PUBLIC RELEASE DRAFT
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EPA Document #EPA-740-D-24-018
December 2024
Office of Chemical Safety and
Pollution Prevention
SEPA
United States
Environmental Protection Agency
Draft Meta-analysis and Benchmark Dose Modeling of Fetal Testicular
Testosterone for Di(2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate
(DBP), Butyl Benzyl Phthalate (BBP), Diisobutyl Phthalate (DIBP), and
Dicyclohexyl Phthalate (DCHP)
Technical Support Document for the Draft Risk Evaluations
CASRNs: 117-81-7 (DEHP), 84-74-2 (DBP), 85-68-7 (BBP), 84-69-5 (DIBP), and
84-61-7 (DCHP)
December 2024
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38 TABLE OF CONTENTS
39 ACKNOWLEDGEMENTS 6
40 1 BACKGROUND 7
41 2 METHODS 8
42 3 REPLICATION OF NASEM META-ANALYSIS AND BENCHMARK DOSE
43 MODELING APPROACH 10
44 4 META-ANALYSIS AND BMD MODELING OF FETAL TESTICULAR
45 TESTOSTERONE 13
46 4.1 Dibutyl Phthalate (DBP) 13
47 4.2 Di(2-ethylhexyl) Phthalate (DEHP) 19
48 4.3 Diisobutyl Phthalate (DIBP) 23
49 4.4 Butyl Benzyl Phthalate (BBP) 26
50 4.5 Dicyclohexyl Phthalate (DCHP) 31
51 5 COMPARISON OF BENCHMARK DOSE ESTIMATES 35
52 6 CONCLUSION AND NEXT STEPS 38
53 REFERENCES 39
54 APPENDICES 42
55 Appendix A SUPPORTING MATERIALS FOR THE META-ANALYSIS AND BMD
56 ANALYSIS OF FETAL TESTICULAR TESTOSTERONE IN RATS 42
57 A. I Replication of NASEM 2017 Results for Fetal Testosterone in Rats for DIBP 43
58 A.2 Dibutyl Phthalate (DBP) - Updated Analysis 46
59 A.3 Di(2-ethylhexyl) Phthalate (DEHP) - Updated Analysis 50
60 A.4 Diisobutyl Phthalate (DIBP) - Updated Analysis 54
61 A.5 Butyl Benzyl Phthalate (BBP) - Updated Analysis 58
62 A.6 Dicyclohexyl Phthalate (DCHP) - Analysis 62
63
64 LIST OF TABLES
65 Table 3-1. Replication of NASEM (2017) Results: Comparison of Overall Meta-Analyses of Rat Studies
66 of DIBP and Fetal Testicular Testosterone Using Metafor Version 2.0.0 and Version
67 4.6.0 11
68 Table 3-2. Replication of NASEM (2017) Results: Comparison of Benchmark Dose Estimates for
69 Decreased Fetal Testicular Testosterone in Rats Following Gestational Exposure to DIBP
70 using Metafor Version 2.0.0 and Version 4.6.0 11
71 Table 4-1. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for DBP
72 13
73 Table 4-2. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DBP and Fetal
74 Testosterone (Metafor Version 2.0.0) 16
75 Table 4-3. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DBP and Fetal
76 Testosterone (Metafor Version 4.6.0) 17
77 Table 4-4. Comparison of Benchmark Dose Estimates for DBP and Fetal Testosterone in Rats 18
78 Table 4-5. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
79 DEHP 19
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Table 4-6. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal
Testosterone (Metafor Version 2.0.0) 21
Table 4-7. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal
Testosterone (Metafor Version 4.6.0) 22
Table 4-8. Comparison of Benchmark Dose Estimates for DEHP and Fetal Testosterone in Rats 23
Table 4-9. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
DIBP 24
Table 4-10. Updated Overall Analyses and Sensitivity Analyses of Rat Studies of DIBP and Fetal
Testosterone (Metafor Version 2.0.0) 25
Table 4-11. Updated Overall Analyses and Sensitivity Analyses of Rat Studies of DIBP and Fetal
Testosterone (Metafor Version 4.6.0) 25
Table 4-12. Comparison of Benchmark Dose Estimates for DIBP and Fetal Testosterone in Rats 26
Table 4-13. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
BBP 27
Table 4-14. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of BBP and Fetal
Testosterone (Metafor Version 2.0.0) 29
Table 4-15. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of BBP and Fetal
Testosterone (Metafor Version 4.6.0) 30
Table 4-16. Comparison of Benchmark Dose Estimates for BBP and Fetal Testosterone in Rats 31
Table 4-17. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
DCHP 32
Table 4-18. Overall Meta-analyses of Rat Studies of DCHP and Fetal Testosterone (Metafor Version
2.0.0) 33
Table 4-19. Overall Meta-analyses of Rat Studies of DCHP and Fetal Testosterone (Metafor Version
4.6.0) 33
Table 4-20. Comparison of Benchmark Dose Estimates for DCHP and Fetal Testosterone in Rats 34
Table 5-1. Comparison of BMD Modeling Results for DEHP, DBP, DIBP, BBP, DCHP, and DINP ... 37
LIST OF APPENDIX FIGURES
FigureApx A-l. Replication of NASEM (2017) Meta-analysis of Studies of DIBP and Fetal
Testosterone in Rats Using Metafor Version 2.0.0 43
FigureApx A-2. Replication of NASEM (2017) Meta-analysis of Studies of DIBP and Fetal
Testosterone in Rats Using Metafor Version 4.6.0 44
FigureApx A-3. Replication of NASEM (2017) Results: Benchmark Dose Estimates from Rat Studies
of DIBP and Fetal Testosterone (Metafor Version 2.0.0) 45
FigureApx A-4. Replication of NASEM (2017) Results: Benchmark Dose Estimates from Rat Studies
of DIBP and Fetal Testosterone (Metafor Version 4.6.0) 46
FigureApx A-5. Updated Meta-analysis of Studies of DBP and Fetal Testosterone in Rats (Metafor
Version 2.0.0) 47
Figure Apx A-6. Updated Benchmark Dose Estimates from Rat Studies of DBP and Fetal Testosterone
(Metafor Version 2.0.0) 48
Figure Apx A-7. Updated Meta-analysis of Studies of DBP and Fetal Testosterone in Rats (Metafor
Version 4.6.0) 49
Figure Apx A-8. Updated Benchmark Dose Estimates from Rat Studies of DBP and Fetal Testosterone
(Metafor Version 4.6.0) 50
Figure Apx A-9. Updated Meta-analysis of Studies of DEHP and Fetal Testosterone in Rats (Metafor
Version 2.0.0) 51
Figure Apx A-10. Updated Benchmark Dose Estimates from Rat Studies of DEHP and Fetal
Testosterone (Metafor Version 2.0.0) 52
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FigureApx A-l 1. Updated Meta-analysis of Studies of DEHP and Fetal Testosterone in Rats (Metafor
Version 4.6.0) 53
Figure Apx A-12. Updated Benchmark Dose Estimates from Rat Studies of DEHP and Fetal
Testosterone (Metafor Version 4.6.0) 54
Figure Apx A-13. Updated Meta-analysis of Studies of DIBP and Fetal Testosterone in Rats (Metafor
Version 2.0.0) 55
Figure Apx A-14. Updated Benchmark Dose Estimates from Rat Studies of DIBP and Fetal
Testosterone (Metafor Version 2.0.0) 56
FigureApx A-15. Updated Meta-analysis of Studies of DIBP and Fetal Testosterone in Rats (Metafor
Version 4.6.0) 57
Figure Apx A-16. Updated Benchmark Dose Estimates from Rat Studies of DIBP and Fetal
Testosterone (Metafor Version 4.6.0) 58
Figure Apx A-17. Updated Meta-analysis of Studies of BBP and Fetal Testosterone in Rats (Metafor
Version 2.0.0) 59
Figure Apx A-18. Updated Benchmark Dose Estimates from Rat Studies of BBP and Fetal Testosterone
(Metafor Version 2.0.0) 60
Figure Apx A-19. Updated Meta-analysis of Studies of BBP and Fetal Testosterone in Rats (Metafor
Version 4.6.0) 61
Figure Apx A-20. Updated Benchmark Dose Estimates from Rat Studies of BBP and Fetal Testosterone
(Metafor Version 4.6.0) 62
Figure Apx A-21. Meta-analysis of Studies of DCHP and Fetal Testosterone in Rats (Metafor Version
2.0.0) 63
Figure Apx A-22. Benchmark Dose Estimates from Rat Studies of DCHP and Fetal Testosterone
(Metafor Version 2.0.0) 64
FigureApx A-23. Meta-analysis of Studies of DCHP and Fetal Testosterone in Rats (Metafor Version
4.6.0) 65
Figure Apx A-24. Updated Benchmark Dose Estimates from Rat Studies of DCHP and Fetal
Testosterone (Metafor Version 4.6.0) 66
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KEY ABBREVIATIONS AND ACRONYMS
AIC
Akaike information criterion
AGD
Anogenital distance
BBP
Butyl benzyl phthalate
BMD
Benchmark dose
BMDL
Benchmark dose (lower confidence limit)
BMR
Benchmark response
CASRN
Chemical abstracts service registry number
CRA
Cumulative risk assessment
DBP
Dibutyl phthalate
DCHP
Dicyclohexyl phthalate
DEHP
Di(2-ethylhexyl) phthalate
DIBP
Diisobutyl phthalate
DINP
Diisononyl phthalate
EPA
(U.S) Environmental Protection Agency (or "the Agency")
GD
Gestation day
MOA
Mode of action
NASEM
National Academies of Sciences, Engineering, and Medicine
NR
Nipple/areolae retention
OCSPP
Office of Chemical Safety and Pollution Prevention
OPPT
Office of Pollution Prevention and Toxics
RPF
Relative potency factor
SACC
Science Advisory Committee on Chemicals
SD
Sprague-Dawley (rat)
TSCA
Toxic Substances Control Act
UF
Uncertainty factor
U.S.
United States
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ACKNOWLEDGEMENTS
Acknowledgements
The Assessment Team gratefully acknowledges the participation, input, and review comments from the
U.S. Environmental Protection Agency (EPA or the Agency) Office of Pollution Prevention and Toxics
(OPPT) and Office of Chemical Safety and Pollution Prevention (OCSPP) senior managers and science
advisors, as well as intra-agency reviewers including the Office of Children's Health Protection (OCHP)
and Office of Research and Development (ORD). The Agency is also grateful for assistance from EPA
contractors SRC, Inc. (Contract No. 68HERH19D0022).
Special acknowledgement is given for the contributions of technical experts from EPA's OCHP,
including Chris Brinkerhoff for providing review of this technical support document.
Docket
Supporting information can be found in the public dockets Docket IDs (EPA-HQ-QPPT-2018-0504.
EPA-HQ-QPPT-2018-0434. EPA-HQ-QPPT-2018-0503. EPA-HQ-QPPT-2018-0433. and EPA-HO-
QPPT-2018-0501Y
Disclaimer
Reference herein to any specific commercial products, process, or service by trade name, trademark,
manufacturer, or otherwise does not constitute or imply its endorsement, recommendation, or favoring
by the United States Government.
Author: Anthony Luz
Contributors: John Allran, Collin Beachum (Branch Chief), Brandall Ingle-Carlson, Ashley Peppriell,
and Susanna Wegner
Technical Support: Mark Gibson, Hillary Hollinger, and S. Xiah Kragie
This report was reviewed and cleared for release by OPPT and OCSPP leadership.
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1 BACKGROUND
This technical support document (TSD) is for the draft risk evaluations for butyl benzyl phthalate (BBP)
(U.S. EPA. 2025c). dibutyl phthalate (DBP) (U.S. EPA. 2025d). dicyclohexyl phthalate (DCHP) (U.S.
EPA. 2024a). diethylhexyl phthalate (DEHP) (U.S. EPA. 2025e). diisobutyl phthalate (DIBP) (U.S.
EPA. 2025f). as well as the Draft Technical Support Document for the Cumulative Risk Analysis of
Di(2-ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), Butyl Benzyl Phthalate (BBP), Diisobutyl
Phthalate (DIBP), Dicyclohexyl Phthalate (DCHP), and Diisononyl Phthalate (DINP) Under the Toxic
Substances Control Act (TSCA) (U.S. EPA. 2024c).
In 2017, the National Academies of Sciences, Engineering, and Medicine (NASEM) demonstrated the
utility of a meta-analysis and meta-regression approach to combine fetal rat testicular testosterone data
from multiple studies of similar design prior to conducting benchmark dose (BMD) modeling (NASEM.
2017). Meta-analysis is a statistical procedure that can be used to summarize outcomes from a number
of studies and explore sources of heterogeneity in the data through use of random effects models.
Therefore, meta-analysis can help overcome limitations associated with results from individual studies.
In the mode of action (MOA) for "phthalate syndrome," which has been described by EPA elsewhere
(U.S. EPA. 2023). decreased fetal testicular testosterone is an early, upstream event in the MOA that
precedes downstream apical outcomes such as male nipple retention, decreased anogenital distance, and
male reproductive tract malformations (e.g., hypospadias, cryptorchidism). Decreased fetal testicular
testosterone should occur at doses that are lower than or equal to doses that cause downstream apical
outcomes associated with a disruption of androgen action. Therefore, consistent with the best available
science, EPA conducted an updated meta-analysis and BMD modeling analysis of decreased fetal rat
testicular testosterone using similar methods as employed by NASEM (2017) and incorporating more
recent studies. The purpose of this updated meta-analysis and BMD modeling analysis is to provide the
most up-to-date dose-response information in support of the individual draft phthalate risk evaluations
as well as the cumulative risk assessment of phthalates. The remainder of this TSD is organized as
follows:
• Section 2 provides an overview of the methods employed by EPA for the updated meta-analysis
and BMD modeling analysis of fetal rat testicular testosterone. A description of differences
between the NASEM (2017) analysis and EPA's updated analysis is also provided.
• Section 3 summarizes the results of EPA's replicate analysis of NASEM's meta-analysis and
BMD modeling analysis of DIBP.
• Section 4 summarizes EPA's updated meta-analysis and BMD modeling results of fetal rat
testicular testosterone for DBP (Section 4.1), DEHP (Section 0), DIBP (Section 4.3), BBP
(Section 4.4), and DCHP (Section 4.5).
• Section 5 compares BMD modeling results obtained by EPA as part of the updated analysis and
results from NASEM (2017).
• Section 6 section describes EPA's preliminary conclusions and next steps.
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2 METHODS
In 2017, NASEM demonstrated the utility of meta-analysis and meta-regression to summarize several
outcomes from experimental animal studies (NASEM. 2017). The 2017 NASEM analysis included
reduced fetal testicular testosterone, reduced male anogenital distance (AGD), and increased incidence
of hypospadias in rodents following oral exposure to DEHP, DBP, BBP, DIBP, and DINP. DCHP was
not included as part of the NASEM analysis. Boxes 3-3 and 3-4 in (NASEM. 2017) provide detailed
descriptions of the meta-analysis approach employed by NASEM. Briefly, NASEM conducted meta-
analyses using the Metafor (Version 2.0.0) meta-analysis package for R. which employs a standard
random effects model using the Restricted Maximum Likelihood Estimate. The meta-analyses
conducted by NASEM focused on the dose-response relationship and employed three models, linear,
log-linear, and linear-quadratic models. The linear meta-regressions with dose in original and log-
transformed units were used to assess the presence or absence of a gradient. For the linear and linear-
quadratic models, BMD values were estimated based on benchmark response (BMR) levels of 5 and 40
percent. NASEM did not provide explicit justification for selection of a BMR of 5 percent. However,
justification for the BMR of 5 percent can be found elsewhere (U.S. EPA. 2012; Allen et al.. 1994a. b;
Faustman et al.. 1994).
As discussed in EPA's Benchmark Dose Technical Guidance (U.S. EPA. 2012). a BMR of 5 percent is
supported for BMD modeling of most endpoints in developmental and reproductive studies.
Comparative analyses of a large database of developmental toxicity studies demonstrated that
developmental NOAELs are approximately equal to the BMDL5 (Allen et al.. 1994a. b; Faustman et al..
1994). NASEM (2017) also modeled a BMR of 40 percent using the following justification: "previous
studies have shown that reproductive-tract malformations were seen in male rats when fetal testosterone
production was reduced by about 40% (Gray et al.. 2016; Howdeshell et al.. 2015)." The R code used by
NASEM to conduct all meta-analyses is publicly available (https://github.com/wachiuphd/NASEM-
2017-Endocrine-Low-Dose).
