227
16
3.205412
3
-0.043633258
175
29.4
0.204695235
15
3.070429
2
-0.240145327
350
21.5
0.971795484
3
2.915386
3
0.201065485
350
23
0.901250165
2
1.8025
2
0.372789514
350
24.6
0.695111669
13
9.036452
13
0.848375256
350
24.6
0.695111669
7
4.865782
1
-1.502678856
350
25.1
0.601246578
3
1.80374
3
0.961150815
350
25.1
0.601246578
11
6.613712
0
-1.565382323
350
25.3
0.562306321
14
7.872288
2
-1.085132125
350
25.4
0.542866281
1
0.542866
1
0.91764604
350
25.8
0.467290016
13
6.07477
13
1.367719528
350
26.2
0.398842995
12
4.786116
2
-0.606043119
350
26.2
0.398842995
17
6.780331
2
-0.740295677
350
26.3
0.383300844
12
4.59961
1
-0.788584398
350
26.4
0.368470315
13
4.790114
1
-0.774204472
350
27.3
0.269132881
16
4.306126
0
-0.781258285
350
27.4
0.261775084
13
3.403076
0
-0.762807027
350
27.4
0.261775084
16
4.188401
3
-0.217527974
350
27.6
0.249017755
9
2.24116
3
0.246847242
350
27.7
0.243559594
13
3.166275
0
-0.726875687
350
28.2
0.224244443
14
3.139422
14
2.387132337
350
28.8
0.214724836
16
3.435597
2
-0.281313821
350
29.2
0.214117934
13
2.783533
13
2.454127084
350
29.2
0.214117934
7
1.498826
2
0.218630258
350
29.5
0.215777472
12
2.58933
1
-0.411519634
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
D.7. DELAYED EYE OPENING-Fi MALE AND FEMALE MICE fDasetal..
20081
Table D-25. Dose-response data for delayed eye opening in male
and female mice (Das etal.. 2008)
Dose (mg/kg-day)
n
Mean
SD
0
20
16.28
1.19
35
22
17.38
0.79
175
17
17.69
0.68
350
15
17.8
0.83
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-26. Benchmark dose results for delayed eye opening in male and
female mice—constant variance, BMR = 5% relative deviation (Das et al..
2008)
Models
Restriction
5% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
252.3387
178.6688
0.0008
211.1176
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Exponential 3
(CV—normal)
Restricted
252.3380
178.7347
0.0008
211.1176
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Exponential 4
(CV—normal)
Restricted
20.4436
0.0000
0.7270
198.8811
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
Exponential 5
(CV—normal)
Restricted
175.5239
0.0000
NA
215.6060
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
| Residual at control | >2
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Hill
(CV—normal)
Restricted
16.1508
4.8878
0.8659
198.7878
Viable-
recommended
Lowest AIC
BMDL 3x lower than
lowest nonzero dose
Polynomial
(3 degree)
(CV—normal)
Restricted
247.2477
172.9292
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Polynomial
(2 degree)
(CV—normal)
Restricted
247.2476
172.9292
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Power
(CV—normal)
Restricted
247.2483
172.9366
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Linear
(CV—normal)
Unrestricted
247.2471
172.9288
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Frequentist Hill Model with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower
Confidence Limit for the BMDL
Dose
Figure D-5. Dose-response curve for the Hill model fit to delayed eye opening
in male and female mice (Das etal.. 20081.
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Hill vl.l
Dataset Name
Das EO litter SDs
User notes
[Add user notes here]
Dose-Response Model
M[dose] = g + v*doseAn/(kAn + doseAn)
Variance Model
Var[i] = alpha
Model Options
BMR Type
Rel. Dev.
BMRF
0.05
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Constant
Model Data
Dependent Variable
[Dose]
Independent Variable
[Mean]
Total # of Observations
4
Adverse Direction
Automatic
This document is a draft for review purposes only and does not constitute Agency policy.
D-48 DRAFT-DO NOT CITE OR QUOTE
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Toxicological Review ofPFBA and Ammonium PFBA
Model Results
Benchmark Dose
BMD
16.15084927
BMDL
4.88775303
BMDU
58.67497527
AIC
198.7877861
Test 4 P-value
0.865852068
D.O.F.