As part of its updated analysis, EPA used a similar meta-analysis and BMD modeling approach as
employed by NASEM (2017). but with several notable differences. First, EPA used the most recent
version of the R Metafor package (Version 4.6.0) available at the time of the updated analysis, while
NASEM used Metafor Version 2.0.0. However, EPA also conducted the updated analysis with Metafor
Version 2.0.0 so that results from the two different versions of Metafor could be compared. Similar to
the NASEM approach, EPA's updated meta-analysis focused on the dose-response relationship and
employed the linear and log-linear models for trend analysis and the linear and linear-quadratic models
for BMD analysis. Another notable difference between the NASEM analysis and EPA's updated
analysis is that EPA evaluated BMRs of 5, 10, and 40 percent, while NASEM evaluated BMRs of 5 and
40 percent. EPA added evaluation of a BMR of 10 percent because BMD modeling of fetal testosterone
conducted by NASEM (2017) indicated that BMDs estimates are more than three-fold below the lowest
dose with empirical testosterone data for several of the phthalates (e.g., DIBP). As discussed in EPA's
Benchmark Dose Technical Guidance (U.S. EPA. 2012) "For some datasets the observations may
correspond to response levels far in excess of a selected BMR and extrapolation sufficiently below the
observable range may be too uncertain to reliably estimate BMDs BMDLs for the selected BMR. "
Therefore, EPA modelled a BMR of 10 percent because datasets for some of the phthalates may not
include sufficiently low doses to support modeling of a 5 percent response level. For the linear and
linear-quadratic models, BMD values were estimated based on BMR levels of 5, 10, and 40 percent. The
linear meta-regressions with dose in original and log-transformed units were used to assess the presence
or absence of a gradient. BMD models were examined for a visual fit to the data, and the best-fit model
was determined based on the lowest AIC.
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One additional difference between the NASEM (2017) analysis and EPA's updated analysis is that
NASEM included an analysis in which rat data were subjected to a subgroup analysis by strain because
of potential differential sensitivity across strains. NASEM conducted this subgroup analysis only for
DEHP. EPA did not include a subgroup analysis as part of its updated meta-analysis and BMD modeling
analysis because (1) the number of new studies identified by EPA evaluating fetal testicular testosterone
is small; (2) none of the new studies provide obviously different results from the studies analyzed by
NASEM; and (3) only studies of Sprague-Dawley rats are available for DIBP, BBP, and DCHP. Further,
NASEM only identified slight differences in strain sensitivity for effects on fetal testicular testosterone
for DEHP (with Sprague-Dawley rats being slightly more sensitive than Wistar); however, the apparent
difference in sensitivity appears to be due to model choice—instead of a true difference in strain
sensitivity. For example, the linear model provided the best fit (based on lowest AIC) for Wistar rats,
while the Linear-Quadratic Model provided the best fit for Sprague-Dawley and the analysis of all
strains combined.
As part of the updated meta-analysis, EPA utilized all of the same fetal rat testicular testosterone data
included in the original NASEM (2017) analysis, as well as new fetal rat testosterone data identified
through the 2019 TSCA literature searches for DBP, DEHP, DIBP, BBP, and DCHP. EPA also
considered new literature identified outside of the 2019 TSCA literature searches that was identified
through the literature searches conducted in support of EPA's Draft Proposed Approach for Cumulative
Risk Assessment of High-Priority Phthalates and a Manufacturer-Requested Phthalate under the Toxic
Substances Control Act (U.S. EPA. 2023).
Consistent with the meta-analysis and BMD modeling approach employed by NASEM (2017). new fetal
rat testicular testosterone data were only included in the updated meta-analysis if the following criteria
were met:
• Study conducted with pregnant rats (all strains considered relevant, including Sprague-Dawley,
Wistar, Long Evans, F344, etc.). For the updated analysis, studies of mice were excluded
because rats are considered the more sensitive species.
• Study exposed rats via the oral route.
• Study measured fetal testis testosterone content or ex vivo fetal testicular testosterone production.
Studies measuring only serum or plasma testosterone were excluded. Studies measuring
testosterone at non-fetal lifestages were excluded. Studies measuring testosterone production
following stimulation with luteinizing hormone were excluded.
• Study included an exposure that covers the male programming window (defined by NASEM as
gestational days (GD) 16-18).
• Study fully reported data (i.e., mean, standard deviation or standard error, and sample size) to
support inclusion in meta-analysis.
As will described further in Section 4, EPA identified new fetal testicular testosterone data for DEHP,
DBP, DIBP, BBP, and DCHP to support the updated meta-analysis. All studies included in the updated
meta-analysis and BMD modeling analysis of fetal testicular testosterone were evaluated for study
quality as described in the draft systematic review protocols for DCHP (U.S. EPA. 2024b).
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3 REPLICATION OF NASEM META-ANALYSIS AND
BENCHMARK DOSE MODELING APPROACH
As a proof of principle and to demonstrate replicability of NASEM's meta-analysis and BMD modeling
approach, EPA first used publicly available R-code provided by NASEM to attempt to replicate results
from the 2017 NASEM meta-analysis and BMD modeling analysis of fetal testicular testosterone in rats
for DIBP. The analysis by NASEM (2017) included ex vivo fetal testicular testosterone production data
from two rat studies of DIBP (Hannas et al.. 2011; Howdeshell et al.. 2008). EPA used the same ex vivo
fetal testicular testosterone production data from these two studies as part of its replicate analysis.
Initially, EPA was unable to replicate the meta-analysis and BMD modeling results reported by NASEM
(2017) for DIBP, with results varying significantly between the NASEM and EPA's analysis (Table 3-1
and Table 3-2). The Agency determined the discrepancies between the results obtained by NASEM
(2017) and its replicate analysis were due to updates in the Metafor package in R. In 2017, the NASEM
analysis relied on Metafor Version 2.0.0. EPA was able to replicate the NASEM (2011) results for DIBP
exactly using Metafor Version 2.0.0 (Table 3-1 and Table 3-2). However, use of Metafor version 4.6.0
resulted in different meta-analysis and BMD modeling results for DIBP (Table 3-1 and Table 3-2). EPA
was unable to determine the precise reasons for the deviations in the results using Metafor Versions
2.0.0 and 4.6.0. The primary functions from Metafor used in the meta-analysis repeatedly are rma() and
forest(), which have many updates in each version of Metafor. The complete Metafor package changelog
is available at https://wviechtb.github.io/metafor/news/index.html.
Table 3-1 and Table 3-2 provide a comparison of overall meta-analysis results and BMD modeling
results, respectively, obtained by NASEM (2017) and by EPA using Metafor Versions 2.0.0 and 4.6.0.
Additional meta-analysis results (i.e., forest plots) and BMD model fit curves obtained by EPA using
Metafor Versions 2.0.0 and 4.6.0 are provided in Appendix A.l. As can be seen from Table 3-2, for
NASEM (2017) and EPA's analysis using Metafor Version 2.0.0, there was a statistically significant
overall effect and linear trends in logio(dose) and dose and both analyses support BMDs and BMD40
values of 27 mg/kg-day (95% confidence interval [95% CI]: 23, 34) and 271 mg/kg-day (95% CI: 225,
342), respectively, based on the best fit linear model (based on lower AIC than the linear quadratic
model). EPA's analysis using Metafor Version 4.6.0 provided nearly identical results as Metafor
Version 2.0.0 for the linear model (Table 3-2). However, using Metafor Version 4.6.0 the linear-
quadratic model provided the best fit (based on lowest AIC) and supports a BMD40 of 263 mg/kg-day. A
BMD5 could not be derived using Metafor Version 4.6.0 for the linear-quadratic model.
Overall, EPA selected BMD modeling results obtained using Metafor Version 4.6.0 for use in the single
phthalate risk evaluations andphthalate cumulative risk assessment because these results were obtained
using the most up-to-date version of the Metafor package available at the time of the updated meta-
analysis and BMD modeling analysis. However, EPA conducted all subsequent meta-analyses and BMD
modeling analyses reported in Section 4 using both versions of Metafor (version 2.0.0 and version 4.6.0)
so that results could be compared.
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384
385
Table 3-1. Replication of NASEM (2017) Results: Comparison of Overall Meta-Analyses of Rat
Studies of DIBP and Feta
Testicular Testosterone Using Mel
tafor Version 2.0.0 and Version 4.6.0
Analysis
Estimate
Beta
CI,
Lower
Bound
CI,
Upper
Bound
P
value
Tau
I2
P value for
Heterogeneity
AIC
NASEM (2017) analysis using Metafor Version 2.0.0 (from Table C6-11 in NASEM (2017))
Overall
intrcpt
-82.31
-135.11
-29.52
0.002
71.76
96.96
0.000
87.28
Trend in loglO(dose)
loglO(dose)
-169.23
-234.13
-104.33
0.000
28.14
77.83
0.001
78.52
Linear indoselOO
doselOO
-18.84
-22.73
-14.94
0.000
18.64
78.78
0.001
75.51*
Linear Quadratic in doselOO
doselOO
-11.61
-22.13
-1.08
0.031
12.22
57.12
0.02
77.04
Linear Quadratic in doselOO
I(dosel00A2)
-1.00
-2.42
0.42
0.169
EPA analysis using Metafor Version 2.0.0
Overall
intrcpt
-82.31
-135.11
-29.52
0.002
71.76
96.96
0.000
87.28
Trend in loglO(dose)
loglO(dose)
-169.23
-234.13
-104.33
0.000
28.14
77.83
0.001
78.52
Linear indoselOO
doselOO
-18.84
-22.73
-14.94
0.000
18.64
78.78
0.001
75.51*
Linear Quadratic in doselOO
doselOO
-11.61
-22.13
-1.08
0.031
12.22
57.12
0.02
77.04
Linear Quadratic in doselOO
I(dosel00A2)
-1.00
-2.42
0.42
0.169
EPA analysis using Metafor Version 4.6.0
Overall
intrcpt
-82.31
-135.11
-29.52
0.00
71.76
96.96
0.000
87.28
Trend in loglO(dose)
loglO(dose)
-169.3
-234.13
-104.33
0.00
28.14
77.83
0.001
78.52
Linear indoselOO
doselOO
-18.64
-27.52
-9.76
0.00
65.25
97.85
0.00
81.28
Linear Quadratic in doselOO
doselOO
-19.78
-50.04
10.48
0.20
54.97
96.42
0.00
80.73*
Linear Quadratic in doselOO
I(dosel00A2)
0.14
-3.72
4.00
0.94
" Indicates model with lowest AIC.
Table 3-2. Replication of NASEM (2017) Results: Comparison of Benchmark Dose Estimates for
Decreased Fetal Testicular Testosterone in Rats Following Gestational Exposure to DIBP using
Metafor Version 2.0.0 and Version 4.6.0
Analysis
BMR
BMD
(mg/kg-
day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
NASEM (2017) analysis using Metafor Version 2.0.0 (from Tables C6-11 and C6-12 in NASEM (2017))11
Linear in doselOO*
5%
27
23
34
75.51*
Linear in doselOO*
40%
271
225
342
Linear Quadratic in doselOO
5%
43
23
127
77.04
Linear Quadratic in doselOO
40%
341
239
453
EPA analysis using Metafor Version 2.0.0'1
Linear in doselOO*
5%
27
23
34
75.51*
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Analysis
BMR
BMD
(mg/kg-
day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
Linear in doselOO*
40%
271
225
342
Linear Quadratic in doselOO
5%
43
23
127
77.04
Linear Quadratic in doselOO
40%
341
239
453
EPA analysis using Metafor Version 4.6.0
Linear in doselOO
5%
28
19
53
81.28
Linear in doselOO
40%
274
186
523
Linear Quadratic in
doselOO*
5%
NA
NA
343
80.73*
Linear Quadratic in
doselOO*
40%
263
NA
585
* Indicates model with lowest AIC.
° EPA noted an anna rent discrepancy in the NASEM (2017) rcDort. In Table 3-26. NASEM notes that no BMD/BMDL
estimates could be generated at the 5% response level for DIBP because "the 5% change was well below the range of the
data, but it will be 10 times lower because a linear model was used." However, in Table C6-12 of the NASEM report,
BMD/BMDL estimates at the 5% response level are provided for DIBP for the best-fit linear model. In EPA's replicate
analysis, identical BMD/BMDL estimates for the 5% response level were obtained. Therefore, BMD/BMDL estimates at
the 5% response level for DIBP are reported in this table.
391
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4 META-ANALYSIS AND BMD MODELING OF FETAL
TESTICULAR TESTOSTERONE
4.1 Dibutyl Phthalate (DBP)
In 2017, NASEM included fetal rat testicular testosterone data from seven studies as part of its meta-
analysis and BMD modeling analysis for DBP (Table 4-1). EPA identified new fetal rat testicular
testosterone data from one study (Gray et al.. 2021). which was included as part of the updated meta-
analysis and BMD modeling analysis for DBP. Table 4-1 provides an overview of the eight studies
included in the updated analysis. EPA conducted the updated meta-analysis using random effects
models, as implemented in the R Metafor package. Metafor versions 2.0.0 and 4.6.0 were used so that
results could be compared. Additionally, the updated analysis included a sensitivity analysis to
determine if the meta-analysis was sensitive to leaving out results from individual studies.
Table 4-1. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
DBP
Reference
(TSCA Study
Quality
Rating)
Included in
NASEM Meta-
analysis and BMD
Modeling Analysis?
Brief Study Description
Measured Outcome
(Martino-
Andrade et al..
2008) (Medium)
Yes
Pregnant Wistar rats (7-8 dams/group)
gavaged with 0, 100, 500 mg/kg-day
DBP on GD 13-21
Fetal testis testosterone content
on GD 21
(Furr et al..
2014)(High)
Yes
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 33, 50, 100, 300
mg/kg-day DBP on GD 14-18 (Block
18)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Yes
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 1, 10, 100 mg/kg-day
DBP on GD 14-18 (Block 22)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Yes
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 1, 10, 100 mg/kg-day
DBP on GD 14-18 (Block 26)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
(Howdeshell et
al.. 2008)
(High)
Yes
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 33, 50, 100, 300, 600
mg/kg-day DBP on GD 8-18
Ex vivo fetal testicular
testosterone production (2-
hour incubation) on GD 18
(Kuhl et al..
2007) (Low)
Yes
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 100, 500 mg/kg-day
DBP on GD 18
Fetal testis testosterone content
on GD 19
(Striivc et al..
2009) (Medium)
Yes
Pregnant SD rats (7-9 dams/group)
gavaged with 0, 112, 581 mg/kg-day
DBP on GD 12-19
Fetal testis testosterone content
on GD 19 (4-hour post-
exposure)
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Reference
(TSCA Study
Quality
Rating)
Included in
NASEM Meta-
analysis and BMD
Modeling Analysis?
Brief Study Description
Measured Outcome
Pregnant SD rats (7-9 dams/group)
gavaged with 0, 112, 581 mg/kg-day
DBP on GD 12-19
Fetal testis testosterone content
on GD 20 (24-hour post-
exposure)
(Johnson et al..
2011) (Medium)
Yes
Pregnant SD rats (5-6 dams/group)
gavaged with 0, 100 mg/kg-day DBP
on GD 12-20
Fetal testis testosterone content
on GD 20
Pregnant SD rats (5-6 dams/group)
gavaged with 0, 500 mg/kg-day DBP
on GD 12-20
Fetal testis testosterone content
on GD 20
(Johnson et al..
2007) (Medium)
Yes
Pregnant SD rats (5 dams/group)
gavaged with 0, 1, 10, 100 mg/kg-day
DBP on GD 19
Fetal testis testosterone content
on GD 19
(Grav et al..
No (new study)
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 300, 600, 900 mg/kg-
day DBP on GD 14-18 (Block 70)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
2021)(High)
No (new study)
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 300, 600, 900 mg/kg-
day DBP on GD 14-18 (Block 71)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Overall meta-analyses and sensitivity analyses results obtained using Metafor Versions 2.0.0 and 4.6.0
are shown in Table 4-2 and Table 4-3, respectively. A comparison of BMD estimates obtained by
NASEM (2017) and as part of EPA's updated analysis are shown in Table 4-4. Additional meta-analysis
results {i.e., forest plots) and BMD model fit curves are shown in Appendix A.2. For meta-analyses
conducted using both versions of Metafor, there was a statistically significant overall effect and linear
trends in logio(dose) and dose, with an overall effect that is large in magnitude (>50% change). For both
meta-analyses, there was substantial, statistically significant heterogeneity in all cases (I2> 80% for
Metafor v.2.0.0; I2> 88% for Metafor v.4.6.0). The statistical significance of these effects was robust to
leaving out individual studies for analyses conducted with both versions of Metafor. Although there was
substantial heterogeneity, standard deviation of the random effect (tau) was less than the estimated size
of the effect at higher doses. Therefore, the heterogeneity does not alter the conclusion that gestational
exposure to DBP reduces fetal testicular testosterone in the rat.
For meta-analyses conducted using both versions of Metafor, the linear-quadratic model provided the
best fit {i.e., had lower AIC than the linear model) (Table 4-4). BMD estimates from the linear-quadratic
model were 15 mg/kg-day (95% CI: 11, 21) for a 5 percent change (BMR = 5%), 30 mg/kg-day (95%
CI: 23, 43) for a 10 percent change (BMR = 10%), and 154 mg/kg-day (95% CI: 119, 211) for a 40
percent change (BMR = 40%) when Metafor Version 2.0.0 was used for the updated analysis including
the new study by Gray et al. (2021). Similarly, BMD estimates from the linear-quadratic model were 14
mg/kg-day (95% CI: 9, 27) for a 5 percent change (BMR = 5%), 29 mg/kg-day (95% CI: 20, 54) for a 10
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percent change (BMR = 10%), and 149 mg/kg-day (95% CI: 101, 247) for a 40 percent change (BMR =
40%) when Metafor Version 4.6.0 was used to model all of the studies including the new data.
Notably, Metafor versions 2.0.0 and 4.6.0 provided similar BMDs (15 vs. 14 mg/kg-day), BMDio (30 vs.
29 mg/kg-day), and BMD40 (154 vs. 149 mg/kg-day) estimates for the best fitting, linear-quadratic
model (Table 4-4) for the updated analysis including the new study by Gray et al. (2021). and these
results are similar to those obtained in the 2017 NASEM meta-analysis (i.e., BMD5 and BMD40
estimates of 12 and 125 mg/kg-day, respectively, based on the best fitting linear quadratic model). At
the evaluated BMRs of 5 and 40 percent, inclusion of the new data results in slightly higher BMD5 and
BMD40 estimates with similar 95 percent confidence intervals compared to results obtained in the 2017
NASEM analysis.
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438 Table 4-2. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DBP and Fetal Testosterone (Metafor Version
439 2.0.0) ^
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-71.85
-95.76
-47.95
3.82E-09
67.01
95.60
2.74E-152
383.39
Trend in loglO(dose)
loglO(dose)
-62.44
-81.70
-43.19
2.08E-10
41.61
88.70
4.43E-50
349.26
Linear in dose 100
dose 100
-25.02
-28.72
-21.32
3.76E-40
32.26
83.67
2.85E-39
344.58
Linear Quadratic in dose 100
dose 100
-35.58
-46.64
-24.52
2.84E-10
30.36
80.93
7.99E-22
334.19*
Linear Quadratic in dose 100
I(dosel00A2)
1.61
0.02
3.19
4.73E-02
30.36
80.93
7.99E-22
334.19
Sensitivity analysis
Overall minus Furr et al. (2014)
intrcpt
-88.38
-117.31
-59.45
2.14E-09
67.21
93.19
2.16E-55
270.22
Overall minus Johnson et al. (2007)
intrcpt
-76.78
-102.25
-51.31
3.47E-09
68.66
96.10
3.84E-153
350.04
Overall minus Howdeshell et al. (2008)
intrcpt
-78.30
-105.70
-50.91
2.11E-08
70.83
95.72
3.63E-139
329.10
Overall minus Johnson et al. (2011)
intrcpt
-69.59
-93.70
-45.48
1.53E-08
65.39
95.51
3.39E-148
359.45
Overall minus Kuhl et al. (2007)
intrcpt
-72.06
-97.37
-46.75
2.39E-08
68.92
95.94
3.87E-152
362.13
Overall minus Martino-Andrade et al.
(2008)
intrcpt
-72.43
-97.80
-47.06
2.19E-08
69.11
95.94
1.74E-152
362.26
Overall minus Struve et al. (2009)
intrcpt
-63.19
-86.77
-39.61
1.50E-07
62.87
95.50
2.53E-148
329.62
Overall minus Grav et al. (2021)
intrcpt
-56.97
-80.64
-33.31
2.37E-06
59.25
94.78
3.05E-115
311.44
* Indicates lowest AIC.
440
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442 Table 4-3. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DBP and Fetal Testosterone (Metafor Version
443 4.6.0) ^
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-71.85
-95.76
-47.95
3.82E-09
67.01
95.60
2.74E-152
383.39
Trend in loglO(dose)
loglO(dose)
-62.44
-81.70
-43.19
2.08E-10
41.61
88.70
4.43E-50
349.26
Linear in dose 100
dose 100
-25.69
-31.55
-19.83
8.64E-18
57.78
94.26
3.38E-119
354.71
Linear Quadratic in dose 100
dose 100
-36.78
-54.53
-19.03
4.89E-05
54.79
93.26
1.72E-117
343.82*
Linear Quadratic in dose 100
I(dosel00A2)
1.70
-0.86
4.26
1.94E-01
54.79
93.26
1.72E-117
343.82
Sensitivity analysis
Overall minus Furr et al. (2014)
intrcpt
-88.38
-117.31
-59.45
2.14E-09
67.21
93.19
2.16E-55
270.22
Overall minus Johnson et al. (2007)
intrcpt
-76.78
-102.25
-51.31
3.47E-09
68.66
96.10
3.84E-153
350.04
Overall minus Howdeshell et al. (2008)
intrcpt
-78.30
-105.70
-50.91
2.11E-08
70.83
95.72
3.63E-139
329.10
Overall minus Johnson et al. (2011)
intrcpt
-69.59
-93.70
-45.48
1.53E-08
65.39
95.51
3.39E-148
359.45
Overall minus Kuhl et al. (2007)
intrcpt
-72.06
-97.37
-46.75
2.39E-08
68.92
95.94
3.87E-152
362.13
Overall minus Martino-Andrade et al.
(2008)
intrcpt
-72.43
-97.80
-47.06
2.19E-08
69.11
95.94
1.74E-152
362.26
Overall minus Struve et al. (2009)
intrcpt
-63.19
-86.77
-39.61
1.50E-07
62.87
95.50
2.53E-148
329.62
Overall minus Grav et al. (2021)
intrcpt
-56.97
-80.64
-33.31
2.37E-06
59.25
94.78
3.05E-115
311.44
* Indicates lowest AIC.
444
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Table 4-4. Comparison of Benchmark Dose Estimates for DBP and Fetal Testosterone in Ral
s
Analysis
BMR
BMD
(mg/kg-day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
2017 NASEM analysis using Metafor Version 2.0.0 (as reported in Tables C6-7 and C6-8 of NASEM (2017))
Linear in dose 100
5%
17
14
22
285.72
Linear in dose 100
40%
174
143
222
Linear Quadratic in doselOO*
5%
12
8
22
277.00*
Linear Quadratic in doselOO*
40%
125
85
205
Updated analysis using Metafor Version 2.0.0 including new study by Gray et al. (2021)
Linear in doselOO
5%
20
18
24
344.58
Linear in doselOO
10%
42
37
49
Linear in doselOO
40%
204
178
240
Linear Quadratic in doselOO*
5%
15
11
21
334.19*
Linear Quadratic in doselOO*
10%
30
23
43
Linear Quadratic in doselOO*
40%
154
119
211
Updated analysis using Metafor Version 4.6.0 including new study by Gray et al. (2021)
Linear in doselOO
5%
20
16
26
354.71
Linear in doselOO
10%
41
33
53
Linear in doselOO
40%
199
162
258
Linear Quadratic in doselOO*
5%
14
9
27
343.82*
Linear Quadratic in doselOO*
10%
29
20
54
Linear Quadratic in doselOO*
40%
149
101
247
* Indicates model with lowest AIC.
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4.2 Di(2-ethylhexyl) Phthalate (DEHP)
In 2017, NASEM included fetal rat testicular testosterone data from seven publications as part of its
meta-analysis and BMD modeling analysis for DEHP (Table 4-5). EPA identified new fetal rat testicular
testosterone data from one study (Gray et al.. 2021). which was included as part of the updated meta-
analysis and BMD modeling analysis for DEHP. Table 4-5 provides an overview of the eight
publications included in the updated analysis. EPA conducted the updated meta-analysis using random
effects models, as implemented in the R Metafor package. Metafor versions 2.0.0 and 4.6.0 were used so
that results could be compared. Additionally, the updated analysis included a sensitivity analysis to
determine if the meta-analysis was sensitive to leaving out results from individual studies.
Table 4-5. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
DEHP
Reference
(TSCA Study
Quality
Rating)
Included in
NASEM Meta-
analysis and BMD
Modeling Analysis?
Brief Study Description
Measured Outcome
(Lin et al..
2008)
(Medium)
Yes
Pregnant Long-Evans rats (6-9
dams/group) gavaged with 0, 10, 100,
750 mg/kg-day DEHP on GD 2-20
Fetal testis testosterone
content on GD 21
(Martino-
Andrade et al..
2008)
(Medium)
Yes
Pregnant Wistar rats (7 dams/group)
gavaged with 0, 150 mg/kg-day DEHP
on GD 13-21
Fetal testis testosterone
content on GD 21
(Hannas et al..
2011)
(Medium)
Yes
Pregnant Wistar rats (3-6 dams/group)
gavaged with 0, 100, 300, 500, 625, 750,
875 mg/kg-day DEHP on GD 14-18
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Yes
Pregnant SD rats (3-6 dams/group)
gavaged with 0, 100, 300, 500, 625, 750,
875 mg/kg-day DEHP on GD 14-18
(Cultv et al..
2008)
(Medium)
Yes
Pregnant SD rats (3 dams/group)
gavaged with 0, 117, 234, 469, 938
mg/kg-day DEHP on GD 14-20
Ex vivo fetal testicular
testosterone production (24-
hour incubation) on GD 21
(Furr et al..
2014)(High)
Yes
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DEHP on GD 14-18 (Block
31)
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Yes
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DEHP on GD 14-18 (Block
32)
(Howdeshell et
al.. 2008)
(High)
Yes
Pregnant SD rats (4 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DEHP on GD 14-18
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
(Saillenfait et
al.. 2013)
(High)
Yes
Pregnant SD rats (8-16 dams/group)
gavaged with 0, 50, 625 mg/kg-day
DEHP on GD 12-19
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 19
(Grav et al..
2021)(Hiah)
No (new study)
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
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Reference
(TSCA Study
Quality
Rating)
Included in
NASEM Meta-
analysis and BMD
Modeling Analysis?
Brief Study Description
Measured Outcome
mg/kg-day DEHP on GD 14-18 (Block
76).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
No (new study)
Pregnant SD rats (3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DEHP on GD 14-18 (Block
77).
Overall meta-analyses and sensitivity analyses results obtained using Metafor Versions 2.0.0 and 4.6.0
are shown in Table 4-6 and Table 4-7, respectively. A comparison of BMD estimates obtained by
NASEM (2017) and as part of EPA's updated analysis including new data are shown in Table 4-8.
Additional meta-analysis results (i.e., forest plots) and BMD model fit curves are shown in Appendix
A.3. For meta-analyses conducted using both versions of Metafor, there was a statistically significant
overall effect and linear trends in logio(dose) and dose, with an overall effect that is large in magnitude
(>50% change). For both meta-analyses, there was substantial, statistically significant heterogeneity in
all cases (I2 > 90% for Metafor v.2.0.0; I2 > 90% for Metafor v.4.6.0). The statistical significance of
these effects was robust to leaving out individual studies for analyses conducted with both versions of
Metafor. Although there was substantial heterogeneity, standard deviation of the random effect (tau) was
less than the estimated size of the effect at higher doses. Therefore, the heterogeneity does not alter the
conclusion that gestational exposure to DEHP reduces fetal testicular testosterone in the rat.
For meta-analyses conducted using both versions of Metafor, the linear-quadratic model provided the
best fit (i.e., had lower AIC than the linear model) (Table 4-8). BMD estimates from the linear-quadratic
model were 17 mg/kg-day (95% CI: 12, 26) for a 5 percent change (BMR = 5%), 35 mg/kg-day (95%
CI: 26, 52) for a 10 percent change (BMR = 10%), and 178 mg/kg-day (95% CI: 134, 251) for a 40
percent change (BMR = 40%) when Metafor Version 2.0.0 was used. Similarly, BMD estimates from
the linear-quadratic model were 17 mg/kg-day (95% CI: 11, 31) for a 5 percent change (BMR = 5%), 35
mg/kg-day (95% CI: 24, 63) for a 10 percent change (BMR = 10%), and 178 mg/kg-day (95% CI: 122,
284) for a 40 percent change (BMR = 40%) when Metafor Version 4.6.0 was used.
Notably, Metafor versions 2.0.0 and 4.6.0 provided identical BMDs (17 mg/kg-day), BMDio (35 mg/kg-
day), and BMD40 (178 mg/kg-day) estimates for the best fitting, linear-quadratic model for the updated
analysis including the new data (Table 4-8), and these results are similar to those obtained in the 2017
NASEM meta-analysis (i.e., BMD5 and BMD40 estimates of 15 and 161 mg/kg-day, respectively, based
on the best fitting linear quadratic model). At the evaluated BMRs of 5 and 40 percent, inclusion of the
new data results in slightly higher BMD5 and BMD40 estimates with similar 95 percent confidence
intervals compared to results obtained in the 2017 NASEM analysis.
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489 Table 4-6. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal Testosterone (Metafor Version
490 2.0.0)
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-103.69
-127.11
-80.27
4.04E-18
75.18
98.65
5.73E-270
477.69
Trend in loglO(dose)
loglO(dose)
-135.61
-170.18
-101.03
1.5 IE—14
46.35
96.47
2.53E-177
432.47
Linear in dose 100
dose 100
-21.83
-24.55
-19.11
9.90E-56
45.36
96.60
1.03E-164
439.18
Linear Quadratic in dose 100
dose 100
-30.80
-41.57
-20.03
2.06E-08
44.20
95.91
1.14E-151
429.15*
Linear Quadratic in dose 100
I(dosel00A2)
1.21
-0.20
2.62
9.15E-02
44.20
95.91
1.14E-151
429.15
Sensitivity analysis
Overall minus Lin et al. (2008)
intrcpt
-108.89
-132.57
-85.22
1.95E-19
73.35
98.67
3.02E-264
441.10
Overall minus Saillenfait et al. (2013)
intrcpt
-103.49
-127.52
-79.45
3.21E-17
75.21
98.61
4.86E-234
454.76
Overall minus Furr et al. (2014)
intrcpt
-89.06
-112.06
-66.07
3.20E-14
66.18
98.48
3.72E-220
377.11
Overall minus Grav et al. (2021)
intrcpt
-110.14
-136.73
-83.54
4.76E-16
76.76
98.49
1.55E-166
386.87
Overall minus Hannas et al. (2011)
intrcpt
-106.48
-136.42
-76.55
3.13E-12
81.07
97.77
1.03E-181
343.54
Overall minus Howdeshell et al.
(2008)
intrcpt
-106.36
-131.60
-81.12
1.47E-16
77.33
98.83
6.46E-270
433.45
Overall minus Cultv et al. (2008)
intrcpt
-99.32
-124.00
-74.65
3.02E-15
75.33
98.75
1.25E-251
431.74
Overall minus Martino-Andrade et al.
(2008)
intrcpt
-105.35
-129.11
-81.59
3.64E-18
75.39
98.68
4.27E-270
466.34
* Indicates lowest AIC.
491
492
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493 Table 4-7. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of DEHP and Fetal Testosterone (Metafor Version
494 4.6.0) ^
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-103.69
-127.11
-80.27
4.04E-18
75.18
98.65
5.73E-270
477.69
Trend in loglO(dose)
loglO(dose)
-135.61
-170.18
-101.03
1.5 IE—14
46.35
96.47
2.53E-177
432.47
Linear in dose 100
dose100
-21.92
-25.82
-18.02
3.46E-28
67.96
98.46
0.00E+00'1
448.00
Linear Quadratic in dose 100
dose100
-30.88
-45.45
-16.31
3.26E-05
61.77
97.86
4.22E-238
435.16*
Linear Quadratic in dose 100
I(dosel00A2)
1.21
-0.69
3.10
2.13E-01
61.77
97.86
4.22E-238
435.16
Sensitivity analysis
Overall minus Lin et al. (2008)
intrcpt
-108.89
-132.57
-85.22
1.95E-19
73.35
98.67
3.02E-264
441.10
Overall minus Saillenfait et al. (2013)
intrcpt
-103.49
-127.52
-79.45
3.21E-17
75.21
98.61
4.86E-234
454.76
Overall minus Furr et al. (2014)
intrcpt
-89.06
-112.06
-66.07
3.20E-14
66.18
98.48
3.72E-220
377.11
Overall minus Grav et al. (2021)
intrcpt
-110.14
-136.73
-83.54
4.76E-16
76.76
98.49
1.55E-166
386.87
Overall minus Hannas et al. (2011)
intrcpt
-106.48
-136.42
-76.55
3.13E-12
81.07
97.77
1.03E-181
343.54
Overall minus Howdeshell et al. (2008)
intrcpt
-106.36
-131.60
-81.12
1.47E-16
77.33
98.83
6.46E-270
433.45
Overall minus Cultv et al. (2008)
intrcpt
-99.32
-124.00
-74.65
3.02E-15
75.33
98.75
1.25E-251
431.74
Overall minus Martino-Andrade et al.
(2008)
intrcpt
-105.35
-129.11
-81.59
3.64E-18
75.39
98.68
4.27E-270
466.34
* Indicates lowest AIC.
11 p-value too small to calculate and rounded to zero.