1
Model Parameters
#of Parameters
5
Variable
Estimate
g
16.28027637
V
1.557732828
k
14.75612987
n
Bounded
alpha
0.771309051
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
20
16.28027637
16.28
16.28
0.87824202
1.19
1.19
-0.001407337
35
22
17.3760338
17.38
17.38
0.87824202
0.79
0.79
0.021182211
175
17
17.71687421
17.69
17.69
0.87824202
0.68
0.68
-0.126167037
350
15
17.77499146
17.8
17.8
0.87824202
0.83
0.83
0.110285841
Likelihoods of Interest
# of
Model
Log Likelihood*
Parameters
AIC
A1
-95.37962446
5
200.759249
A2
-91.88601151
8
199.772023
A3
-95.37962446
5
200.759249
fitted
-95.39389305
4
198.787786
R
-109.7197233
2
223.439447
* Includes additive constant of -68.00145. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
-2*Log(Likelihood
Test
Ratio)
Test df
p-value
1
35.6674235
6
<0.0001
2
6.987225901
3
0.07230604
3
6.987225901
3
0.07230604
4
0.028537187
1
0.86585207
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-27. Benchmark dose results for delayed eye opening in male and
female mice—constant variance, BMR = 1 standard deviation (Das etal.. 2008)
Models
Restriction
1 Standard deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
289.0417
204.0632
0.0008
211.1176
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
Exponential 3
(CV—normal)
Restricted
289.0397
204.0631
0.0008
211.1176
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
Exponential 4
(CV—normal)
Restricted
23.0895
12.5328
0.7270
198.8811
Viable-
recommended
Lowest AIC
Exponential 5
(CV—normal)
Restricted
-9,999.0000
0.0000
NA
215.6060
Unusable
BMD computation
failed
BMD not estimated
BMDL not estimated
| Residual at control |
>2
df = 0, saturated
model (goodness-of-fit
p-value cannot be
calculated)
Hill
(CV—normal)
Restricted
19.0723
0.0000
0.8659
198.7878
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
Polynomial
(3 degree)
(CV—normal)
Restricted
284.0211
198.2059
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
Polynomial
(2 degree)
(CV—normal)
Restricted
284.0211
198.2059
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
Power
(CV—normal)
Restricted
284.0218
198.2009
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
Linear
(CV—normal)
Unrestricted
284.0204
198.2054
0.0008
210.9441
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control |
>2
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
D.8. VAGINAL OPENING-Fi FEMALE MICE fDas etal.. 20081
Table D-28. Dose-response data for delayed vaginal opening in
female mice (Das et al.. 2008)
Dose (mg/kg-day)
n
Mean
SD
0
83
31.59
5.386
35
97
33.598
5.715
175
89
34.292
5.714
350
87
35.023
5.188
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-29. Benchmark dose results for delayed vaginal opening in female
mice—constant variance, 5% relative deviation (Das et al.. 2008)
Models
Restriction
5% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
199.6149
137.1410
0.0106
348.8761
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Exponential 3
(CV—normal)
Restricted
199.6216
137.1431
0.0106
348.8761
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Exponential 4
(CV—normal)
Restricted
17.1139
0.0000
0.6944
341.9320
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
Exponential 5
(CV—normal)
Restricted
30.5201
0.0000
NA
343.9392
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Hill
(CV—normal)
Restricted
13.5161
3.7929
0.8401
341.8184
Viable-
recommended
Lowest AIC
BMDL 3x lower than
lowest nonzero dose
Polynomial (3
degree)
(CV—normal)
Restricted
193.4400
130.5619
0.0115
348.7113
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Polynomial (2
degree)
(CV—normal)
Restricted
193.4443
130.5615
0.0115
348.7113
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Power
(CV—normal)
Restricted
193.4434
130.5626
0.0115
348.7113
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Linear
(CV—normal)
Unrestricted
193.4436
130.5610
0.0115
348.7113
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Frequentist Hill Model with BMR of 0.05 Rel. Dev. for the BMD and 0.95 Lower
Confidence Limit for the BMDL
37
Dose
Figure D-6. Dose-response curve for the Hill model fit to delayed vaginal
opening in female mice (Das etal.. 2008).
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Hill vl.l
Dataset Name
Das VO litter SDs
User notes
[Add user notes here]
Dose-Response Model
M[dose] = g + v*doseAn/(kAn + doseAn)
Variance Model
Var[i] = alpha
Model Options
BMR Type
Rel. Dev.