495
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Table 4-8. Comparison o
'Benchmark Dose Es
timates for DEH
* and Fetal Testosterone in Rats
Analysis
BMR
BMD
(mg/kg-day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
2017 NASEM Analysis for all strains of rats using Metafor Version 2.0.0
(as reported in Tables C5-7. C5-8. and C5-9 of NASEM (2017))
Linear indoselOO
5%
22
20
26
358.32
Linear indoselOO
40%
222
195
258
Linear Quadratic in doselOO*
5%
15
11
24
348.01*
Linear Quadratic in doselOO*
40%
161
118
236
Undated analysis usins Metafor Version 2.0.0 includins new study by Gray et al. (2021)
Linear indoselOO
5%
24
21
27
439.18
Linear indoselOO
10%
48
43
55
Linear indoselOO
40%
234
208
267
Linear Quadratic in doselOO*
5%
17
12
26
429.15*
Linear Quadratic in doselOO*
10%
35
26
52
Linear Quadratic in doselOO*
40%
178
134
251
Undated analysis usins Metafor Version 4.6.0 includins new study by Gray et al. (2021)
Linear indoselOO
5%
23
20
28
448.00
Linear indoselOO
10%
48
41
58
Linear indoselOO
40%
233
198
283
Linear Quadratic in doselOO*
5%
17
11
31
435.16*
Linear Quadratic in doselOO*
10%
35
24
63
Linear Quadratic in doselOO*
40%
178
122
284
* Indicates model with lowest AIC.
4.3 Diisobutyl Phthalate (DIBP)1
In 2017, NASEM included fetal rat testicular testosterone data from two studies (Hannas et al.. 201 1;
Howdeshell et al.. 2008) as part of its meta-analysis and BMD modeling analysis for DIBP. EPA
identified new fetal rat testicular testosterone data from one study (Gray et al.. 2021). which was
included as part of the updated meta-analysis and BMD modeling analysis for DIBP. Table 4-9 provides
an overview of the three studies included in the updated analysis. EPA conducted the updated meta-
analysis using random effects models, as implemented in the R metafor package. Metafor versions 2.0.0
and 4.6.0 were used so that results could be compared. Additionally, the updated analysis included a
sensitivity analysis to determine if the meta-analysis was sensitive to leaving out results from individual
studies. In 2017, NASEM did not conduct a sensitivity analysis because there were too few studies
available to do so.
1 In addition to the meta-analysis, EPA also conducted additional BMD modeling of the three individual studies of DIBP
reporting reduced fetal testicular testosterone using all standard continuous models in EPA's BMD software (BMDS 3.3.2)
(Gray et al.. 2021: Hannas et al.. 2011: Howdeshell et al.. 2008). BMD model results are reported in EPA's Draft Non-cancer
Human Health Hazard Assessment for Diisobutyl phthalate (DIBP) (U.S. EPA. 2025b).
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510
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512
513
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523
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Table 4-9. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis for
DIBP
Reference
(TSCA Study
Quality
Rating)
Included in NASEM
Meta-analysis and
BMD Modeling
Analysis?
Brief Study Description
Measured Outcome
(Hannas et al..
2011)
(Medium)
Yes
Pregnant SD rats (3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DIBP on GD 14-18.
Ex vivo fetal testicular
testosterone production (3-hour
incubation) on GD 18
(Howdeshell et
al.. 2008)
(High)
Yes
Pregnant SD rats (2-8 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DIBP on GD 8-18.
Ex vivo fetal testicular
testosterone production (3-hour
incubation) on GD 18
(Grav et al..
2021)
(Medium)
No (new study)
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DIBP on GD 14-18
(Block 67 rats).
Ex vivo fetal testicular
testosterone production (3-hour
incubation) on GD 18
Overall meta-analyses and sensitivity analyses results obtained using Metafor Versions 2.0.0 and 4.6.0
are shown in Table 4-10 and Table 4-11, respectively. A comparison of BMD estimates obtained by
NASEM (2017) and as part of EPA's updated analysis are shown in Table 4-12. Additional meta-
analysis results {i.e., forest plots) and BMD model fit curves are shown in Appendix A.4. For meta-
analyses conducted using both versions of Metafor, there was a statistically significant overall effect and
linear trends in logio(dose) and dose, with an overall effect that is large in magnitude (>50% change).
For both meta-analyses, there was substantial, statistically significant heterogeneity in all cases (I2>50%
for Metafor v.2.0.0; I2> 65% for Metafor v.4.6.0). The statistical significance of these effects was robust
to leaving out individual studies for analyses conducted with both versions of Metafor. Although there
was substantial heterogeneity, standard deviation of the random effect (tau) was less than the estimated
size of the effect at higher doses. Therefore, the heterogeneity does not alter the conclusion that
gestational exposure to DIBP reduces fetal testicular testosterone in the rat.
For meta-analyses conducted using both versions of Metafor, the linear-quadratic model provided the
best fit {i.e., had lower AIC than the linear model) (Table 4-12). BMD estimates from the linear-
quadratic model were 36 mg/kg-day (95% CI: 23, 79) for a 5 percent change (BMR = 5%), 74 mg/kg-
day (95% CI: 47, 140) for a 10 percent change (BMR = 10%), and 326 mg/kg-day (95% CI: 239, 428)
for a 40 percent change (BMR = 40%) when Metafor Version 2.0.0 was used. Similarly, BMD estimates
were 55 mg/kg-day (95% CI: NA, 266) for a 10 percent change (BMR = 10%) and 270 mg/kg-day (95%
CI: 136, 517) for a 40 percent change (BMR = 40%) when Metafor Version 4.6.0 was used. No BMD
value could be estimated for a 5 percent change (BMR = 5%), nor could the 95 percent lower confidence
limit be estimated for a 10 percent change (BMDLio) using Metafor Version 4.6.0. Given that there were
only two studies included in the NASEM meta-analysis in 2017, the updated analysis with the addition
of the new study by Gray et al. (2021) resulted in a higher BMD and wider confidence interval at both
BMRs compared to the NASEM analysis that did not include the new study, although the BMDLs of 23
mg/kg-day was identical between NASEM's analysis and the updated analysis including the new study,
when using Metafor Version 2.0.0.
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538
Table 4-10. Updated Overall Analyses and Sensitivity Analyses of Rat St
udies of DI
3P and Fel
tal Testosterone (Metafor Version 2.0.0)
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-82.21
-122.85
-41.56
7.36E-05
68.02
96.52
4.18E-54
130.45
Trend in loglO(dose)
loglO(dose)
-165.55
-205.47
-125.64
4.31E-16
19.89
65.48
3.53E-03
106.31
Linear in dose 100
dose100
-18.15
-20.60
-15.70
1.09E-47
13.49
60.77
3.93E-03
108.69
Linear Quadratic in dose 100
dose100
-13.89
-22.51
-5.28
1.57E-03
11.98
50.83
2.01E-02
104.31*
Linear Quadratic in dose 100
I(dosel00A2)
-0.55
-1.64
0.54
3.22E-01
11.98
50.83
2.01E-02
104.31
Sensitivity analysis
Overall minus Grav et al. (2021)
intrcpt
-82.31
-135.11
-29.52
2.24E-03
71.76
96.96
3.48E-30
87.28
Overall minus Hannas et al. (2011)
intrcpt
-69.98
-110.63
-29.34
7.39E-04
55.43
95.94
7.26E-37
83.66
Overall minus Howdeshell et al. (2008)
intrcpt
-94.90
-151.74
-38.06
1.07E-03
78.38
94.86
3.49E-32
88.36
* Indicates lowest AIC.
Table 4-11. Updated Overall Analyses and Sensitivity Analyses of Rat Studies of DIBP and Fetal Testosterone (Metafor Version 4.6.0)
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P value
Tau
I2
P value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-82.21
-122.85
-41.56
7.36E-05
68.02
96.52
4.18E-54
130.45
Trend in loglO(dose)
loglO(dose)
-165.55
-205.47
-125.64
4.31E-16
19.89
65.48
3.53E-03
106.31
Linear in dose 100
dose 100
-18.48
-25.14
-11.81
5.50E-08
60.86
96.92
1.55E-111
120.04
Linear Quadratic in dose 100
dose 100
-19.18
-41.21
2.85
8.79E-02
48.79
94.49
3.45E-39
111.51*
Linear Quadratic in dose 100
I(dosel00A2)
0.09
-2.70
2.88
9.50E-01
48.79
94.49
3.45E-39
111.51
Sensitivity analysis
Overall minus Grav et al. (2021)
intrcpt
-82.31
-135.11
-29.52
2.24E-03
71.76
96.96
3.48E-30
87.28
Overall minus Hannas et al. (2011)
intrcpt
-69.98
-110.63
-29.34
7.39E-04
55.43
95.94
7.26E-37
83.66
Overall minus Howdeshell et al.
(2008)
intrcpt
-94.90
-151.74
-38.06
1.07E-03
78.38
94.86
3.49E-32
88.36
* Indicates lowest AIC.
542
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543 Table 4-12. Comparison of Benchmark Dose Estimates for DIBP and Fetal Testosterone in Rats
Analysis
BMR
BMD
(mg/kg-day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
2017 NASEM analysis using Metafor Version 2.0.0 (as reported in Tables C6-11 and C6-12 of NASEM (2017))"
Linear in doselOO*
5%
27
23
34
75.51*
Linear in doselOO*
40%
271
225
342
Linear Quadratic in doselOO
5%
43
23
127
77.04
Linear Quadratic in doselOO
40%
341
239
453
Undated analysis usins Metafor Version 2.0.0 includins new study by Gray et al. (2021)
Linear in doselOO
5%
28
25
33
108.69
Linear in doselOO
10%
58
51
67
Linear in doselOO
40%
281
248
325
Linear Quadratic in doselOO*
5%
36
23
79
104.31*
Linear Quadratic in doselOO*
10%
74
47
140
Linear Quadratic in doselOO*
40%
326
239
428
Undated analysis usins Metafor Version 4.6.0 includins new Study by Gray et al. (2021)
Linear in doselOO
5%
28
20
43
120.04
Linear in doselOO
10%
57
42
89
Linear in doselOO
40%
276
203
432
Linear Quadratic in doselOO*
5%
NA*
NA*
207
111.51*
Linear Quadratic in doselOO*
10%
55
NA*
266
Linear Quadratic in doselOO*
40%
270
136
517
* Indicates model with lowest AIC.
"EPA noted an apparent discrepancy in the NASEM (2017) report. In Table 3-26, NASEM (2017) notes that no
BMD/BMDL estimates could be generated at the 5% response level for DIBP because "the 5% change was well below the
range of the data, but it will be 10 times lower because a linear model was used." However, in Table C6-12 of the
NASEM (2017) report, BMD/BMDL estimates at the 5% response level are provided for DIBP for the best-fit linear
model. In EPA's replicate analysis, identical BMD/BMDL estimates for the 5% response level were obtained. Therefore,
BMD/BMDL estimates at the 5% response level for DIBP are reported in this table.
b Estimate could not be derived.
544
545
546
547
548
549
550
4.4 Butyl Benzyl Phthalate (BBP)2
In 2017, NASEM included fetal rat testicular testosterone data from two studies (Furr et al.. 2014;
Howdeshell et al.. 2008) as part of its meta-analysis and BMD modeling analysis for BBP. EPA
identified new fetal rat testicular testosterone data from one study (Gray et al.. 2021). which was
included as part of the updated meta-analysis and BMD modeling analysis for BBP. Table 4-13 provides
an overview of the three studies included in the updated analysis. EPA conducted the updated meta-
analysis using random effects models, as implemented in the R metafor package. Metafor versions 2.0.0
2 In addition to the meta-analysis, EPA also conducted additional BMD modeling of the four individual studies of BBP
reporting reduced fetal testicular testosterone using all standard continuous models in EPA's BMD software (BMDS 3.3.2)
(Gray et al.. 2021; Furret al.. 2014; Howdeshell et al.. 2008). BMD model results are reported in EPA's Draft Non-cancer
Human Health Hazard Assessment for Butyl Benzyl phthalate (BBP) (U.S. EPA. 2025a).
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and 4.6.0 were used so that results could be compared. Additionally, the updated analysis included a
sensitivity analysis to determine if the meta-analysis was sensitive to leaving out results from individual
studies. In 2017, NASEM did not conduct a sensitivity analysis because there were too few studies
available to do so.
Table 4-13. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis
for BBP
Reference
(TSCA Study
Quality
Rating)
Included in NASEM
Meta-analysis and
BMD Modeling
Analysis?
Brief Study Description
Measured Outcome
(Howdeshell
et al.. 2008)
(High)
Yes
Pregnant SD rats (2-9 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day BBP on GD 8-18.
Ex vivo fetal testicular
testosterone production (2-
hour incubation) on GD 18
(Furr et al..
2014)(High)
Yes
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day BBP on GD 14-18 (Block
36 rats).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Yes
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 11,33, 100 mg/kg-day
BBP on GD 14-18 (Block 37 rats).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
(Grav et al..
2021)(High)
No (new study)
Pregnant SD rats (3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day BBP on GD 14-18 (Block
78 rats).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Overall meta-analyses and sensitivity analyses results obtained using Metafor Versions 2.0.0 and 4.6.0
are shown in Table 4-14 and Table 4-15, respectively. A comparison of BMD estimates obtained by
NASEM (2017) and as part of EPA's updated analysis are shown in Table 4-16. Additional meta-
analysis results {i.e., forest plots) and BMD model fit curves are shown in Appendix A.5. For meta-
analyses conducted using both versions of Metafor, there was a statistically significant overall effect and
linear trends in logio(dose) and dose, with an overall effect that is large in magnitude (>50% change).
For both meta-analyses, there was substantial, statistically significant heterogeneity in all cases (I2>
50% for Metafor v.2.0.0; I2> 90% for Metafor v.4.6.0). The statistical significance of these effects was
robust to leaving out individual studies for analyses conducted with both versions of Metafor. Although
there was substantial heterogeneity, standard deviation of the random effect (tau) was less than the
estimated size of the effect at higher doses. Therefore, the heterogeneity does not alter the conclusion
that gestational exposure to BBP reduces fetal testicular testosterone in the rat.
For meta-analyses conducted using both versions of Metafor, the linear-quadratic model provided the
best fit {i.e., had lower AIC than the linear model) (Table 4-16). BMD estimates from the linear-
quadratic model were 31 mg/kg-day (95% CI: 17, 103) for a 5 percent change (BMR = 5%), 63 mg/kg-
day (95% CI: 36, 163) for a 10 percent change (BMR = 10%), and 276 mg/kg-day (95% CI: 179, 408)
for a 40 percent change (BMR = 40%) when Metafor Version 2.0.0 was used. Similarly, a BMD of 284
mg/kg-day (95% CI: 150, 481) for a 40 percent change (BMR = 40%) was estimated using Metafor
Version 4.6.0; however, no BMD estimates could be derived for 5 and 10 percent changes (BMRs = 5
and 10%) using Metafor Version 4.6.0. Again, inclusion of the new study by Gray et al. (2021) resulted
in a higher BMD at both response rates, although the BMDLs for EPA's updated analysis including the
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581 new study (17 mg/kg-day) was similar to the NASEM 2017 analysis when both are compared using
582 Metafor Version 2.0.0 (13 mg/kg-day).
583
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584 Table 4-14. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of BBP and Fetal Testosterone (Metafor Version
585 2.0.0) ^
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P Value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-83.62
-127.17
-40.06
1.68E-04
83.98
98.20
4.78E-151
169.89
Trend in loglO(dose)
loglO(dose)
-120.36
-169.45
-71.28
1.54E-06
49.93
94.66
3.34E-36
149.12
Linear in dose 100
dose 100
-22.64
-26.33
-18.96
2.10E-33
29.83
86.32
2.75E-22
143.19
Linear Quadratic in dose 100
dose 100
-16.12
-29.93
-2.30
2.22E-02
30.72
84.75
1.74E-20
136.90*
Linear Quadratic in dose 100
I(dosel00A2)
-0.87
-2.64
0.90
3.35E-01
30.72
84.75
1.74E-20
136.90
Sensitivity analysis
Overall minus Furr et al. (2014)
intrcpt
-90.83
-160.08
-21.59
1.01E-02
97.63
97.87
2.72E-33
91.46
Overall minus Grav et al. (2021)
intrcpt
-78.47
-125.70
-31.24
1.13E-03
77.72
98.17
5.38E-125
122.09
Overall minus Howdeshell et al.
(2008)
intrcpt
-84.05
-134.86
-33.24
1.19E-03
84.27
98.27
8.30E-102
123.25
* Indicates lowest AIC.
586
587
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588 Table 4-15. Updated Overall Meta-analyses and Sensitivity Analyses of Rat Studies of BBP and Fetal Testosterone (Metafor Version
589 4.6.0)
Analysis
Estimate
Beta
CI, Lower
Bound
CI, Upper
Bound
P Value
Tau
I2
P value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-83.62
-127.17
-40.06
1.68E-04
83.98
98.20
4.78E-151
169.89
Trend in loglO(dose)
loglO(dose)
-120.36
-169.45
-71.28
1.54E-06
49.93
94.66
3.34E-36
149.12
Linear in dose 100
dose 100
-22.98
-30.32
-15.63
8.69E-10
69.12
97.13
7.81E-82
153.33
Linear Quadratic in dose 100
dose 100
-15.00
-36.40
6.40
1.70E-01
50.89
93.85
8.24E-53
140.94*
Linear Quadratic in dose 100
I(dosel00A2)
-1.04
-3.78
1.69
4.54E-01
50.89
93.85
8.24E-53
140.94
Sensitivity analysis
Overall minus Furr et al. (2014)
intrcpt
-90.83
-160.08
-21.59
1.01E-02
97.63
97.87
2.72E-33
91.46
Overall minus Grav et al. (2021)
intrcpt
-78.47
-125.70
-31.24
1.13E-03
77.72
98.17
5.38E-125
122.09
Overall minus Howdeshell et al.
(2008)
intrcpt
-84.05
-134.86
-33.24
1.19E-03
84.27
98.27
8.30E-102
123.25
* Indicates lowest AIC.
590
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591 Table 4-16. Comparison of Benchmark Dose Estimates for BBP and Fetal Testosterone in Rats
Analysis
BMR
BMD
(mg/kg-day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
2017 NASEM analysis usins Metafor Version 2.0.0 (as reported in Tables C6-3 and C6-4 of NASEM. (2017))
Linear indoselOO
5%
23
19
29
103.86
Linear indoselOO
40%
231
192
290
Linear Quadratic in doselOO*
5%
23
13
74
100.00*
Linear Quadratic in doselOO*
40%
228
140
389
Undated analysis usins Metafor Version 2.0.0 includins new study by Gray et al. (2021)
Linear indoselOO
5%
23
19
27
143.19
Linear indoselOO
10%
47
40
56
Linear indoselOO
40%
226
194
269
Linear Quadratic in doselOO*
5%
31
17
103
136.90*
Linear Quadratic in doselOO*
10%
63
36
163
Linear Quadratic in doselOO*
40%
276
179
408
Undated analysis usins Metafor Version 4.6.0 includins new study by Gray et al. (2021)
Linear indoselOO
5%
22
17
33
153.33
Linear indoselOO
10%
46
35
67
Linear indoselOO
40%
222
168
327
Linear Quadratic in doselOO*
5%
NA "
NA "
236
140.94*
Linear Quadratic in doselOO*
10%
NA "
NA "
280
Linear Quadratic in doselOO*
40%
284
150
481
* Indicates model with lowest AIC.
" BMD and BMDL estimates could not be derived.
592
593
594
595
596
597
4.5 Dicyclohexyl Phthalate (DCHP)
NASEM (2017) did not include DCHP as part of its phthalate meta-analysis. EPA identified fetal rat
testicular data from two publications (Gray et al.. 2021; Furr et al.. 2014). Table 4-17 provides an
overview of the studies included in EPA's analysis. Meta-analyses were conducted using Metafor
Versions 2.0.0 and 4.6.0 so that results could be compared. No sensitivity analysis was conducted
because too few studies were available to do so.
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Table 4-17. Summary of Studies Included in EPA's Meta-analysis and BMD Modeling Analysis
for DCHP
Reference
(TSCA Study
Quality
Rating)
Included in NASEM
Meta-analysis and
BMD Modeling
Analysis?
Brief Study Description
Measured Outcome
(Furr et al..
2014)(High)
No
Pregnant SD rats (3-4 dams/group)
gavaged with 0, 33, 100, 300 mg/kg-
day DCHP on GD 14-18 (Block 33).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
No
Pregnant SD rats (2-3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DCHP on GD 14-18
(Block 23).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
(Grav et al..
2021)(High)
No
Pregnant SD rats (3 dams/group)
gavaged with 0, 100, 300, 600, 900
mg/kg-day DCHP on GD 14-18
(Block 148).
Ex vivo fetal testicular
testosterone production (3-
hour incubation) on GD 18
Overall meta-analysis results obtained using Metafor Versions 2.0.0 and 4.6.0 are shown in Table 4-18
and Table 4-19, respectively, while a comparison of BMD estimates obtained using both versions of
Metafor are shown in Table 4-20. Additional meta-analysis results (i.e., forest plots) and BMD model fit
curves are shown in Appendix A.6. Metafor Versions 2.0.0 and 4.6.0 provided similar meta- analysis
and BMD modeling results for DCHP. For meta-analysis conducted using both versions of Metafor,
there was a statistically significant overall effect and linear trends in logio(dose) and dose, with an
overall effect that is large in magnitude (>50% change). For both meta-analysis, there was substantial,
statistically significant heterogeneity in all cases (I2> 75% for Metafor v.2.0.0; I2> 80% for Metafor
v.4.6.0). Although there was substantial heterogeneity, standard deviation of the random effect (tau) was
less than the estimated size of the effect at higher doses. Therefore, the heterogeneity does not alter the
conclusion that gestational exposure to DCHP reduces fetal testicular testosterone in the rat.
For meta-analyses conducted using both versions of Metafor, the linear-quadratic model provided the
best fit (i.e., had lower AIC than the linear model) (Table 4-20). BMD estimates from the linear-
quadratic model were 8.2 mg/kg-day (95% CI: 6.5, 11) for a 5 percent change (BMR = 5%), 17 mg/kg-
day (95% CI: 13, 23) for a 10 percent change (BMR = 10%), and 88 mg/kg-day (95% CI: 69, 121) for a
40 percent change (BMR = 40%) when Metafor Version 2.0.0 was used. Similarly, BMD estimates were
8.4 mg/kg-day (95% CI: 6.0, 14) for a 5 percent change (BMR = 5%), 17 mg/kg-day (95% CI: 12, 29)
for a 10 percent change (BMR = 10%), and 90 mg/kg-day (95% CI: 63, 151) for a 40 percent change
(BMR = 40%) when Metafor Version 4.6.0 was used.
Notably, Metafor versions 2.0.0 and 4.6.0 provided similar BMDs (8.2 vs. 8.4 mg/kg-day), BMDio (17
mg/kg-day for both versions of Metafor), and BMD40 (88 vs. 90 mg/kg-day) estimates for the best
fitting, linear-quadratic model (Table 4-20).
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626 Table 4-18. Overall Meta-analyses of Rat Studies of DCHP and Fetal Testosterone (Metafor
627 Version 2.0.0)
Analysis
Estimate
Beta
CI,
Lower
Bound
CI,
Upper
Bound
P Value
Tau
I2
P Value for
Heterogeneity
AIC
Primary analysis
Overall
intrcpt
-113.99
-146.03
-81.95
3.1E-12
50.13
88.36
3.6E-12
114.46
Trend in
loglO(dose)
loglO(dose)
-77.00
-135.97
-18.04
1.0E-02
39.19
81.97
5.5E-08
104.45
Linear in dose 100
dose100
-22.30
-31.07
-13.52
6.4E-07
68.41
93.45
2.3E-32
119.27
Linear Quadratic in
dose100
dose100
-62.86
-79.25
-46.47
5.7E-14
32.05
75.41
7.6E-05
103.12*
Linear Quadratic in
dose100
I(dosel00A2)
5.64
3.48
7.79
2.9E-07
32.05
75.41
7.6E-05
103.12
* Indicates lowest AIC.
628
629
630 Table 4-19. Overall Meta-analyses of Rat Studies of DCHP and Fetal Testosterone (Metafor
631 Version 4.6.0)
Analysis
Estimate
Beta
CI,
Lower
Bound
CI,
Upper
Bound
P value
Tau
I2
P Value for
Heterogeneity
AIC
Overall
intrcpt
-113.99
-146.03
-81.95
3.1E-12
50.13
88.36
3.6E-12
114.46
Trend in loglO(dose)
loglO(dose)
-77.00
-135.97
-18.04
1.0E-02
39.19
81.97
5.5E-08
104.45
Linear indoselOO
doselOO
-22.14
-28.75
-15.54
5.0E-11
49.12
88.03
8.1E-13
121.53
Linear Quadratic in doselOO
doselOO
-61.83
-86.20
-37.46
6.6E-07
51.94
88.95
1.4E-12
104.92*
Linear Quadratic in doselOO
I(dosel00A2)
5.39
2.21
8.56
8.8E-04
51.94
88.95
1.4E-12
104.92
* Indicates lowest AIC.
632
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633 Table 4-20. Comparison of Benchmark Dose Estimates for DCHP and Fetal Testosterone in Rats
Analysis
BMR
BMD (mg/kg-
day)
CI, Lower Bound
(mg/kg-day)
CI, Upper Bound
(mg/kg-day)
AIC
Analysis using Metafor Version 2.0.0
Linear in dose 100
5%
23
17
38
119.27
Linear indoselOO
10%
47
34
78
Linear indoselOO
40%
229
164
378
Linear Quadratic in doselOO*
5%
8.2
6.5
11
103.12*
Linear Quadratic in doselOO*
10%
17
13
23
Linear Quadratic in doselOO*
40%
88
69
121
Analysis using Metafor Version 4.6.0
Linear indoselOO
5%
23
18
33
121.53
Linear indoselOO
10%
48
37
68
Linear indoselOO
40%
231
178
329
Linear Quadratic in doselOO*
5%
8.4
6.0
14
104.92*
Linear Quadratic in doselOO*
10%
17
12
29
Linear Quadratic in doselOO*
40%
90
63
151
* Indicates model with lowest AIC.
634
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5 COMPARISON OF BENCHMARK DOSE ESTIMATES
Table 5-1 compares NASEM and EPA's updated BMD modeling results (reported herein) for decreased
fetal testicular testosterone in rats for DBP, DEHP, DIBP, BBP, and DCHP. Table 5-1 also includes
NASEM and EPA's updated BMD modeling results for DINP, which are reported in EPA's Non-Cancer
Raman Health Hazard Assessment for Diisononyl Phthalate (DINP) (U.S. EPA. 2025g) to allow for a
comparison of BMD modeling results for all phthalates for which modeling of fetal testicular
testosterone was conducted.3 As can be seen from Table 5-1 and as discussed further below, EPA's
updated meta-analysis and BMD modeling results generated using Metafor Version 2.0.0 and 4.6.0 are
similar for DEHP, DBP, DCHP, and DINP at the evaluated BMRs of 5, 10, and 40 percent. In contrast,
for BBP and DIBP, Metafor Version 2.0.0 and 4.6.0 provided differing results. The following
similarities and differences are apparent based on BMD/BMDL results provided in Table 5-1.
• DBP: The linear-quadratic model provided the best fit (based on lowest AIC), regardless of
which version of Metafor was used. For EPA's updated analysis, BMD/BMDL estimates at the
5, 10, and 40 percent response levels are similar, regardless of which version of Metafor was
used. BMD/BMDL estimates at the 5, 10, and 40 percent response levels are: 15/11, 30/23, and
154/119 mg/kg-day, respectively, using Metafor version 2.0.0 compared to 14/9, 29/20, and
149/101 mg/kg-day, respectively, using Metafor version 4.6.0. These results are similar to the
BMD/BMDL estimates of 12/8 and 125/85 mg/kg-day at the 5 and 40 percent response levels,
respectively, reported by NASEM (2017).
• DEHP: The linear-quadratic model provided the best fit (based on lowest AIC), regardless of
which version of Metafor was used. For EPA's updated analysis, BMD/BMDL estimates at the
5, 10, and 40 percent response levels are similar, regardless of which version of Metafor was
used. BMD/BMDL estimates at the 5, 10, and 40 percent response levels are: 17/12, 35/26, and
178/134 mg/kg-day, respectively, using Metafor version 2.0.0 compared to 17/11, 35/24, and
178/122 mg/kg-day, respectively, using Metafor version 4.6.0. These results are similar to the
BMD/BMDL estimates of 15/11 and 161/118 mg/kg-day at the 5 and 40 percent response levels,
respectively, reported by NASEM (2017).
• DIBP: For EPA's updated analysis, the linear-quadratic model provided the best fit (based on
lowest AIC), regardless of which version of Metafor was used. For EPA's updated analysis,
BMD/BMDL estimates differed depending on which version of Metafor was used. BMD/BMDL
estimates at the 5, 10, and 40 percent response levels are: 36/23, 74/47, and 326/239 mg/kg-day,
respectively using Metafor version 2.0.0. These results are similar to the BMD/BMDL estimates
of 27/23 and 271/225 mg/kg-day at the 5 and 40 percent response levels, respectively, reported
by NASEM (2017). however, in the NASEM (2017) the linear model provide the best fit (based
on lowest AIC). When Metafor Version 4.6.0 was used, similar BMD/BMDL results were
obtained at the 40 percent response level (BMD40/BMDL40 = 279/136 mg/kg-day). At the 10
percent response level, the BMD was estimated to 55 mg/kg-day, however, no BMDL10 could be
estimated. Similarly, no BMD/BMDL estimates could be generated at the 5 percent response
level using Metafor Version 4.6.0. Presently, the exact reason(s) why BMD and/or BMDL
estimates could not be generated at the 5 or 10 percent response levels are unclear. As described
in Section 3 of this document, many updates have been made to the Metafor Version 4.6.0 since
Version 2.0.0.
• BBP: The linear-quadratic model provided the best fit (based on lowest AIC), regardless of
which version of Metafor was used. For EPA's updated analysis, BMD/BMDL estimates
differed depending on which version of Metafor was used. BMD/BMDL estimates at the 5, 10,
3 Note that EPA plans to publicly release the completed DINP assessment in early 2025.
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and 40 percent response levels are: 31/17, 63/36, and 276/179 mg/kg-day, respectively using
Metafor version 2.0.0. These results are similar to the BMD/BMDL estimates of 23/13 and
228/140 mg/kg-day at the 5 and 40 percent response levels, respectively, reported by NASEM
(2017). When Metafor Version 4.6.0 was used, similar BMD/BMDL results were obtained at the
40 percent response level (BMD40/BMDL40 = 284/150 mg/kg-day), however, no BMD/BMDL
estimates could be generated at the 5 or 10 percent response levels. Presently, the precise
reason(s) why BMD/BMDL estimates could not be generated at the 5 or 10 percent response
levels are unclear. As described in Section 3 of this document, many updates have been made to
the Metafor Version 4.6.0 since Version 2.0.0.
• DCHP: The linear-quadratic model provided the best fit (based on lowest AIC), regardless of
which version of Metafor was used. For EPA's updated analysis, BMD/BMDL estimates at the
5, 10, and 40 percent response levels are similar, regardless of which version of Metafor was
used. BMD/BMDL estimates at the 5, 10, and 40 percent response levels are: 8.2/6.5, 17/13, and
88/69 mg/kg-day, respectively, using Metafor version 2.0.0 compared to 8.4/6.0, 17/12, and
90/63 mg/kg-day, respectively, using Metafor version 4.6.0. NASEM (2017) did not include
DCHP in its 2017 analysis.
• DINP: The linear-quadratic model provided the best fit (based on lowest AIC), regardless of
which version of Metafor was used. For EPA's updated analysis, BMD/BMDL estimates at the
5, 10, and 40 percent response levels are similar, regardless of which version of Metafor was
used. BMD/BMDL estimates at the 5, 10, and 40 percent response levels are: 79/52, 160/108,
and 715/584 mg/kg-day, respectively, using Metafor version 2.0.0 compared to 74/47, 152/97,
and 699/539 mg/kg-day, respectively, using Metafor version 4.6.0. These results are similar to
the BMD/BMDL estimates of 76/49 and 701/552 mg/kg-day at the 5 and 40 percent response
levels, respectively, reported by NASEM (2017). {Note: see EPA's Non-Cancer Raman Health
Hazard Assessment for Diisononyl Phthalate (DINP) (XJ.S. EPA. 2025 q) for Meta-analysis and
BMD Model Results.)
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706 Table 5-1. Comparison of BMP Modeling Results for DEHP, DBP, DIBP, BBP, DCHP, and DINP
Phthalate
Model
Providing
Best Fit
NASEM (2017) Analysis
(Metafor Version 2.0.0)
EPA Updated Analysis (Metafor Version 2.0.0)
EPA Updated Analysis (Metafor Version 4.6.0)
BMD5
Estimates
(mg/kg-day)
[95% CI]
BMD40
Estimates
(mg/kg-day)
[95% CI]
BMD5
Estimates
(mg/kg-day)
[95% CI]
BMD10
Estimates
(mg/kg-day)
[95% CI]
BMD40
Estimates
(mg/kg-day)
[95% CI]
BMD5
Estimates
(mg/kg-day)
[95% CI]
BMD10
Estimates
(mg/kg-day)
[95% CI]
BMD40
Estimates
(mg/kg-day)
[95% CI]
DBP
Linear
Quadradic"
12 [8, 22]
125 [85, 205]
15 [11,21]
30 [23, 43]
154 [119,211]
14 [9, 27]
29 [20, 54]
149 [101, 247]
DEHP
Linear
Quadradic"
15 [11,24]
161 [118, 236]
17 [12, 26]
35 [26, 52]
178 [134, 251]
17 [11,31]
35 [24, 63]
178 [122, 284]
DIBP
Linear
Quadradic"h
27 [23, 34] 6
271 [225, 342] 6
36 [23, 79]
74 [47, 140]
326 [239, 428]
C
55 [NA, 266]c
279 [136, 517]
BBP
Linear
Quadradic"
23 [13, 74]
228 [140, 389]
31 [17, 103]
63 [36, 163]
276 [179, 408]
C
C
284 [150, 481]
DCHP
Linear
Quadradic"
-d
_ d
8.2 [6.5, 11]
17 [13,23]
88 [69, 121]
8.4 [6.0, 14]
17 [12, 29]
90 [63, 151]
DINPe
Linear
Quadradic"
76 [49, 145]
701 [552, 847]
79 [52, 145]
160 [108, 262]
715 [584, 842]
74 [47, 158]
152 [97, 278]
699 [539, 858]
" Unless otherwise noted, the linear quadratic model provided the best fit (based on lowest AIC) for NASEM and EPA updated analyses using Metafor versions 2.0.0
and 4.6.0.
b Linear model provided the best fit (bast on lowest AIC) for NASEM (2017) modeling of DIBP.