BMRF
0.05
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Constant
Model Data
Dependent Variable
[Dose]
Independent Variable
[Mean]
Total # of Observations
4
Adverse Direction
Automatic
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Model Results
Benchmark Dose
BMD
13.51609885
BMDL
3.792905489
BMDU
58.81907947
AIC
341.8183924
Test 4 P-value
0.840124836
D.O.F.
1
Model Parameters
#of Parameters
5
Variable
Estimate
g
31.25160173
V
3.782877454
k
19.2052612
n
Bounded
alpha
6.040525655
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
19
31.25160173
31.25
31.25
2.45774809
2.62
2.62
-0.002840717
35
21
33.69418217
33.71
33.71
2.45774809
2.59
2.59
0.029493016
175
17
34.66038453
34.57
34.57
2.45774809
2.59
2.59
-0.151628625
350
15
34.83770206
34.92
34.92
2.45774809
2.23
2.23
0.129687238
Likelihoods of Interest
# of
Model
Log Likelihood*
Parameters
AIC
A1
-166.8888479
5
343.777696
A2
-166.5982185
8
349.196437
A3
-166.8888479
5
343.777696
fitted
-166.9091962
4
341.818392
R
-177.364099
2
358.728198
* Includes additive constant of -66.16357. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
-2*Log(Likelihood
Test
Ratio)
Test df
p-value
1
21.53176107
6
0.00147157
2
0.581258883
3
0.900709
3
0.581258883
3
0.900709
4
0.040696527
1
0.84012484
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-28. Benchmark dose results for delayed vaginal opening in female
mice—constant variance, 1 standard deviation (Das et al.. 2008)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
316.9350
218.4320
0.0106
348.8761
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Exponential 3
(CV—normal)
Restricted
316.9457
218.4320
0.0106
348.8761
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Exponential 4
(CV—normal)
Restricted
35.1705
15.4720
0.6944
341.9320
Viable-
recommended
Lowest AIC
Exponential 5
(CV—normal)
Restricted
34.9991
15.4632
NA
343.9392
Questionable
df = 0, saturated model
(goodness-of-fit p-value
cannot be calculated)
Hill
(CV—normal)
Restricted
35.6204
0.0000
0.8401
341.8184
Unusable
BMD computation
failed; lower limit
includes zero
BMDL not estimated
Polynomial
(3 degree)
(CV—normal)
Restricted
311.4806
211.1287
0.0115
348.7113
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Polynomial
(2 degree)
(CV—normal)
Restricted
311.4877
211.1313
0.0115
348.7113
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Power
(CV—normal)
Restricted
311.4864
211.1303
0.0115
348.7113
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
Linear
(CV—normal)
Unrestricted
311.4866
211.1307
0.0115
348.7113
Questionable
Goodness-of-fit
p-value <0.1
| Residual at control | >2
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
D.9. PREPUTIAL SEPARATION—Fi MALE MICE fDas etal.. 20081
Table D-29. Dose-response data for delayed preputial separation
in male mice (Das etal.. 2008)
Dose (mg/kg-day)
n
Mean
SD
0
17
29.55
1.14
35
21
30.21
1.99
175
17
30.56
1.84
350
15
31.88
1.72
Table D-30. Benchmark dose results for delayed preputial separation in male
mice—constant variance, BMR = 5% relative deviation (Das etal.. 2008)
Models
Restriction
5% Relative
deviation
p-Value
AIC
BMDS classification
BMDS
notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
254.8183
179.1436
0.6004
277.5960
Viable—alternate
Exponential 3
(CV—normal)
Restricted
254.8005
179.1431
0.6004
277.5960
Viable—recommended
Lowest AIC
Exponential 4
(CV—normal)
Restricted
252.8480
102.0115
0.3080
279.6149
Viable—alternate
Exponential 5
(CV—normal)
Restricted
252.5410
101.9527
0.3076
279.6166
Viable—alternate
Hill
(CV—normal)
Restricted
194.2094
175.4639
0.2286
280.0252
Viable—alternate
Polynomial
(3 degree)
(CV—normal)
Restricted
276.4524
176.5648
0.3427
279.4759
Viable—alternate
Polynomial
(2 degree)
(CV—normal)
Restricted
269.5337
175.9153
0.3268
279.5372
Viable—alternate
Power
(CV—normal)
Restricted
252.7648
175.1179
0.5950
277.6140
Viable—alternate
Linear
(CV—normal)
Unrestricted
252.7653
175.1182
0.5950
277.6140
Viable—alternate
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Frequentist Exponential Degree 3 Model with BMR of 0.05 Rel. Dev. for the BMD and
0.95 Lower Confidence Limit for the BMDL
—Estimated Probability
— Response at BMD
0 Data
BMD
BMDl
Figure D-7. Dose-response curve for the Exponential 3 model fit to delayed
preputial separation in male mice (Das etal.. 2008).