CBMD and/or BMDL estimate could not be derived.
''DCHP was not included in the 2017 NASEM meta-analysis.
e See EPA's Non-Cancer Human Health Hazard Assessment for Diisononvl Phthalate (DINP) (U.S. EPA. 2025g) for meta-analvsis and BMD model results.
707
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6 CONCLUSION AND NEXT STEPS
Herein, EPA conducted an updated meta-analysis and BMD modeling analysis of decreased fetal
testicular testosterone in rats. This analysis represents an update of the analysis conducted by NASEM
(2017). As part of the updated analysis, EPA conducted modeling using Metafor Version 2.0.0 (version
originally used by NASEM in 2017) and Version 4.6.0 (most recent version available at the time of
EPA's updated analysis). EPA also evaluated BMRs of 5, 10, and 40 percent. Comparatively, NASEM
(2017) evaluated BMRs of 5 and 40 percent. As discussed in Section 5, similar BMD/BMDL estimates
at the 5, 10, and 40 percent response levels were obtained using Metafor Version 2.0.0 and 4.6.0 for
DEHP, DBP, DCHP, and DINP. However, for DIBP and BBP, Metafor Version 2.0.0 and 4.6.0
provided differing results, particularly at the 5 and 10 percent response levels, where BMD and/or
BMDL estimates could not be generated using Metafor Version 4.6.0. The precise reason(s) for the
differing results for DIBP and BBP using Metafor Version 2.0.0 and 4.6.0 are unclear. As described in
Section 3 of this document, many updates have been made to Metafor Version 4.6.0 since Version 2.0.0.
Overall, EPA selected BMD modeling results obtained using Metafor Version 4.6.0 for use in the single
phthalate risk evaluations andphthalate cumulative risk assessment bzcmsQ these results were obtained
using the most up-to-date version of the Metafor package available at the time of the updated meta-
analysis and BMD modeling analysis.
EPA is soliciting comments from the Science Advisory Committee on Chemicals (SACC) and the public
on the meta-analysis and BMD modeling approach and results.
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REFERENCES
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Furr. JR; Lambright. CS: Wilson. VS: Foster. PM; Gray. LE. Jr. (2014). A short-term in vivo screen
using fetal testosterone production, a key event in the phthalate adverse outcome pathway, to
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Gray. LE: Furr. J: Tatum-Gibbs. KR; Lambright. C: Sampson. H; Hannas. BR: Wilson. VS: Hotchkiss.
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Phthalate Reductions in Fetal Rat Testosterone Production and Plasma and Testis Testosterone
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Hannas. BR: Lambright. CS: Furr. J: Howdeshell. KL: Wilson. VS: Gray. LE. (2011). Dose-response
assessment of fetal testosterone production and gene expression levels in rat testes following in
utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and
diisononyl phthalate. Toxicol Sci 123: 206-216. http://dx.doi.org/10.1093/toxsci/kfr 146
Howdeshell. KL: Rider. CV: Wilson. VS: Furr. JR: Lambright. CR: Gray. LE. (2015). Dose addition
models based on biologically relevant reductions in fetal testosterone accurately predict postnatal
reproductive tract alterations by a phthalate mixture in rats. Toxicol Sci 148: 488-502.
http://dx.doi. org/10.1093/toxsci/kfv 196
Howdeshell. KL: Wilson. VS: Furr. J: Lambright. CR: Rider. CV: Blystone. CR: Hotchkiss. AK; Gray.
LE. Jr. (2008). A mixture of five phthalate esters inhibits fetal testicular testosterone production
in the Sprague-Dawley rat in a cumulative, dose-additive manner. Toxicol Sci 105: 153-165.
http://dx.doi.org/10.1093/toxsci/kfn077
Johnson. KJ: Henslev. JB: Kelso. MP: Wallace. DG: Gaido. KW. (2007). Mapping gene expression
changes in the fetal rat testis following acute dibutyl phthalate exposure defines a complex
temporal cascade of responding cell types. Biol Reprod 77: 978-989.
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Johnson. KJ: Mcdowell. EN: Viereck. MP: Xia. JO. (2011). Species-specific dibutyl phthalate fetal
testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression
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Kuhl. AJ; Ross. SM; Gaido. KW. (2007). CCAAT/enhancer binding protein beta, but not steroidogenic
factor-1, modulates the phthalate-induced dysregulation of rat fetal testicular steroidogenesis.
Endocrinology 148: 5851-5864. http://dx.doi.org/10.1210/en.2007-093Q
Lin. H; Ge. R; Chen. G: Hu. G: Dong. L; Lian. O; Hardy. D; Sottas. C: Li. X: Hardy. M. (2008).
Involvement of testicular growth factors in fetal Ley dig cell aggregation after exposure to
phthalate in utero. Proc Natl Acad Sci USA 105: 7218-7222.
http://dx.doi.org/10.1073/pnas.07092601Q5
Martino-Andrade. AJ: Morais. RN: Botelho. GG: Muller. G: Grande. SW: Carpentieri. GB; Leao. GM;
Dalsenter. PR. (2008). Coadministration of active phthalates results in disruption of foetal
testicular function in rats. Int J Androl 32: 704-712. http://dx.doi.org/10.1111/i .1365-
2605.2008.00939.x
NASEM. (2017). Application of systematic review methods in an overall strategy for evaluating low-
dose toxicity from endocrine active chemicals. Washington, D.C.: The National Academies
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Saillenfait. AM: Sabate. JP; Robert. A: Rouiller-Fabre. V: Roudot. AC: Moison. D; Denis. F. (2013).
Dose-dependent alterations in gene expression and testosterone production in fetal rat testis after
exposure to di-n-hexyl phthalate. J Appl Toxicol 33: 1027-1035.
http://dx.doi.org/10.1002/iat.2896
Struve. MF; Gaido. KW: Henslev. JB; Lehmann. KP; Ross. SM: Sochaski. MA: Willson. GA; Dorman.
DC. (2009). Reproductive toxicity and pharmacokinetics of di-n-butyl phthalate (DBP) following
dietary exposure of pregnant rats. Birth Defects Res B Dev Reprod Toxicol 86: 345-354.
http://dx.doi. org/10.1002/bdrb .20199
U.S. EPA. (2012). Benchmark dose technical guidance [EPA Report], (EPA100R12001). Washington,
DC: U.S. Environmental Protection Agency, Risk Assessment Forum.
https://www.epa.gov/risk/benchmark-dose-technical-guidance
U.S. EPA. (2023). Draft Proposed Approach for Cumulative Risk Assessment of High-Priority
Phthalates and a Manufacturer-Requested Phthalate under the Toxic Substances Control Act.
(EPA-740-P-23-002). Washington, DC: U.S. Environmental Protection Agency, Office of
Chemical Safety and Pollution Prevention. https://www.regulations.gov/document/EPA-HQ-
QPPT-2022-0918-0009
U.S. EPA. (2024a). Draft Risk Evaluation for Dicyclohexyl Phthalate (DCHP). Washington, DC: Office
of Pollution Prevention and Toxics.
U.S. EPA. (2024b). Draft Systematic Review Protocol for Dicyclohexyl Phthalate (DCHP). Washington,
DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2024c). Draft Technical Support Document for the Cumulative Risk Analysis of Di(2-
ethylhexyl) Phthalate (DEHP), Dibutyl Phthalate (DBP), Butyl Benzyl Phthalate (BBP),
Diisobutyl Phthalate (DIBP), Dicyclohexyl Phthalate (DCHP), and Diisononyl Phthalate (DINP)
Under the Toxic Substances Control Act (TSCA). Washington, DC: Office of Chemical Safety
and Pollution Prevention.
U.S. EPA. (2025a). Draft Non-cancer Human Health Hazard Assessment for Butyl benzyl phthalate
(BBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025b). Draft Non-cancer Human Health Hazard Assessment for Diisobutyl phthalate
(DIBP). Washington, DC: Office of Pollution Prevention and Toxics.
U.S. EPA. (2025c). Draft Risk Evaluation for Butyl Benzyl Phthalate (BBP). Washington, DC: Office of
Pollution Prevention and Toxics.
U.S. EPA. (2025d). Draft Risk Evaluation for Dibutyl Phthalate (DBP). Washington, DC: Office of
Pollution Prevention and Toxics.
U.S. EPA. (2025e). Draft Risk Evaluation for Diethylhexyl Phthalate (DEHP). Washington, DC: Office
of Pollution Prevention and Toxics.
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825 U.S. EPA. (2025f). Draft Risk Evaluation for Diisobutyl Phthalate (DIBP). Washington, DC: Office of
826 Pollution Prevention and Toxics.
827 U.S. EPA. (2025g). Non-Cancer Human Health Hazard Assessment for Diisononyl Phthalate (DINP).
828 Washington, DC: Office of Pollution Prevention and Toxics.
829 https://www.regulations.gov/docket/EPA-HQ-OPPT-2018-0436
830
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831 APPENDICES
832
833 Appendix A SUPPORTING MATERIALS FOR THE META-
834 ANALYSIS AND BMD ANALYSIS OF FETAL
835 TESTICULAR TESTOSTERONE IN RATS
836 The measured outcome of free testes T log transformed ratio of means was converted to a percent
837 change, as described in section C-6 of NASEM (2017). In the plots below in Appendices A.l through
838 A.6, 5, 10 and 40 percent changes are shown as the equivalent log transformed ratio of means (i.e.,
839 BMRs of-5.1, -11 and -51, respectively).
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A.l Replication of NASEM 2017 Results for Fetal Testosterone in Rats for
DIBP
Study and animal group
Rat DIBP All Doses
Dose (mg/kg-d)
Estimate [95% CI]
842
843
844
845
Hannas et al. 2011 b Sprague Dawley rats.1
Howdeshell et al. 2M8 Sprague Dawley rats: DiBP.1
Hannas et al. 2011 b Sprague Dawley rats.2
Howdeshell et al. 2D08 Sprague Dawley rats: DiBP.2
Hannas et al. 2011 b Sprague Dawley rats.3 I—
Howdeshell et al. 2D08 Sprague Dawley rats: DiBP.3
Hannas et al. 2011 b Sprague Dawley rats.4 i ¦ 1
Howdeshell et al. 2Q08 Sprague Dawley rats: DiBP.4
(12=07%)
0.37 [-17.33, 36.08]
-4.67 [-12.84, 3.51]
-82.70 [-158.14, -7.25]
-51.07 [-68.42, -34.92]
-150.79 [-238.88, -80.71]
-90.32 [-120.35, -60.20]
-207.75 [-247.00, -167.90]
-1D0.33 [-185.79, -14.8
-82.31 [-135.11, -29.52]
~l 1 1 1
-200 -100 0 100
Fetal testes T log (Ratio of mean)
FigureApx A-l. Replication of NASEM (2017) Meta-analysis of Studies of DIBP and Fetal
Testosterone in Rats Using Metafor Version 2.0.0
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Rat DIBP All Doses
Study and ariimal group Dose (mg/kg-d) Estimate [95% CI]
Hannas et al. 2011b Sprague Dawley rats
Howdeshell et al 2008 Sprague Dawley rats DiBP
Hannas et al. 2011b Sprague Dawley rats 1
Howdeshell et al 2000 Sprague Dawley rats DiBP 1
Hannas et al. 2011b Sprague Dawley rats 2
Hannas et al. 2011b Sprague Dawley rats.3
Howdeshell et al 2008 Sprague Dawley rats DiBP 3
Howdeshell et al 2008 Sprague Dawley rats DiBP 2 i-
100
300
300
900
900
9.37 [-17,33, 36.081
-4 67 [-12.84, 3,51]
-82 70 [-1S6.14. -7,25]
-51.67 [-68 42, -34.92]
-159 79 [-238 88, -80.71]
-90 32 [-120 35, -60.29]
-207.75 [-247.60, -167.90]
-100.33 [-185.79, -14.88]
(12=97%)
-82 31 [-135 11, -29.52)
846
847
848
849
¦300 -200
Fetal testes T log(Ratra of mean)
FigureApx A-2. Replication of NASEM (2017) Meta-analysis of Studies of DIBP and Fetal
Testosterone in Rats Using Metafor Version 4.6.0
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RatDIBP
o -
o -
_ ^ Log-linear model
o
o _
^ — ¦— _
r —
-
^ ~
— _ ~~~¦
ft
CO
1
E
¦5
S
«
8
100
DIBP Dose mg/kg-d
Rat DIBP
1000
Linear model
f
BMD(-51 )=271 [225, 342]
^ ;
I
100
DIBP Dose mg/kg-d
I
1000
! 8-|
a
850
851
852
853
g 8
8 v
Rat PI BP
Linear-quadratic model
BMD(-51 )=341 [239, 453]
L >
100
1000
DIBP Dose mg/kg-d
FigureApx A-3. Replication of NASEM (2017) Results: Benchmark Dose Estimates from Rat
Studies of DIBP and Fetal Testosterone (Metafor Version 2.0.0)
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DIBP Dose mg/kg-d
DIBP Dose mg/kg-d
Rat DIBP
BMD(-51)=2
BMD
63[NA, 5851
-5.1)=NA[NA. 3431
100 1000
DIBP Dose mg/kg-d
854
855 FigureApx A-4. Replication of NASEM (2017) Results: Benchmark Dose Estimates from Rat
856 Studies of DIBP and Fetal Testosterone (Metafor Version 4.6.0)
857 A.2 Dibutyl Phthalate (DBP) - Updated Analysis
858
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Rat DBP All Doses
Study and animal group Dose (mg/kg-d) Estimate [95% CI]
Funret al. 2D14 Sprague Dawley. 1
¦
1
-12.67 [-27.31, 1.96]
Furr et aJ 2014 .Sprague Dawley.2
m 1
47.00 [ 26.D9. 67.91]
Johnson et al. 2007 Sprague Dawley rat. 1
¦ I 1
8.84 [ -66.09, 83.77]
Furr et al. 2014 Sprague Dawley.3
m
1D
-22.621-41.31, -4.33]
Furr et af. 2014 Sprague Dawley .4
¦ 10
17.17 [ -5.05, 39.40]
Johnson et al. 2007 Sprague Dawley rat.2
H 1D
-39.71 [-97.40, 17.96]
Furr et al. 2014 Sprague Dawley.5
i—¦—i
33
-115.15 [-164.60, -65.70]
Howdeshetl et al. 2008 Sprague Dawtey rats: D6P.1
l* 33
-6.56 [ -28.44. 15.31]
Fun" et al. 2014 Sprague Dawley.6
W 50
-15.60 [-37.59, 6.39]
Howdeshetl et al. 2008 Sprague Dawley rats: D6P.2
m
50
-24.56 [-43.52, -5.61]
Furr et al. 2014 Sprague Dawley.7
¦ m
1D0
-42.69 [ -90.65, 5.27]
Furr et al. 2014 Sprague Dawley.8
100
-44.67 [-76.30, -11.04]
Furretal. 2014 Sprague Dawley.9
I—¦-
H 10D
-28.28 [ -73.87, 17.31]
Howdeshetl et al. 2008 Sprague Dawtey rats: D6P.3
m
100
-17.62 [-38.10, 2.67]
Johnson et al. 2007 Sprague Dawley rat.3
¦
i inn
-17.40 [ -83.57, 46.77]
¦
I l UU
Jotinson et al. 2011 Sprague Dawley rats: Study 1
< ¦
100
-26.33 [-58.11, 5.45]
Kutil et al. 2007 Sprague Dawley rats.1
i—¦—
100
-34.09 [-70.61, 2.42]
Martino-Andrade et al. 2009 Wistar rat.1
HtH
1DD
-34.60 [-64,60, -4.39]
Struve et at. 2009 Sprague-Dawtey rat-1
-58.78 [-137.30, 19.74]
I I IZ .®?
Stnwe et a(. 2009 Sprague-Dawley rat.2
h-B-H
112.4
-125.26 [-162.46, -66.07]
Furr et al. 2014 Sprague Dawley. 10
¦
300
-146.40 [-156.72, -136.06]
Gray et al. 2021 Sprague-Dawley rat: Study 1.1
I—¦—I
300
-47.98 [ -96.16, 0.20]
Gray et al. 2021 Sprague-Dawley rat: Study 2.1
l-B-l
30D
-75.30 [-107.15, -43.44]
Howdeshell et al. 2008 Sprague Dawtey rats: DBP.4
t-BH
300
-42.01 [ -77.06, -6.96]
Johnson et al. 2011 Sprague Dawley rats: Study 2
I ¦ I
500
-192.79 [-247.96, -137.62]
Kultl et al. 2007 Sprague Dawley rats.2
I—¦—!
500
-109.86 [-150.37, -69.35]
Martino-Andrade et al. 20DQ Wistar rat.2
i-B-i
500
-99.99 [-146,63, -53.15]
Struve et at. 2009 Sprague-Dawtey rat.3 i
—• 1
5S2.1
-329.56 [-530.36, -126.61]
Struve et an. 20D9 Sprague-Dawley rat.4
¦ 1
582.1
-263.91 [-365.63, -161.99]
Gray et al. 2021 Sprague-Dawley rat: Study 1.2
I ¦ I
600
-140.16 [-186.53, -93.63]
Gray et al. 2021 Sprague-Dawley rat: Study 2.2
HH
600
-15323[-182.92, -123.54]
Howdeshell et al. 2008 Sprague Dawtey rats: D6P.5
i—¦—i
60D
-111.32 [-150.42, -72.23]
Gray et al. 2021 Sprague-Dawley rat: Study 1.3
I ¦ i
900
-183.41 [-237.73, -129.09]
Gray et al. 2021 Sprague-Dawley rat: Study 2.3
9DD
-202.43 [-227.61, -177.24]
RE Model
¦+¦ (
2=95.6%)
-71.65 [-95.76, -47.95]
-6D0 -40D -20D 0 200
Fetal testes T logiRatio of mean!
859
860 FigureApx A-5. Updated Meta-analysis of Studies of DBP and Fetal Testosterone in Rats
861 (Metafor Version 2.0.0)
862
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Rat DBP
Log-linear model
S1
DBP Dose mg/kg-d
Rat DBP
Linear model
F It -T-
~ n - -
± 4 „
— —
—y£__'T' -»
5»_
I
1
s"
^7
BMD(-11 )=42.1 [36."/B MHDft51 )=204[ 178, 240]
BMD(-5.1)=20.5ri7.9.124.11 -
X
«J a
tz 8
T
-S
CQ I
—I 1—I—I—I I I
10
''"I
100
r 1 1 1——i—r
1000
DBP Dose mg/kg-d
863
864
865
866
Rat DBP
4) t-
E
* o
Q
I §
o "
\-
0
3
~ CT)
5 '
-413
Linear-quadratic model
BMDM1 )=30[22.9BfcM)(-51 )=154[119,211]
BMDf-5.1)=14.5T11.1, 20.91
-I 1 r1—i—i—i—' 1—i '—i 1—1—i I 1 1—i—i
-1 1 1—i—rn—r
100
1000
DBP Dose mg/kg-d
FigureApx A-6. Updated Benchmark Dose Estimates from Rat Studies of DBP and Fetal
Testosterone (Metafor Version 2.0.0)
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Study and animal group
Rat DBP All Doses
Dose (mg/kg-d) Estimate [95% CI]
Furr et al. 2014 Sprague Dawley. 1
Furr et a!. 2014 Sprague Dawley .2
Johnson et al. 2007 Sprague Dawley rat.1
Furr et al. 2014 Sprague Dawley.3
Furr et al. 2014 Sprague Dawley.4
Johnson et al. 2007 Sprague Dawley rat.2
Furr et al. 2014 Sprague Dawley.5
Howdeshell et al. 2008 Sprague Dawley rats: D6P.1
Furr et al. 2014 Sprague Dawley.6
Howdeshell et al. 2008 Sprague Dawley rats: D6P.2
Furr et al. 2D14 Sprague Dawley.7
Furr et al. 2014 Sprague Dawley.8
Furr et al. 2014 Sprague Dawley.9
Howdeshell et al. 2008 Sprague Dawfey rats: D6P.3
Johnson et al. 2007 Sprague Dawley rat.3
Johnson et al. 2011 Sprague Dawley rats: Study 1
Kuhl etal. 2007 Sprague Dawley rats.1
Martino-Andrade et al. 20D9 Wtstar rat.1
Struve et all 2009 Sprague-Darwley rat.1
Starve et all 2009 Sprague-Dawiey rat.2
Furr et al. 2014 Sprague Dawley. 10
Gray et al. 2021 Sprague-Dawiey rat: Study 1.1
Gray et al. 2021 Sprague-Dawiey rat: Study 2.1
Howdeshell et al. 2008 Sprague Dawfey rats: D6P.4
Johnson et al. 2011 Sprague Dawley rats: Study 2
Kuhl et al. 2007 Sprague Darwley rats.2
Martino-Aridrade et al. 2009 Wistar rat.2
Struve et al. 2009 Sprague-Dawiey rat.3
Struve et all. 2009 Sprague-Dawiey rat.4
Gray et al. 2021 Sprague-Dawiey rat: Study 1.2
Gray et al. 2021 Sprague-Dawfey rat: Study 2.2
Howdeshell et al. 2008 Sprague Dawfey rats: D6P.5
Gray et al. 2021 Sprague-Dawfey rat: Study 1.3
Gray et al. 2021 Sprague-Dawiey rat: Study 2.3
4 1
100
100
100
1112.4
112.4
300
300
300
300
500
500
500
582.1
582.1
600
600
600
900
900
-12.67[-27.31, 1.96]
47.00 [ 26.09, 67.91]
8.84 [-66.09, 63.77]
-22.62 [ —41.31, —4.33]
17.17 [ -5.05, 39.40]
-39.71 [ -97.40, 17.98]
-115.15 [-164.60, -65.70]
-6.56 [-28.44. 15.31]
-15.60 [-37.59, 6.39]
-24.56 [ -43.52, -5.61]
-42.69 [ -90.65, 5.27]
-44.671-78.30, -11.04]
-28.28 [-73.87, 17.31]
-17.62 [-38.10, 2.67]
-17.40 [-83.57, 48.77]
-26.33 [-58.11, 5.45]
-34.09 [ -70.61, 2.42]
-34.60 [-64.80, -4.39]
-58.78 [-137.30, 19.74]
-125.28 [-162.48, -88.07]
-146.40 [-156.72, -136.08]
-47.98 [-96.16, 0.20]
-75.30 [-107.15, -43.44]
-42.01 [ -77.06, -6.96]
-192.79 [-247.96, -137.62]
-109.86 [-150.37, -69.35]
-99.99 [-146.83, -53.15]
-329.58 [-530.36, -128.81]
-263.91 [-3S5.S3, -161.99]
-140.18[-186.53, -93.83]
-153.23 [-182.92, -123.54]
-111.32 [-150.42, -72.23]
-183.41 [-237.73, -129.09]
-202.43 [-227.61, -177.24]
RE Mode)
(12=95.6%) -71.85 [-95.76, -47.95]
-600
-400
-200
200
g g j Fetal testes T log( Ratio of mean)
868 FigureApx A-7. Updated Meta-analysis of Studies of DBP and Fetal Testosterone in Rats
869 (Metafor Version 4.6.0)
870
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Rat DBF
Log-linear model
£
£ 8
s 1
— CO
(0 I
us
DBP Dose mg/kg-d
Rat DBP
On ear mndef-
4-
1
BM D(-11 )=41 [33.4 JBB3DQ-51 )=199[162, 258]
BMD(~5.1 )=20[16 3. 25.91
~T 1 1—I I |
10
-r——i—i—i |—
100
~l 1 r~
1 1 'I
1000
DBP Dose mg/kg-d
871
872
873
E °
tn o —
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Rat DEHP All Doses
Study and animal group
Dose (mg/kg-d)
Estimate [95% CI]
Lin et al. 2008 Long-Evans rats.1
Saillenfait et al. 2013a Sprague-Dawley rat.1
Furr et al. 2014 Sprague Dawley. 1
Furr et al. 2014 Sprague Dawley.2
Gray et al. 2021 Sprague-Dawley rat: Study 1.1
Gray et al. 2021 Sprague-Dawley rat: Study 2.1
Hannas et al. 2011b Sprague Dawley rats.1
Hamas et al. 2011b Wistar rat.1
Hcwdeshell et al. 2008 Spxague Dawley rats: DEHP.1
Lin et al. 2008 Long-Evans rats.2
Cutty et al. 2D08 Sprague Dawley rats: Group 2.1
Marti no-Andrade et al. 2009 Wistar rat
Cutty et al. 2008 Sprague Dawley rats: Group 2.2
Furr et al. 2014 Sprague Dawley.3
Furr et al. 2014 Sprague Dawley .4
Gray et al. 2021 Sprague-Dawley rat: Study 1.2
Gray et al. 2021 Sprague-Dawley rat: Study 2.2
Hannas et al. 2011b Sprague Dawley rats.2
Hannas et al. 2011 b Wistar rat.2
Hcwdeshell et al. 2008 Sprague Dawley rats: DEHP.2
Cutty et al. 2008 Sprague Dawley rats: Group 2.3
Hannas et al. 2011 b Sprague Dawley rats.3
Hannas et al. 2011b Wistar rat.3
Furr et al. 2014 Sprague Dawley.5 i—a-
Furr et al. 2014 Sprague Dawley.6
Gray et al. 2021 Sprague-Dawley rat: Study 1.3
Gray et al. 2021 Sprague-Dawley rat: Study 2.3
Hcwdeshell et al. 2008 Sprague Dawley rats: DEHP.3
Hannas et al. 2011b Sprague Dawley rats.4
Hannas et al. 2011b Wistar rat.4
Saillenfait et al. 2013a Sprague-Dawley rat2
Hannas et al. 2011 b Sprague Dawley rats.5
Hannas etal. 2011b Wistar rat.5
Lin et al. 2Q08 Long-Evans rats.3
Hannas et al. 2011b Sprague Dawley rats.6
Hannas et al. 2011b Wistar rat.6
Furr et al. 2014 Sprague Dawley.7 i ¦—
Furr et al. 2014 Sprague Dawley.8 \-
Gray et al. 2021 Sprague-Dawley rat: Study 1.4
Gray et al. 2021 Sprague-Dawiey rat: Study 2.4
Hcwdeshell et al. 2008 Sprague Dawley rats: DEHP.4
Cutty et ai. 2008 Sprague Dawley rats: Group 2.4 i—
I—M—I
I—S—I
10
50
100
100
100
100
100
100
100
100
117
150
234
300
300
300
300
300
300
300
469
500
500
600
600
600
600
600
625
625
625
750
750
750
875
875
900
900
900
900
900
938
45.30 [ 6.22,
-32.94[-45.13,
-98.91 [-111.29,
-23.37 [-67.88,
4.36 [-22.96,
-0.64 [-30.33,
6.33 [-17.99,
0.00 [-29.52,
-19.82 [-62.03,
-25.45 [-99.39,
-89.13 [-120.35,
-34.60 [-76.21.
-98.54 [-136.02,
-171.58 [-209.06, -
-105.65 [-167.14,
-28.43 [ -33.39,
-40.37 [ -67.89,
-49.72 [ -68.00,
-69.31 [ -74.20,
-55.12[-95.92,
-147.79 [-181.73, -
-91.35 [-102.78,
-102.51 [-114.39,
-264.43 [-305.08, -
-188.78 [-235.15, -
-121.87 [-155.29,
-137.54 [-186.05,
-90.12 [-140.00',
-157.46 [-172.61, -
-144.82 [-168.22, -
-182.80 [-201.29, -
-124.07 [-135.58. -
-195.72 [-230.72,-
-112.13 [-167.43,
-73.12[-83.11,
-174.30 [-230.49, -
-279.03 [-328.21, -
-214.71 [-268.18, -
-158.94 [-187.12,-
-139.35 [-176.67, -
-149.29 [-202.64,
-246.21 [-284.94, -
84.38]
-20.75]
-86.52]
21.13]
31.69]
29.06]
30.64]
29.52]
22.39]
48.49]
-57.91]
7.02]
-61.07]
134.10]
-44.17]
-23.48]
-12.85]
-31.45]
-64.43]
-14.32]
113.85]
-79.92]
-90.64]
¦223.79]
142.42]
-88,46]
-89.03]
-40.23]
142.31]
121.41]
164.31]
112.56]
160.72]
-56.84]
-63.12]
118.10]
229.85]
161.24]
130.77]
102.03]
-95.94]
207.48]
RE Model
(12=98,6%)
-103.69 [-127.11. -80.27]
-400
-300
-200
-100
100
g ig Fetal testes T log(FRatio of mean)
877 Figure Apx A-9. Updated Meta-analysis of Studies of DEHP and Fetal Testosterone in Rats
878 (Metafor Version 2.0.0)
879
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Rat DEHP
o -
I
_
o
o _
T
o
o _
0
1
BMD(—11 )=4€
BMD(-5.1 )=23.5[20.9. 26.8
r " T ¦ m m m , *
~jf - _ t
.3142.9,55.1] BMD(-51)=234[208,267] -
¦ "^s, ¦
r "**¦ ffc.
*¦>»
i 1
10
100
DEHP Dose mg/kg-d
i i i i
1000
Rat DFHP
DEHP Dose mg/kg-d
881 FigureApx A-10. Updated Benchmark Dose Estimates from Rat Studies of D EHP and Fetal
882 Testosterone (Metafor Version 2.0.0)
883
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Rat DEHP All Doses
Study and animal group
Dose (mg/kg-d) Estimate [95% CI]
Lin et al. 2008 Long-Evans rats.1
Saillenfeit et al. 2013a Sprague-Dawley rat.1
Furr et al. 2014 Sprague Dawley.1
Furr et al. 2014 Sprague Dawley.2
Gray et al. 2021 Sprague-Dawley rat: Study 1.1
Gray et al. 2021 Sprague-Dawley rat: Study 2.1
Hannas et al. 2011b Sprague Dawley rats.1
Hannas et al. 2011b Wistar rat.1
Howdeshell et ai. 2008 Sprague Dawley rats: DEHP.1
Lin et ail. 20O8 Long-Evans rats.2
Culty et a). 2008 Sprague Dawley rats: Group 2.1
Martino-Andrade et al. 2009 Wistar rat
Culty et a!. 2008 Sprague Dawley rats: Group 2.2
Furr et al. 2014 Sprague Dawley.3
Furr et al. 2014 Sprague Dawley.4
Gray et al. 2021 Sprague-Dawley rat: Study 1.2
Gray et al. 2021 Sprague-D^vley rat: Study 2.2
Hannas et al. 2011b Sprague Dawley rats.2
Hannas et al. 2011b Wistar rat.2
Howdeshell et al. 20O8 Sprague Dawley rats: DEHP.2
Culty et a!. 2008 Sprague Dawley rats: Group 2.3
Hannas et al. 2011b Sprague Dawley rats.3
Hannas et al. 2011b Wistar rat.3
Furr et al. 2014 Sprague Dawley.5
Furr et al. 2014 Sprague Dawley.6
Gray et al. 2021 Sprague-Dawley rat: Study 1.3
Gray et al. 2021 Sprague-Dawley rat: Study 2.3
Howdeshell et ai. 20Q8 Sprague Dawley rats: DEHP.3
Hannas et al. 2011b Sprague Dawley rats.4
Hannas et al. 2011b Wistar rat.4
Saillenfait et al. 2013a Sprague-Dawley rat.2
Hannas et al. 2011b Sprague Dawley rats.5
Hannas et al. 2011b 'Wistar rat.5
Lin et al. 2008 Long-Evans rats.3
Hannas et al. 2011b Sprague Dawley rats.6
Hannas et al. 2011b Wistar rat.6
Furr et al. 2014 Sprague Dawley.7
Furr et al. 2014 Sprague Dawley.8
Gray et al. 2021 Sprague-Dawley rat: Study 1.4
Gray et al. 2021 Sprague-Dawley rat: Study 2.4
HowdeshelJ et al. 20G8 Sprague Dawley rats: DEHP.4
Culty et al. 2008 Sprague Dawley rats: Group 2.4
50
100
100
100
100
100
100
100
-1100
117
150
234
300
300
300
300
300
300
300
469
500
500
600
600
600
600
600
625
625
625
750
750
750
875
875
900
900
900
900
900
938
45.30 [ 6.22,
-32.94 [ -45.13,
-98.91 [-111.29,
-23.37 [-67.88,
4.36 [-22.96,
-0.64 [-30.33,
6.33 [-17.99,
Q.OO [ -29.52,
-19.82 [-62.03,
-25.45 [ -99.39,
-89.13 [-120.35,
-34.60 [-76.21.