This document is a draft for review purposes only and does not constitute Agency policy,
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Toxicological Review ofPFBA and Ammonium PFBA
User Input
Info
Model
frequentist Exponential degree 3 vl.l
Dataset Name
Das PS litter SDs
User notes
[Add user notes here]
Dose-Response Model
M[dose] = a * exp(±l * (b * dose)Ad)
Variance Model
Var[i] = alpha
Model Options
BMR Type
Rel. Dev.
BMRF
0.05
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Constant
Model Data
Dependent Variable
[Dose]
Independent Variable
[Mean]
Total # of Observations
4
Adverse Direction
Automatic
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Model Results
Benchmark Dose
BMD
254.8005164
BMDL
179.1431485
BMDU
443.2041287
AIC
277.5960319
Test 4 P-value
0.600364435
D.O.F.
2
Model Parameters
#of Parameters
4
Variable
Estimate
a
29.74458616
b
0.000191484
d
Bounded
log-alpha
1.042066246
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
17
29.74458616
29.55
29.55
1.68376629
1.14
1.14
-0.47649088
35
21
29.94460185
30.21
30.21
1.68376629
1.99
1.99
0.722313504
175
17
30.75820529
30.56
30.56
1.68376629
1.84
1.84
-0.485353184
350
15
31.80636595
31.88
31.88
1.68376629
1.72
1.72
0.169372344
Likelihoods of Interest
# of
Model
Log Likelihood*
Parameters
AIC
A1
-135.2877975
5
280.575595
A2
-132.4445224
8
280.889045
A3
-135.2877975
5
280.575595
fitted
-135.7980159
3
277.596032
R
-142.6419354
2
289.283871
* Includes additive constant of -64.3257. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
-2*Log(Likelihood
Test
Ratio)
Test df
p-value
1
20.39482594
6
0.00235492
2
5.686550161
3
0.12789698
3
5.686550161
3
0.12789698
4
1.020436835
2
0.60036443
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Table D-31. Benchmark dose results for delayed preputial separation in male
mice—constant variance, BMR = 1 standard deviation (Das et al.. 2008)
Models
Restriction
1 Standard
deviation
p-Value
AIC
BMDS classification
BMDS
notes
BMD
BMDL
Constant variance
Exponential 2
(CV—normal)
Restricted
287.5467
201.6707
0.6004
277.5960
Viable—alternate
Exponential 3
(CV—normal)
Restricted
287.5612
201.6697
0.6004
277.5960
Viable—recommended
Lowest AIC
Exponential 4
(CV—normal)
Restricted
286.3951
198.7931
0.3080
279.6149
Viable—alternate
Exponential 5
(CV—normal)
Restricted
286.1679
197.6553
0.3076
279.6166
Viable—alternate
Hill
(CV—normal)
Restricted
201.3711
94.7311
0.2286
280.0252
Viable—alternate
Polynomial
(3 degree)
(CV—normal)
Restricted
302.3780
199.5688
0.3427
279.4759
Viable—alternate
Polynomial
(2 degree)
(CV—normal)
Restricted
297.6581
198.8516
0.3268
279.5372
Viable—alternate
Power
(CV—normal)
Restricted
286.2526
197.9759
0.5950
277.6140
Viable—alternate
Linear
(CV—normal)
Unrestricted
286.2531
197.9763
0.5950
277.6140
Viable—alternate
D.10. RELATIVE LIVER WEIGHT-MALE HUMANIZED PPARct MICE
fForeman etal.. 20091
Table D-32. Dose-response data for relative liver weight in male
humanized PPARamice (Foreman etal.. 2009)
Dose (mg/kg-day)
n
Mean
SD
0
10
4.07
0.261
35
10
5.62
0.719
175
10
6.65
0.784
350
10
7.38
0.719
This document is a draft for review purposes only and does not constitute Agency policy.