-98.54 [-136.02,
-171.58 [-209.06, -
-105.65 [-167.14,
-28.43 [ -33.39,
-40.37 [ -67.89,
-49.72 [ -68.00,
-69.31 [ -74.20,
-55.12 [ -95.92,
-147.79 [-181.73, -
-91.35 [-102.78,
-102.51 [-114.39,
-264.43 [-305.08, -
-188.78 [-235.15, -
-121.87 [-155.29,
-137.54 [-186.05,
-90.12 [-140.00,
-157.46 [-172.61, -
-144.82 [-168.22,-
-182.80 [-201.29, -
-124.07 [-135.58, -
-195.72 [-230.72, -
-112.13 [-167.43,
-73.12 [-83.11,
-174.30 [-230.49,-
-279.03 [-328.21, -
-214.71 [-268.18, -
-158.94 [-187.12, -
-139.35 [-176.67, -
-149.29 [-202.64,
-246.21 [-284.94, -
84.38]
-20.75]
-86.52]
21.13]
31.69]
29.06]
30.64]
29.52]
22.39]
48.49]
-57.91]
7.02]
—61.07]
134.10]
-44.17]
-23.48]
-12,85]
-31.45]
-64.43]
-14.32]
113 85]
-79.92]
-90.64]
•223.79]
•142.42]
-88.46]
-89.03]
-40.23]
•142.31]
121.41]
•164.31]
112.56]
160.72]
-56.84]
-63.12]
118.10]
¦229.85]
•161.24]
130.77]
102.03]
-95.94]
•207.48]
RE Model
(12=96
6%)
-103.69 [-127.11, -80.27]
-400
-300
-200
-100
1Q0
gg^ Fetal testes Ttog(Ratio of mean)
885 FigureApx A-ll. Updated Meta-analysis of Studies of DEHP and Fetal Testosterone in Rats
886 (Metafor Version 4.6.0)
887
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Rat DEHP
"LinSarmoctel —
BMD(-5.1
100
DEHP Dose mg/kg-d
Rat DFHP
DEHP Dose mg/kg-d
889 FigureApx A-12. Updated Benchmark Dose Estimates from Rat Studies of DEHP and Fetal
890 Testosterone (Metafor Version 4.6.0)
891 A.4 Diisobutyl Phthalate (DIBP) - Updated Analysis
892
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Study and animal group Dose (mg/kg-d) Estimate [95% CI]
Gray et al. 2021 Sprague-Dawley rat 1
Hannas et al. 2011b Sprague Dawley nats.1
Howdeshell et ai. 2008 Sprague Dawley rats: DiBP.1
Gray et al. 2021 Sprague-Dawley rat.2
Hannas et al. 2011b Sprague Dawley rats.2
Howdeshell et al. 20G8 Sprague Dawtey rats: DiBP.2
Gray et al. 2021 Sprague-Dawley rat.3
i ¦ i 100
Hannas et al. 2011 b Sprague Dawley rats.3 i-
Hcwdeshell et ai. 2008 Sprague Dawley rats: DiBP.3
Gray et al. 2021 Sprague-Dawley rat.4
Hannas et al. 2011 b Sprague Dawley rats.4 i-
Howdeshell et al. 2008 Sprague Dawtey rats: DiBP.4 i-
H100
¦ 100
300
300
300
600
600
600
900
900
900
-3.06 [-29.42, 23.30]
9.37 [-17.33, 36.08]
-4.67 [-12.84, 3.51]
-41.75 [-78.92; -4.57]
-82.70 [-158.14, -7.25]
-51.67 [-68.42, -34.92]
-134.33 [-182.93, -85.73]
-159.79 [-238.88, -80.71]
-90.32 [-120.35, -60.29]
-153.92 [-177.82, -130.02]
-207.75 [-247.60, -167.90]
-100.33 [-185.79, -14.88]
RE Model
02=
96.5%)
-82.21 [-122.85, -41.56]
-300
-200
-100
100
893
894
895
896
Fetal testes T !og(Ratio of mean)
Figure Apx A-13. Updated Meta-analysis of Studies of DIBP and Fetal Testosterone in Rats
(Metafor Version 2.0.0)
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DIBP Dose mg/kg-d
DIBP Dose mg/kg-d
o -
o -
Linear-quadratic model
8 _
— -—v. —|
-
o
o
rt
BMD(-51)=^26[239, 428]
§ ^ 1 DIBP Dose mg/kg-d
898 FigureApx A-14. Updated Benchmark Dose Estimates from Rat Studies of DIBP and Fetal
899 Testosterone (Metafor Version 2.0.0)
900
Page 56 of 66
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Rat DlBP All Doses
Study and animal group Dose (mg/kg-d) Estimate [95% CI]
Gray et al. 2021 Sprague-Dawiey rat.1
Hannas et al. 2011b Sprague Dawley rats.1
Howdeshell et aJ. 2008 Sprague Dawley rats: DiBP.1
Gray et al. 2021 Sprague-Dawiey rat.2
Hannas et al. 2011b Sprague Dawley rats.2
Hcwdeshell et al. 2008 Sprague Dawley rats: DiBP.2
Gray et at 2021 Sprague-Dawiey rat.3
Hannas et al. 2011b Sprague Dawley rats.3
Hcwdeshell et al. 2008 Sprague Dawley rats: DiBP.3
Gray et at 2021 Sprague-DapAley rat.4
Hannas et al. 2011b Sprague Dawley rats.4
Hcwdeshell et aJ. 2008 Sprague Dawley rats: DiBP.4
i—B-^iO
¦tea
100
300
-3.06 [ -29.42, 23.30]
9.37 [-17.33, 36.08]
-4.67 [-12.S4, 3.51]
-41.75 [-78.92, -4.57]
300 -82.701-158.14, -7-25]
300 -51.67 [-68.42, -34.92]
600 -134.33 [-182.93, -85.73]
600 -159.79 [-238.88, -80.71]
600 -90.32 [-120.35, -6029]
900 -153.92 [-177.82,-130.02]
900 -207.75 [-247.60, -167.90]
900 -100.33 [-185.79, -14.88]
RE Ntodel
(12=96.5%) -82.21 [-122.85, -41.56]
-300
-200
-100
100
901
902
903
904
Fetal testes T log(Ratio of mean)
Figure Apx A-15. Updated Meta-analysis of Studies of DIBP and Fetal Testosterone in Rats
(Metafor Version 4.6.0)
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DIBP Dose mg/kg-d
DIBP Dose mg/kg-d
Rat DIBP
c o
CD o -
a>
E
¦S O -
Linear-quadratic model
retal testes T log(Ratic
-300 -100
i i i
_ 4* '
mmm ""
BMD(-51)=270[136, 517]
BMD(-f5.1 j=NA[NA, 2071
T"
«¦«
100 1000
DIBP Dose mg/kg-d
906 FigureApx A-16. Updated Benchmark Dose Estimates from Rat Studies of DIBP and Fetal
907 Testosterone (Metafor Version 4.6.0)
908 A.5 Butyl Benzyl Phthalatc (BBP) - Updated Analysis
909
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Study and animal group
PUBLIC RELEASE DRAFT
December 2024
Rat BBP All Doses
Dose (mg/kg-d)
Estimate [95% CI]
Furr et al. 2014 Sprague Dawley. 1
Fun et al. 2014 Sprague Dawley.2
Furr et al. 2014 Sprague Dawley.3
Furr et al. 2014 Sprague Dawley.4
Gray et al. 2021 Sprague-Dawley rat.1
Howdeshell et al. 2008 Sprague Dawley rats: BzBP.1
Furr et al. 2014 Sprague Dawley.5
Gray et al. 2021 Sprague-Dawley rat.2
Howdeshell et al. 20O8 Sprague Dawley rats: BzBP.2
Furr et al. 2014 Sprague Dawley.6
Gray et al. 2021 Sprague-Dawley rat.3
Howdeshell et al. 2008 Sprague Dawley rats: BzBP.3
Furr et al. 2014 Sprague Dawley.7
Gray et al. 2021 Sprague-Dawtey rat.4 i ¦
Howdeshell et al. 2008 Sprague Dawley rats: BcBP.4
11 10.65 [-18.79, 40.10]
33 -8.96 [-52.44, 34.47]
100 -76.16 [-97.21, -55.12]
10O -12.75 [-49.16, 23.65]
100 6.90 [-17.95, 31.75]
100 5.91 [-10.42, 22.23]
300 -111.60 [-122.62, -100.57]
300 -47.55 [-70.29. -24.80]
300 -25.26 [-46.76, -3.75]
600 -143.47 [-190.22, -96.72]
600 -98.83 [-148.65, -49.02]
600 -107.29 [-148.05, -66.52]
900 -190.55 [-200.98, -180.12]
900 -256.60 [-301.90, -211.30]
900 -231.72 [-312.87, -150.57]
RE Model
(12=98.2%)
-83.62 [-127.17, -40.06]
910
911
912
913
-400
-300 -200
-100
100
Fetal testes T log( Ratio of mean)
FigureApx A-17. Updated Meta-analysis of Studies of BBP and Fetal Testosterone in Rats
(Metafor Version 2.0.0)
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BBP Dose mg/kg-d
BBP Dose mg/kg-d
Rat BBP
Linear-quadratic model
. ... ~ ~ ~ -
_ _ _
- - *
"
sn
BMD(-11)=63.2[35.6, 1631 BMD(-51)=276[179, 4081
BMD{-5 1 )=31 3f17.2, 1031
10 100 1000
914 BBP Dose mg/kg-d
915 FigureApx A-18. Updated Benchmark Dose Estimates from Rat Studies of BBP and Fetal
916 Testosterone (Metafor Version 2.0.0)
917
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Study and animal group
PUBLIC RELEASE DRAFT
December 2024
Rat BBP All Doses
Dose (mg/kg-d) Estimate [95% CI]
Furr et al. 2014 Sprague Dawley. 1
Furr et al. 2014 Sprague Dawley.2
Furr et al. 2014 Sprague Dawley.3
Furr et al. 2014 Sprague Dawley.4
Gray et al. 2021 Sprague-DaMey rat.1
Howdeshell et al. 2008 Sprague Dawley rats: BzBP.1
Furr et al. 2014 Sprague Dawley.5
Gray et al. 2021 Sprague-DawJey rat.2
Howdeshell et a], 20G8 Sprague Dawley rats: BzBP.2
Furr et al. 2014 Sprague Dawley.6
Gray et al. 2021 Sprague-Dawley rat.3
Ho-A-deshell et al. 20Q8 Sprague Dawley rats: BzBP.3
Furr et al. 2014 Sprague Dawley.7
Gray et al. 2021 Sprague-Dawley rat.4
Howdeshell et al. 2008 Sprague Dawley rats: BzBP.4 i-
¦44H 10.65 [-18.79, 40.10]
-30 -8.98 [ -52.44, 34.47]
100 -76.16 [-97.21, -55.12]
400 -12.75 [-49.16, 23.65]
1-pieO 6.90 [-17.95, 31.75]
h*tOO 5.91 [-10.42, 22.23]
300 -111.60 [-122.62,-100.57]
300 -47.55 [-70.29, -24.80]
300 -25.26 [ -46.76, -3.75]
600 -143.47 [-190.22, -96.72]
600 -98.83 [-148.65, -49.02]
600 -107.29 [-148.05, -66.52]
900 -190.55 [-200.98, -160.12]
900 -256.60 [-301.90, -211.30]
900 -231.72 [-312.87, -150.57]
RE Model
(12-98.2%) -83.62 [-127.17, -40.06]
918
919
920
921
-400 -300 -200 -100 0
Fetal testes T log(Ratio of mean)
100
FigureApx A-19. Updated Meta-analysis of Studies of BBP and Fetal Testosterone in Rats
(Metafor Version 4.6.0)
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Rat BBP
-Log^linear model
E
o
Q
CD
tr
-------
PUBLIC RELEASE DRAFT
December 2024
Study and animal group Dose (mg/kg-d) Estimate [95% CI]
Furr et al. 2014 Sprague-Dawley rat.1
-29.25 [-61.79, 3.29]
Furr et al. 2014 Sprague-Dawley rat-2
I—•—
100
-115.81 1-143.60, -88.02]
Furr et al. 2014 Sprague-Dawley rat.3
i
r 1
100
-80.57 [-140.23, -20.90]
Gray et al. 2021 Sprague-Dawtey rat.1
• 1
100
-52.29 [-85.81, -18.77]
Furr et al. 2014 Sprague-Dawley rat.4
i ¦ 1
300
-150.10 [-190.11, -110.10]
Furr et al. 2014 Sprague-Dawley rat.5
i—¦—
300
-117.30 [-149.28, -85.32]
Gray et al. 2021 Sprague-Dawtey rat.2
i—¦—i
300
-126.93 [-156.26, -97.60]
Furr et al. 2014 Sprague-Dawley rat.6
i—•—i
600
-159.64 [-192.12, -127.15]
Gray et al. 2021 Sprague-Dawtey rat.3
i * 1
600
-176.15 [-221.60, -130.70]
Furr et al. 2014 Sprague-Dawley rat.7
n
—¦ 1
900
-60.50 [-91.78, -29.21]
Gray et al. 2021 Sprague-Dawley rat.4 i—
1
900
-215.77 [-290.10, -141.44]
RE Model
- (12=88.4°
4) -113.99 [-146.03, -81.95]
-300 -200 -100 0 100
Q2 7 Fetal testes T log(Ratto of mean)
928 FigureApx A-21. Meta-analysis of Studies of DCHP and Fetal Testosterone in Rats (Metafor
929 Version 2.0.0)
930
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Rat DCHP
8L
s
H
ss
£
3
DCHP Dose mg/kg-d
Rat DCHP
"LuTearThoCtel
o>
O
OJ
TO
US
o
8
77.9] BMD(-51)=229[164, 378]
BMD(-5.1)=23[16.5. 37.91
10
-i—i—i i i—
100
—i 1 1 r~
1000
DCHP Dose mg/kg-d
931
932
933
934
c
aj
03
u -
E
.2
O -
I
Ui
O
8 _
T—
H
60
-
Rat DCHP
Linear-quadratic model
BMD(—11 )=17[13.5, 23.1] BMD{-51)=88.3[69,1, 121]
22[6.51, 11.11
10
1 i
100
1000
DCHP Dose rng/Kg-d
FigureApx A-22. Benchmark Dose Estimates from Rat Studies of DCHP and Fetal Testosterone
(Metafor Version 2.0.0)
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Study and animal group Dose (mg/kg-d) Estimate [95% CI]
Furr et al. 2014 Sprague-Dawley rati
Furr et al. 2014 Sprague-Dawley rat-2
Furr et al. 2014 Sprague-Dawley rat.3
Gray et al. 2021 Sprague-Dawley nat.1
Furret al. 2014 Sprague-Dawley rat-4
Furr et al. 2014 Sprague-Dawley rat.5
Gray et al. 2021 Sprague-Dawtey nat.2
Furr et al. 2014 Sprague-Dawley rat.6
Gray et al. 2021 Sprague-Dawley nat3
Furr et al. 2014 Sprague-Dawley rat.7
Gray et al. 2021 Sprague-Dawtey nat.4
I W&r
\ -29.25 [-61.79, 3.29]
I—¦—I
10ft -115.81 [-143.60, -B8.02]
1 DO -80.571-140.23, -20.90]
1G'tJ -52.29 [ -S5.81, -16.77]
300 -150.101-190.11,-110.10]
I ¦ 1 300 -117.30 [-149.26, -65.32]
I—¦—| 300: -126.93 [-156.26, -97.60]
600 -159.64 [-192.12,-127.15!
600 -176.15 [-221.60,-130.70]
I a 1900 -60.50 [-91.76, -29.21]
900: -215.77 [-290.10, -141.44]
RE Model
(12=88.4%) -113.99 [-146.03, -81.95]
-300
-200
-100
100
935
936
937
938
Fetal testes T logfRatio of mean)
Figure Apx A-23. Meta-analysis of Studies of DCHP and Fetal Testosterone in Rats (Metafor
Version 4.6.0)
Page 65 of 66
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PUBLIC RELEASE DRAFT
December 2024
Rat DCHP
Log-linear model
100
DCHP Dose mg/kg-d
1000
Rat DCHP
.LiQganriodel
—r
10
BMD(-11)=47.6[36.7, 67.8] BMD(-51 )=231 [178, 329]
BMD(-5.1)-23.2F17.e. 331 !
1 I
1000
100
DCHP Dose mg/kg-d
939
940
941
942
943
® i-
E
"6 oH
,e
I S
S 8 _
ll5.lT=8
Rat DCHP
_Lmear-quadratic model
BMD(-11)=17.3[12.4, 28.6] BMD(-51)=89.6[63.2, 151]
3615.99. 13.81
T
10
-1 1 1-
> I
100
DCHP Dose mg/kg-d
-| 1 I-
1000
Figure Apx A-24. Updated Benchmark Dose Estimates from Rat Studies of DCHP and Fetal
Testosterone (Metafor Version 4.6.0)
Page 66 of 66
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