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Table D-33. Benchmark dose results for delayed preputial separation in male
mice—nonconstant variance, BMR = 10% relative deviation (Das et al.. 2008)
Models
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Nonconstant variance
Exponential 2
(NCV—normal)
Restricted
77.3820
62.7400
<0.0001
107.4138
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Modeled control
response SD >11.51
actual response SD
Exponential 3
(NCV—normal)
Restricted
77.3912
62.7399
<0.0001
107.4138
Questionable
Goodness-of-fit
p-value < 0.1
| Residual at control |
>2
Modeled control
response SD >| 1.51
actual response SD
Exponential 4
(NCV—normal)
Restricted
6.7656
4.8076
0.0951
80.0462
Questionable
Goodness-of-fit
p-value < 0.1
BMD 3x lower than
lowest nonzero dose
BMDL 3x lower than
lowest nonzero dose
Exponential 5
(NCV—normal)
Restricted
6.7678
4.8076
0.0951
80.0462
Questionable
Goodness-of-fit
p-value < 0.1
BMD 3x lower than
lowest nonzero dose
BMDL 3x lower than
lowest nonzero dose
Hill
(NCV—normal)
Restricted
5.4945
4.4070
0.2883
78.3878
Viable-
recommended
Lowest AIC
BMD 3x lower than
lowest nonzero dose
BMDL 3x lower than
lowest nonzero dose
Polynomial
(3 degree)
(NCV—normal)
Restricted
59.5695
46.0032
<0.0001
104.4698
Questionable
Goodness-of-fit
p-value < 0.1
| residual for dose
group near BMD| >2
| residual at control |
>2
Modeled control
response SD >| 1.51
actual response SD
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Models
Restriction
10% Relative
deviation
p-Value
AIC
BMDS
classification
BMDS notes
BMD
BMDL
Nonconstant variance
Polynomial
(2 degree)
(NCV—normal)
Restricted
59.5723
46.0033
<0.0001
104.4698
Questionable
Goodness-of-fit
p-value < 0.1
| residual for dose
group near BMD| >2
| residual at control |
>2
Modeled control
response SD >| 1.51
actual response SD
Power
(NCV—normal)
Restricted
59.5691
46.0034
<0.0001
104.4698
Questionable
Goodness-of-fit
p-value < 0.1
| residual for dose
group near BMD| >2
| residual at control |
>2
Modeled control
response SD >| 1.51
actual response SD
Linear
(NCV—normal)
Unrestricted
59.5725
46.0031
<0.0001
104.4698
Questionable
Goodness-of-fit
p-value < 0.1
| residual for dose
group near BMD| >2
| residual at control |
>2
Modeled control
response SD >| 1.51
actual response SD
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
APPENDIX E. SUMMARY OF PUBLIC COMMENTS
AND EPA'S DISPOSITION
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
APPENDIX F. QUALITY ASSURANCE FOR THE IRIS
TOXICOLOGICAL REVIEW OF
PERFLUOROBUTANOIC ACID AND RELATED
COMPOUND AMMONIUM
PERFLUOROBUTANOIC ACID
This assessment was prepared under the auspices of the U.S. Environmental Protection
Agency's (EPA's) Integrated Risk Information System (IRIS) Program. The IRIS Program is housed
within the Office of Research and Development (ORD) in the Center for Public Health and
Environmental Assessment (CPHEA). EPA has an agency-wide quality assurance policy and that
policy is outlined in the EPA Quality Manual for Environmental Programs (see CIO 2105-P-01.1) and
follows the specifications outlined in EPA Order CIO 2105.1.
As required by CIO 2105.1, ORD maintains a Quality Management Program, which is
documented in an internal Quality Management Plan (QMP). The latest version was developed in
2013 using Guidance for Developing Quality Systems for Environmental Programs (OA/G-11. An
NCEA/CPHEA-specific QMP also was developed in 2013 as an appendix to the ORD QMP. Quality
assurance for products developed within CPHEA is managed under the ORD QMP and applicable
appendices.
The IRIS Toxicological Review ofPerfluorobutanoicAcid and Related Compound Ammonium
Perfluorobutanoic Acid has been designated as Highly Influential Scientific Information
(HISA)/Influential Scientific Information (ISI) and is classified as QA Category A. Category A
designations require reporting of all critical QA activities, including audits. IRIS assessments are
developed through a seven-step process. Documentation of this process is available on the IRIS
website: https://www.epa.gov/iris/basic-information-about-integrated-risk-information-
svstem#process.
Specific management of quality assurance within the IRIS Program is documented in a
Programmatic Quality Assurance Project Plan (PQAPP). A PQAPP was developed using the EPA
Guidance for Quality Assurance Project Plans (OA/G-51. and the latest approved version is dated
March 2020. All IRIS assessments follow the IRIS PQAPP, and all assessment leads and team
members are required to receive QA training on the IRIS PQAPP. During assessment development,
additional QAPPs may be applied for quality assurance management They include:
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
Title
Document Number
Date
Program Quality Assurance Project
Plan (PQAPP)for the Integrated Risk
Information System (IRIS) Program
L-CPAD-0030729-QP-1-4
April 2021
An Umbrella Quality Assurance
Project Plan (QAPP) for Dosimetry
and Mechanism-Based Models
(PBPK)
L-CPAD-0032188-QP-1-2
December 2020
Quality Assurance Project Plan
(QAPP) for Enhancements to
Benchmark Dose Software (BMDS)
L- H E EAD-0032189-QP-1-2
September 2020
Umbrella Quality Assurance Project
Plan for CPHEA PFAS Toxicity
Assessments
L-CPAD-0031652-QP-1-3
October 2020
1 During assessment development, this project underwent two quality audits during
2 assessment development including:
Date
Type of audit
Major findings
Actions taken
August 2020
Technical System Audit
No findings
None
August 2019
Technical System Audit
No findings
None
3 During Step 3 of the IRIS Process, the IRIS Toxicological Review was subjected to external
4 reviews by other federal agency partners including the Executive Offices of the White House.
5 Comments during these IRIS Process steps are available in the Docket [EPA-1 IQ-ORD-2020-0675]
6 on regulations.gov.
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicological Review ofPFBA and Ammonium PFBA
REFERENCES
Butenhoff. I: Bjork. 1: Chang. S: Ehresman. D: Parker. G: Das. K. etal. (2012). Toxicological evaluation
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studies. Reproductive Toxicology 33: 513-530.
http: / /dx. doi. or g/10.1016/i. reprotox. 2011.08.004
Chang. S: Das. K: Ehresman. D: Ellefson. M: Gorman. G: Hart. 1. etal. (2008). Comparative
pharmacokinetics of perfluorobutyrate in rats, mice, monkeys, and humans and relevance to
human exposure via drinking water. Toxicological Sciences 104: 40-53.
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Crump. K. (1995). Calculation of benchmark doses from continuous data. Risk Analysis 15: 79-89.
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Das. K: Grey. B: Zehr. R: Wood. C: Butenhoff. 1: Chang. S. etal. (2008). Effects of perfluorobutyrate
exposure during pregnancy in the mouse. Toxicological Sciences 105: 173-181.
http: / /dx. doi. or g/10.109 3 /toxsci /kfn09 9
Foreman. 1: Chang. S: Ehresman. D: Butenhoff. 1: Anderson. C: Palkar. P. etal. (2009). Differential
hepatic effects of perfluorobutyrate mediated by mouse and human PPAR-alpha.
Toxicological Sciences 110: 204-211. http://dx.doi.org/10.1093/toxsci/kfp077
Li. Y: Fletcher. T: Mucs. D: Scott. K: Lindh. C: Tallying. P. etal. (2018). Half-lives of PFOS, PFHxS and
PFOA after end of exposure to contaminated drinking water. Occupational and
Environmental Medicine 75: 46-51. http://dx.doi.org/10.1136/oemed-2017-104651
Russell. M: Himmelstein. M: Buck. R. (2015). Inhalation and oral toxicokinetics of 6:2 FTOH and its
metabolites in mammals. Chemosphere 120: 328-335.
http://dx.doi.Org/10.1016/i.chemosphere.2014.07.092
U.S. EPA (U.S. Environmental Protection Agency). (2012). Benchmark dose technical guidance.
(EPA/100/R-12/001). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum, https: //www.epa.gov/risk/benchmark-dose-technical-guidance
van Otterdiik. F. (2007). Repeated dose 90-day oral toxicity study with MTDID 8391 by daily gavage
in the rat followed by a 3-week recovery period. (Study Number 06-398). Maplewood, MN:
3M.
This document is a draft for review purposes only and does not constitute Agency policy.
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